bluuebunny/crossref_metadata_2025 huggingface dataset:
Runups of Unusual Size: Rogueness and Variability of Swash
Authors: García‐Medina Gabriel , Özkan‐Haller H. Tuba , Ruggiero Peter , Holman Rob A. , Li Chuan
Published: February 2020

The occurrence of swash larger than those predicted by the Rayleigh distribution is examined using a phase‐resolved numerical model. Multiple realizations of spectral boundary conditions and beach configurations are considered in the analysis. Planar beaches characterized by surf similarity parameters between 0.3 and 0.6 are found to be more likely to produce unusually large swash. Maximum runup is found to correlate with the maximum infragravity (IG) wave height at the location of swash initiation, the landwardmost continuously wet point. The analysis is extended to beaches with bilinear profiles, where the foreshore slope is steeper than the shoaling slope. It is found that the still water level plays a controlling role in the magnitude of large swash. For these beaches it is found that the still water level with respect to the beach toe influences both the IG and shortwave height at swash initiation. Similar to the planar beach case, swash is found to be maximized when the sum of both IG and shortwave height is maximum; this occurs at toe depths 2–3 times the offshore significant wave height.
Clinical efficacy and safety of anti-PD-1/PD-L1 inhibitors for the treatment of advanced or metastatic cancer: a systematic review and meta-analysis
Authors: Sun Leitao , Zhang Leyin , Yu Jieru , Zhang Yinan , Pang Xi , Ma Chenghao , Shen Minhe , Ruan Shanming , Wasan Harpreet S. , Qiu Shengliang
Published: February 2020

Anti-PD-1/PD-L1 inhibitors provide a survival advantage over conventional therapies for treatment of advanced or metastatic cancer. However, the factors determining which patients benefit the most from anti-PD-1/PD-L1 inhibitors are unknown, making treatment-related decisions difficult. We performed a systematic review and meta-analysis of acquired data to assess the efficacy and toxicity of anti-PD-1/PD-L1 inhibitors in advanced and metastatic cancer. A thorough search strategy was applied to identify randomised controlled trials (RCTs) in Pubmed, Embase, Cochrane, and major conferences. Studies meeting predefined selection criteria were selected, and two independent investigators performed data extraction; overall survival (OS), progression-free survival (PFS), and overall response rate were compared between anti-PD-1/PD-L1 inhibitors and control therapies. We calculated the pooled response rate and 95% CIs of all-grade and high-grade (≥3) adverse effects and evaluated the within-study heterogeneity using subgroup, sensitivity, and meta-regression analyses. In final, we included eligible 35 RCTs (21047 patients). The main estimated hazard ratios (HRs) for OS and PFS were 0.76 (0.71–0.82) and 0.81 (0.73–0.89) in a random-effects model. The anti-PD-1/PD-L1 inhibitor group had a significantly high risk for all-grade immune-related adverse events. Anti-PD-1/PD-L1 inhibitors were identified as a preferable treatment option for advanced or metastatic cancer patients who are male, aged < 65 years, current or former smokers, had no CNS or liver metastasis, had not EGFR mutation, and had high PD-L1 expression.
Exploring resveratrol dimers as virulence blocking agents – Attenuation of type III secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa
Authors: Sundin Charlotta , Zetterström Caroline E. , Vo Duc Duy , Brkljača Robert , Urban Sylvia , Elofsson Mikael
Published: February 2020

Bacterial infections continue to threaten humankind and the rapid spread of antibiotic resistant bacteria is alarming. Current antibiotics target essential bacterial processes and thereby apply a strong selective pressure on pathogenic and non-pathogenic bacteria alike. One alternative strategy is to block bacterial virulence systems that are essential for the ability to cause disease but not for general bacterial viability. We have previously show that the plant natural product (-)-hopeaphenol blocks the type III secretion system (T3SS) in the Gram-negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa. (-)-Hopeaphenol is a resveratrol tetramer and in the present study we explore various resveratrol dimers, including partial structures of (-)-hopeaphenol, as T3SS inhibitors. To allow rapid and efficient assessment of T3SS inhibition in P. aeruginosa, we developed a new screening method by using a green fluorescent protein reporter under the control of the ExoS promoter. Using a panel of assays we showed that compounds with a benzofuran core structure i.e. viniferifuran, dehydroampelopsin B, anigopreissin A, dehydro-δ-viniferin and resveratrol-piceatannol hybrid displayed significant to moderate activities towards the T3SS in Y. pseudotuberculosis and P. aeruginosa.
The clinical efficacy of relocation pharyngoplasty to improve retropalatal circumferential narrowing in obstructive sleep apnea patients
Authors: Oh Heonjeong , Kim Hyung Gu , Pyo Suyeon , Ji Jeong-Yeon , Woo Hyunjun , Kim Minju , Kim Dong-Young , Rhee Chae-Seo , Kim Hyun Jik
Published: February 2020

Lateral pharyngeal wall appears to be a critical culprit of obstructive sleep apnea (OSA) subjects and relocation pharyngoplasty has been expected to be a promising surgical option to correct retropalatal circumferential narrowing in OSA patients. The purpose of our study is to evaluate the therapeutic outcomes of relocation pharyngoplasty and its clinical effectiveness in OSA patients with retropalatal circumferential narrowing. We performed relocation pharyngoplasty combined with nasal surgery in 133 OSA patients with the following characteristics: apnea-hypopnea index (AHI) over 10, retropalatal circumferential narrowing greater than grade I when awake, and redundant soft tissue around the lateral pharyngeal wall. The analysis of surgical success rate was performed with the data of 68 subjects who underwent pre and postoperative polysomnography. The objective success rate of relocation pharyngoplasty was 52.9%, and significant reduction of mean AHI with improvement of lowest SpO2 was seen in 69% of patients 3 months after the surgery. The median AHI was decreased from preoperative 37.3 to postoperative 21.4. Median lowest SpO2 changed from 78.4 to 84.1%. Total sleep time, daytime sleepiness, and visual analogue scale for snoring showed improvement as well. Postoperative complications including pain or bleeding were minimal in 133 subjects and a few patients complained of subtle taste loss. Our data demonstrate that relocation pharyngoplasty can be a favorable surgical option fighting against retropalatal circumferential narrowing.
Correction: One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction
Authors: Lei Jie , Song Gui-Ting , He Liu-Jun , Luo Ya-Fei , Tang Dian-Yong , Lin Hui-Kuan , Frett Brendan , Li Hong-yu , Chen Zhong-Zhu , Xu Zhi-Gang
Published: February 2020

Correction for ‘One-pot construction of functionalized aziridines and maleimides via a novel pseudo-Knoevenagel cascade reaction’ by Jie Lei et al., Chem. Commun., 2020, DOI: 10.1039/c9cc08220d.
Artificial produced water as a medium to grow Chlorella sp. for biodiesel production
Authors: Hajjar Rakhmadumila Deby , Setiani Muntalif Barti
Published: February 2020

Increased interest in renewable, carbon-neutral energy sources makes processing biodiesel from microalgae has become the objective for many researchers and companies. Some kind of wastewater including municipal, industrial and agricultural wastewaters have been identified as alternate growth mediums. Produced water is the largest byproduct of the oil and natural gas extraction process which constitutes of high concentration of pollutants, such as dissolved nitrogen, phosphorus, dissolved organic carbon, heavy metal and monocyclic aromatic compound like BTEX. The purpose of this study is to identify Chlorella sp. potential for producing lipid in artificial produced water. Variations made in this study consist of 0%, 25%, 50%, 75% and 100% volume of artificial produced water to the control Walne medium. The highest specific growth rate and biomass productivity of Chlorella sp. achieved by culture grown in 25% wastewater with a value of 0.225 day−1 and 0.175 g L−1day−1, respectively. The highest lipid yield and productivity in mixed culture of artificial produced water and Walne medium achieved by culture in 25% artificial produced water with value of 0.231 and 40.48 mg.L−1.day−1. C16 and C18 fatty acids which dominated the lipids of Chlorella sp. in all culture variations indicated that the lipid of Chlorella sp. were suitable for producing high quality biodiesel.
Aspects influence leachate characteristics on leachate treatment plants in Temesi Landfill Gianyar Regency, Bali Province, Indonesia
Authors: Pradwi Sukma Ayu Putri , Widiadnyana Wardiha Made
Published: February 2020

This paper revealed aspects that influenced leachate characteristics in leachate treatment plants located in Temesi landfill. Four aspects observed refers to Law Number 3/2013 Ministry of Public Works: landfill operation; rainfalls; treatment plant designs; operation and maintenance. Data collected by observation and field survey to identify leachate characteristics. Leachates were collected by grab sampling from inlet through outlet of the treatment plants, to be laboratory analysed to meet the standards set by Ministry of Environmental and Forestry Number 59/2016 and compared to the standards. Leachate discharge calculated using Thornthwaite method to be compared to criteria designed. The result shown that leachate discharge is 0.45 L/sec exceeding the designed discharge 0.42 L/sec. Laboratory test result from leachate sampling shown that the BOD, COD and TSS value exceeding the regulation standard in range of > 2000 mg/L. Findings revealed that the depth of maturation ponds is 2.9 meters exceeded the designed criteria. It is found that the landfill operated with open dumping system and the treatment lagoons has never been regularly drained and recirculate. Those practices increase the leachate volume and degenerate the treatment functions. It can be concluded that the 4 aspects mentioned significantly influenced the leachate characteristics.
Evaluation of Post-Earthquake, Tsunami, and Liquefaction Disaster Waste Management in Palu
Authors: Chandra Putra Parura Tezario , Rahardyan Benno
Published: February 2020

The Central Sulawesi region is known as the meeting place for three of the world's main tectonics. As a result, the region is prone to natural disasters, especially those caused by the movement of these plates, which has prompted a shift in the Palu-Koro Fault. This also caused the 7.4 magnitude earthquake that devastated the coastal area of Palu Bay on September 28, 2018. Post-disaster waste management is one of the most important operational management systems ever developed to help affected communities and restore conditions to a stable situation after the disaster. In this study, the estimation of disaster waste generation was carried. In addition, an evaluation of disaster waste management was carried out as well as the formulation of disaster waste management mitigation, particularly earthquake, tsunami and liquefaction disasters. The estimated generation of construction disaster waste is 80,894,4 m3 and non-construction waste is 52,305.6 m3. Disaster waste management evaluation indicate that the lowest value in the evaluation aspect is in the aspect of community participation (30%) and the Financing aspect (37.5%). The establishment of a disaster waste management system will focus on the preparation of technical guidelines and Standard Operating Procedures (SOPs) on disaster waste management.
Organo Silica Membranes for Wetland Saline Water Desalination: Effect of membranes calcination temperatures
Authors: Ayu Lestari Riani , Elma Muthia , Rahma Aulia , Suparsih Dewi , Anadhliyah Syarifah , Ledyana Sari Norlian , Ari Pratomo Dhimas , Sumardi Anna , Lestari Aptar , Assyaifi Zaini Lambri , Satriaji Gesit
Published: February 2020

Wetland saline water has great potential to overcome water scarcity due to high salinity of intruded seawater. This work determines performance of silica membranes using organo catalyst applied for wetland saline water desalination via pervaporation and investigates the effect of calcination temperatures. These membranes were prepared from precursor tetraethyl orthosilicate (TEOS) for 3 h through sol-gel process refluxed at 0°C (membrane A) and 50°C (membrane B). The sols were dipcoated onto alumina (Al2O3) support for 4 layers followed by calcination for 1 h. Performance of membranes were evaluated by feeding wetland saline water through desalination at room temperature. Results show the water flux for membrane A were 0.27 & 0.15 kg.m-2.h-1 and salt rejection were 97.5 & 99 % as a function of calcination temperature (200 & 250°C), respectively. Furthermore, water flux of membranes B were 0.90 & 0.93 kg.m-2.h-1 and excellent salt rejection (>99.9 %) for both calcination temperatures. The highest water flux and salt rejection were found for membranes B. For both using citric acid under refluxed and calcination process, it gives more vibration of Si-C formation and membrane pores. This membrane is the very first and mesoporous organo silica membranes which is successfully fabricated from organo catalyst.
Perfil cardiovascular en pacientes con disfunción eréctil tratados en un centro de alta complejidad en la ciudad de Medellín, Colombia
Authors: Arcila Juan Fernando Uribe , Colina Vargas Yerlin Andrés , Vélez Gaviria Manuela , Naranjo Laura Ceballos , Vélez Jonathan Cardona , Gómez Jorge Hernando Donado
Published: February 2020

Objetivo Determinar el perfil cardiovascular de los pacientes con disfunción eréctil en un centro de alta complejidad de Medellín.

Métodos Estudio descriptivo, retrospectivo, en el que se incluyeron pacientes con diagnóstico de disfunción eréctil confirmado por el departamento de Urología, tratados en un centro de alta complejidad de Medellín entre 2010 y 2017; excluyendo aquellos con historia clínica con información incompleta o con desenlace cardiovascular previo al diagnóstico de disfunción eréctil. Los datos se obtuvieron de fuentes secundarias y se realizó su registro en una base de datos para su análisis mediante paquete estadístico (SPSS 24 Inc, Chicago, IL).

Resultados Se captaron, durante el periodo de estudio, 67 pacientes con disfunción eréctil que cumplieron los criterios de elegibilidad. Con una media de edad de 47,5 años. El 82% presentó disfunción eréctil severa, que estuvo asociada con el antecedente de angina, enfermedad coronaria y síndrome coronario agudo. Así mismo, más del 80% de los pacientes con diabetes, hipertensión, dislipidemia, tabaquismo, enfermedad renal crónica, obesidad y alcoholismo considerados como marcadores importantes de riesgo cardiovascular, presentaron disfunción eréctil severa.

Conclusión La comorbilidad cardiovascular en pacientes con DE es alta, existiendo una relación al compartir factores de riesgo y vías fisiopatológicas. Los pacientes con DE severa presentan mayor número de patologías asociadas, volviéndolos más propensos a desenlaces cardio-cerebrovasculares.
Implications of processing on the levels of antinutritional factors in cereal grains.
Authors: Burgos V. E. , Armada M.
Published: February 2020

The phytic acid, phenolic compounds, tannins, oxalate and trypsin inhibitors are known as antinutritional factors (ANFs) that commonly are present in cereal grains. They contribute to a lower nutritional value of cereals because they indirectly decrease the bioavailability of nutrients. Fortunately, these ANFs can be modified or reduced through different processing methods such as mechanical (decortication and milling), physical (soaking), heat (boiling, pressure cooking, autoclaving, roasting, extrusion and microwave cooking) and chemical (germination and fermentation). The purpose of this review is to discuss different ANFs of cereals and the influence of their processing on the levels of ANFs.
Erratum: Layout options of spectroscopic X-ray
DEPFETs
Authors: W. Treberspurg  , R. Andritschke  , A. Bähr  , A. Behrens  , G. Hauser  , P. Lechner  , N. Meidinger  , J. Müller-Seidlitz  , R.H. Richter  , J. Treis
Published: February 2020

See pdf for more details
Spiders in Galapagos – diversity, biogeography and origin
Authors: Buchholz Sascha , Baert Léon , Rodríguez Jacqueline , E Causton Charlotte , Jäger Heinke
Published: February 2020

The Galapagos archipelago is an ideal location for studying species differentiation on oceanic islands due to its isolation and geological youth. Spiders, as early colonisers, are good model organisms to understand these processes. The aim of this study is to update the list of spiders found in Galapagos and investigate the current distribution patterns of these species in relation to their probable origin. The updated checklist now comprises 159 species, with half of these species being endemic to Galapagos, 24% cosmopolitan in distribution, and 26% of the species originating from continental America. Although in most cases it was difficult to determine the mode of arrival of these species, at least 16 species are likely to have been introduced accidentally by humans. High elevation islands inhabited by humans harbour the highest number of species and also a higher percentage of cosmopolitan species. The geographical range of most species is small, with 76% of the species occurring on fewer than five islands. Given that many endemic species are restricted to one or a few islands, we recommend additional studies to evaluate their distribution and determine if there are species that should be classified as at risk from extinction.
Employer or Employee
Authors: Lin Kuan-Han , Wu Chau-Chung , Chu Tzong-Shinn , Huang Tien-Shang , Chen Yen-Yuan
Published: February 2020

Objective:

The aims of this study were to examine burnout among full-time workers and to investigate the effect of employment status on burnout.

Methods:

The data of this cross-sectional study were derived from the 2015 Taiwan Social Change Survey. Burnout was measured by the Copenhagen Burnout Inventory's four core items. Employment status was categorized into employer and employee. Multivariate linear regression models were used to assess the associations between employment status and burnout.

Results:

Among 1007 full-time workers, 21.65% were employers and 78.35% were employees. The multivariate linear regression model indicated that after adjusting for all possible risk factors, being an employer (b = 3.95, 95% CI: 0.40 to 7.50) was associated with an increased risk of burnout among full-time workers.

Conclusions:

Employment status was a significant factor of burnout among workers.
Distribution of Head Acceleration Events Varies by Position and Play Type in North American Football
Authors: Lee Taylor A. , Lycke Roy J. , Lee Patrick J. , Cudal Caroline M. , Torolski Kelly J. , Bucherl Sean E. , Leiva-Molano Nicolas , Auerbach Paul S. , Talavage Thomas M. , Nauman Eric A.
Published: February 2020

Objective:

The goal of this pilot study was to evaluate the number of head acceleration events (HAEs) based on position, play type, and starting stance.

Design:

Prospective cohort study.

Setting:

Postcollegiate skill development camp during practice sessions and 1 exhibition game.

Participants:

Seventy-eight male adult North American football athletes.

Independent Variables:

A position was assigned to each participant, and plays in the exhibition game were separated by play type for analysis. During the exhibition game, video data were used to determine the effects of the starting position (“up” in a 2-point stance or “down” in a 3- or 4-point stance) on the HAEs experienced by players on the offensive line.

Main Outcome Measures:

Peak linear acceleration and number of HAEs greater than 20 g (g = 9.81 m/s2) were measured using an xPatch (X2 Biosystems, Seattle, WA).

Results:

Four hundred thirty-seven HAEs were recorded during practices and 272 recorded during the exhibition game; 98 and 52 HAEs, the greatest number of HAEs by position in the game, were experienced by the offensive and defensive linemen, respectively. Linebackers and tight ends experienced high percentages of HAEs above 60 g. Offensive line players in a down stance had a higher likelihood of sustaining a HAE than players in an up stance regardless of the type of play (run vs pass).

Conclusions:

Changing the stance of players on the offensive line and reducing the number of full-contact practices will lower HAEs.
Direct Drive Simulation—Preoperative Sound Simulation of “Vibroplasty-Hearing” in Patients With Mixed Hearing Loss
Authors: Kaulitz Stefan , Großmann Wilma , Steinbach Julia , Hackenberg Stephan , Mlynski Robert , Rak Kristen , Schraven Sebastian Philipp , Hagen Rudolf
Published: February 2020

Objective:

Validation of the preoperative sound simulation test for vibroplasty-hearing so-called “Direct Drive Simulation” (DDS) in case of mixed hearing loss.

Study Design:

Retrospective data analysis.

Setting:

Tertiary referral center with a large hearing implant program.

Main Outcome Measure:

Comparison of sound impression during preoperative Direct Drive Simulation, and postoperative testing with the activated active middle ear implant (AMEI) under free-field condition and in daily routine.

Patients:

Fifty-four data sets from 18 patients with mixed hearing loss with a mean age of 60.78 ± 3.18 were included.

Results:

Comparing the sound impression during DDS preoperatively versus free-field testing with the implanted AMEI, no significant differences were found. DDS offers a slightly better sound quality than the AMEI in daily routine, fitting well to the ideal listening situation in DDS versus some background noise in daily routine.

Conclusion:

The DDS offers the possibility of a realistic preoperative sound simulation of the “vibroplasty-hearing” in cases of mixed hearing loss. This probably facilitates patient's decision towards a vibroplasty. The audiologist as well as the surgeon get additional information regarding the indication especially when audiologic inclusion criteria are critical. Thus, the DDS is a useful extension of preoperative diagnostics before vibroplasty.
Inter-rater Reliability and Validity of the Arabic Version of Categories of Auditory Performance-II (CAP-II) Among Children With Cochlear Implant
Authors: Al-shawi Yazeed , Mesallam Tamer A. , Alfallaj Rayan , Aldrees Turki , Albakheet Nouf , Alshawi Moath , Alotaibi Tahani , Algahtani Ashwag
Published: February 2020

Background:

Categories of Auditory Performance II (CAP-II) is an established audiological test that consists of a rating scale that can be used for prospective assessment of the auditory performance of cochlear implant (CI) recipients.

Objective:

To create and validate an Arabic version of Categories of Auditory Performance scale II (CAP-II), and to evaluate its reliability.

Methods:

In this cross-sectional study, 30 post-CI children (patients’ group) along with 30 control subjects were included. The translated Arabic CAP-II scale has been used by speech-language pathologists and parents to evaluate the study subjects’ auditory abilities. The interrater reliability, test–retest reliability, pre and postintervention score (responsiveness test), case versus control score comparison (discriminate validity), and cross-validation of the new Arabic version of CAP-II have been assessed.

Results:

The Arabic CAP-II demonstrated high test–retest and inter-rater reliability. There was a positive correlation between the Arabic CAP-II and Meaningful auditory integration scale. The Arabic CAP-II scores were higher in the patients’ group compared with control subjects.

Conclusion:

The Arabic CAP-II showed high inter-rater reliability with excellent concurrent and discriminate validity. The Arabic version of CAP-II seems to be a valid and reliable tool in assessing different auditory performance in Arabic speaking children with hearing impairment.
Olfactory Function in Depressed Adolescents
Authors: Uzun Cicek Ayla , Altuntas Emine Elif , Bora Adem , Sarı Seda Aybuke
Published: February 2020

Some researchers have suggested that olfactory deficits might be a sensitive marker for depression in adults. However, olfactory function has not been well studied in relation to depression among children and adolescents. The aim of this study was to evaluate the effect of depression on olfactory function of adolescents. The olfactory threshold, odor identification, and discrimination abilities of adolescents aged 12 to 17 (43 adolescents with major depressive disorder and 43 healthy controls) alongside their sum were evaluated using the Sniffin’ Sticks extended test. Olfactory scores were similar between the groups. However, depressed adolescents perceived their own olfactory function scores significantly lower than the measured values. No correlation was found between olfactory scores and age, sex, severity of depression, and duration of depression. This study conducted with a small sample size revealed that olfactory function of the adolescents with depression was similar to olfactory function of the healthy adolescents. It is required to conduct further adequately powered, longitudinal studies in order to verify these results.
Cognition, Structural Brain Changes, and Systemic Inflammation in Adolescents Living With HIV on Antiretroviral Therapy
Authors: Hoare Jacqueline , Myer Landon , Heany Sarah , Fouche Jean-Paul , Phillips Nicole , Zar Heather J. , Stein Dan J.
Published: February 2020

Objective:

To investigate the association between neurocognitive impairment, neuroimaging, and systemic inflammation in perinatally infected adolescents living with HIV (PHIV) on antiretroviral therapy (ART). Systemic inflammation may be one mechanism driving neurocognitive impairment despite ART, but this has not been investigated in adolescence when the brain is undergoing rapid development.

Setting:

Cape Town, South Africa.

Methods:

Baseline data were drawn from the Cape Town Adolescent Antiretroviral Cohort. PHIV on ART >6 months completed a comprehensive neurocognitive test battery. Diffusion tensor imaging and structural brain magnetic resonance imaging was done to determine whole brain fractional anisotropy, mean diffusion (MD), grey and white matter volumes, and cortical thickness. We examined how neurocognitive and neurostructural measures were associated with a concurrently measured marker of systemic inflammation, high-sensitive C-reactive protein (hs-CRP).

Results:

One hundred sixty-eight PHIV ages 9–12 years (mean CD4 980 cells/µL; 85.3% viral load <50 copies/mL) and 43 controls were included in the analysis. PHIV had similar hs-CRP (P = 0.17) to controls, after participants with hs-CRP >10 were excluded from the analysis. Forty-eight percent of the PHIV in this analysis have a neurocognitive disorder. Whole brain grey (P = 0.049) and white matter volumes (P = 0.044) were lowest in PHIV with a major neurocognitive disorder. Higher MD, was found in PHIV with a major neurocognitive disorder (P = 0.002). Among PHIV with a neurocognitive disorder, hs-CRP negatively correlated with general intelligence, visual spatial acuity, and executive function (all P = < 0.05). Whole brain MD correlated with higher hs-CRP values (P = < 0.01) in PHIV.

Conclusions:

A marker of systemic inflammation was associated with both neurocognitive impairment and MD increases in PHIV.
Estimating hepatitis B virus cccDNA persistence in chronic infection
Authors: Lythgoe Katrina A. , Lumley Sheila F. , Pellis Lorenzo , McKeating Jane A. , Matthews Philippa C.
Published: February 2020

Hepatitis B virus (HBV) infection is a major global health problem with over 240 million infected individuals at risk of developing progressive liver disease and hepatocellular carcinoma. HBV is an enveloped DNA virus that establishes its genome as an episomal, covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Currently available standard-of-care treatments for chronic hepatitis B (CHB) include nucleos(t)ide analogues (NA) that suppress HBV replication but do not target the cccDNA and hence rarely cure infection. There is considerable interest in determining the lifespan of cccDNA molecules to design and evaluate new curative treatments. We took a novel approach to this problem by developing a new mathematical framework to model changes in evolutionary rates during infection which, combined with previously determined within-host evolutionary rates of HBV, we used to determine the lifespan of cccDNA. We estimate that during HBe-antigen positive (HBeAgPOS) infection the cccDNA lifespan is 61 (36-236) days, whereas during the HBeAgNEGphase of infection it is only 26 (16-81) days. We found that cccDNA replicative capacity declined by an order of magnitude between HBeAgPOSand HBeAgNEGphases of infection. Our estimated lifespan of cccDNA is too short to explain the long durations of chronic infection observed in patients on NA treatment, suggesting that either a sub-population of long-lived hepatocytes harbouring cccDNA molecules persists during therapy, or that NA therapy does not suppress all viral replication. These results provide a greater understanding of the biology of the cccDNA reservoir and can aid the development of new curative therapeutic strategies for treating CHB.

Author Summary

Nearly one million people die each year due to hepatitis B virus (HBV) related diseases. Although antiviral treatments for HBV exist, cure is rare and treatment is typically life-long, reflecting the persistence of episomal copies of the viral DNA (cccDNA) in the liver. Our knowledge of the cccDNA reservoir in chronic hepatitis B (CHB) is limited. HBV has a high mutation rate and the key determinants of cccDNA dynamics can be inferred by examining the rate of viral evolution. Combining a mathematical model and known rates of HBV evolution we estimate the cccDNA lifespan during different phases of CHB. Our results provide important insights into the dynamics of the HBV reservoir that will inform the design of future treatment interventions.
Evidence that Telomere Length is Causal for Idiopathic Pulmonary Fibrosis but not Chronic Obstructive Pulmonary Disease: A Mendelian Randomisation Study
Authors: Duckworth Anna , Gibbons Michael A. , Allen Richard J. , Almond Howard , Beaumont Robin N. , Wood Andrew R. , Lunnon Katie , Lindsay Mark A. , Wain Louise V. , Tyrrell Jess , Scotton Chris J.
Published: February 2020

Background

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease accounting for 1% of UK deaths. In the familial form of pulmonary fibrosis, causal genes have been identified in ∼30% of cases, and a majority relate to telomere maintenance. Prematurely shortened leukocyte telomere length has also been associated with IPF, as well as chronic obstructive pulmonary disease (COPD), a disease with a similar demographic and shared risk factors. Using Mendelian randomisation (MR), our study aimed to determine whether short telomeres cause IPF or COPD.

Methods

We performed an MR study for telomere length causality in IPF and COPD with up to 1,369 IPF cases, 14,103 COPD cases and 435,866 controls of European ancestry in UK Biobank. Initial studies using polygenic risk scores followed by two-sample MR analyses were carried out using seven genetic variants previously associated with telomere length, with replication analysis in an IPF cohort of 2,668 IPF cases and 8,591 controls and a COPD cohort of 15,256 cases and 47,936 controls.

Findings

Meta-analysis of the two-sample MR results provided evidence that shorter telomeres cause IPF, with a genetically instrumented one standard deviation shorter telomere length associated with 5.81 higher odds of IPF ([95% CI: 3.56-9.50], P=2.19×10−12. Despite being an age-related lung disease with overlapping risk, there was no evidence that telomere length caused COPD (OR 1.07, [95% CI 0.90-1.27], P = 0.46).

Interpretation

Cellular senescence is hypothesised as a major driving force in both IPF and COPD; telomere shortening may be a contributory factor in IPF, suggesting divergent mechanisms in COPD. This enables greater focus in telomere-related diagnostics, treatments and the search for a cure in IPF. Therapies manifesting improvements in telomere length, including safe telomere activation therapy, may warrant investigation.
ProTrack: An Interactive Multi-Omics Data Browser for Proteogenomic Studies
Authors: Calinawan Anna Pamela , Song Xiaoyu , Ji Jiayi , Dhanasekaran Saravana Mohan , Petralia Francesca , Wang Pei , Reva Boris
Published: February 2020

The Clinical Proteomic Tumor Analysis Consortium (CPTAC) initiative has generated extensive multi-omics data resources of deep proteogenomic profiles for multiple cancer types. To enable the broader community of biological and medical researchers to intuitively query, explore, and download data and analysis results from various CPTAC projects, we built a prototype user-friendly web application called “ProTrack” with the CPTAC clear cell renal cell carcinoma (ccRCC) data set (http://ccrcc.cptac-data-view.org). Here we describe the salient features of this application which provides a dynamic, comprehensive, and granular visualization of the rich proteogenomic data.

Statement of Significance

The CPTAC initiative (https://proteomics.cancer.gov/) has generated multi-omics data for multiple cancer types to understand the proteogenomic aberrations of these malignancies. Collectively this effort has so far produced a large data resource for the research community, including high-throughput profiles for proteome, phosphoproteome, whole exome, whole genome, transcriptome, and DNA methylome. To make this valuable data-resource useful to the larger research community, there is a pressing need for development of user-friendly, readily accessible, and easily shared analytic and visualization tools for aligning multi-omics data and exploring alterations in key cancer genes, to drive and support new biological hypotheses. To bridge this gap, we have developed CPTAC ProTrack, an interactive web application which uses a multilayered, client-server architecture in order to deliver an interactive web experience to any user of a modern web-browser. This tool is intentionally designed accessible for researchers, biologists, and clinicians who are interested in multi-omic data without any need to code.
Thewtf4meiotic driver utilizes controlled protein aggregation to generate selective cell death
Authors: Nuckolls Nicole L. , Mok Anthony C. , Lange Jeffrey J. , Yi Kexi , Kandola Tejbir S. , Hunn Andrew M. , McCroskey Scott , Snyder Julia L. , Bravo Núñez María Angélica , McClain Melainia L. , McKinney Sean A. , Wood Christopher , Halfmann Randal , Zanders Sarah E.
Published: February 2020

Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. Thewtf4gene is a meiotic driver inSchizosaccharomyces pombethat uses a poison-antidote mechanism. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species,Saccharomyces cerevisiae. The Wtf4poisonprotein forms dispersed, toxic aggregates. The similar Wtf4antidoteprotein also forms aggregates but is sequestered within or near vacuoles and is mostly benign. The Wtf4antidotecan co-assemble with the Wtf4poisonand promote its trafficking to vacuoles. We show that neutralization of the Wtf4poisonrequires both co-assembly with the Wtf4antidoteand aggregate sequestration, as mutations that disrupt either of these processes results in cell death. This work reveals thatwtfparasites can exploit protein aggregate management pathways to selectively destroy gametes.
Loop 1 of APOBEC3C regulates its antiviral activity against HIV-1
Authors: Jaguva Vasudevan Ananda Ayyappan , Balakrishnan Kannan , Gertzen Christoph G. W. , Borvető Fanni , Zhang Zeli , Sangwiman Anucha , Held Ulrike , Küstermann Caroline , Banerjee Sharmistha , Schumann Gerald G. , Häussinger Dieter , Bravo Ignacio G. , Gohlke Holger , Münk Carsten
Published: February 2020

APOBEC3 deaminases (A3s) provide mammals with an anti-retroviral barrier by catalyzing dC-to-dU deamination on viral ssDNA. Within primates, A3s have evolved diverselyviagene duplications and fusions. Human APOBEC3C (hA3C) efficiently restricts the replication of viral infectivity factor (vif)-deficientSimian immunodeficiency virus(SIVΔvif), but for unknown reasons, it inhibits HIV-1Δvifweakly. In catarrhines (Old World monkeys and apes), the A3C loop 1 displays the conserved amino acid pair WE, while the corresponding consensus sequence in A3F and A3D is the largely divergent pair RK, which is also the inferred ancestral sequence for the last common ancestor of A3C|D|F in primates. Here, we report that modifying the WE residues in hA3C loop 1 to RK leads to stronger interactions with ssDNA substrate, facilitating catalytic function, which resulted in a drastic increase in both deamination activity and the ability to restrict HIV-1 and LINE-1 replication. Conversely, the modification hA3F_WE resulted only in a marginal decrease in HIV-1Δvifinhibition. The two series of ancestral gene duplications that generated A3C, A3D-CTD and A3F-CTD allowed neo/subfunctionalization: A3F-CTD maintained the ancestral RK residues in loop 1, while strong evolutionary pressure selected for the RK→WE modification in catarrhines A3C, possibly allowing for novel substrate specificity and function.

AUTHOR SUMMARY

The restriction factors of the APOBEC3 (A3) family of cytidine deaminases inhibit the replication of Vif-deficient retroviruses mainly by mutating their viral genomes. While there are seven A3 proteins (A3A-A3H) found in humans only A3G and A3F potently inhibit HIV-1 replication. A3C in general and its retroviral restriction capacity have not been widely studied probably due to its weak anti-HIV-1 activity, however, it displays a strong antiviral effect against SIV. Understanding the role of A3C is important because it is highly expressed in CD4+ T cells, is upregulated upon HIV-1 infection, and is distributed cell-wide. In this study, we report that replacing two residues in loop 1 of A3C protein with conserved positively-charged amino acids enhance the substrate DNA binding, which markedly facilitates its deamination-dependent antiviral activity against HIV-1 as well as increasing the restriction of LINE-1 retroelements. Furthermore, our evolutionary analysis demonstrates that the pressure that caused the loss of potential loop 1 residues occurred only in A3C but not in primate homologues. Overall, our study highlights the possibility of A3C acting as a super restriction factor, however, this was likely evolutionarily selected against to achieve a balance between anti-viral/anti-LINE-1 activity and genotoxicity.
Highly replicated evolution of parapatric ecotypes
Authors: James Maddie E. , Arenas-Castro Henry , Groh Jeffrey S. , Allen Scott L. , Engelstädter Jan , Ortiz-Barrientos Daniel
Published: February 2020

Parallel evolution of ecotypes occurs when selection independently drives the evolution of similar traits across similar environments. The multiple origin of ecotypes is often inferred on the basis of a phylogeny which clusters populations according to geographic location and not by the environment they occupy. However, the use of phylogenies to infer parallel evolution in closely related populations is problematic because gene flow and incomplete lineage sorting can uncouple the genetic structure at neutral markers from the colonization history of populations. Here, we demonstrate multiple origins within ecotypes of an Australian wildflower,Senecio lautus. We observed strong genetic structure as well as phylogenetic clustering by geography and show that this is unlikely due to gene flow between parapatric ecotypes, which is surprisingly low. We further confirm this analytically by demonstrating that phylogenetic distortion due to gene flow often requires higher levels of migration than those observed inS. lautus. Our results imply that selection can repeatedly create similar phenotypes despite the perceived homogenizing effects of gene flow.
Baseline Structural and Functional Magnetic Resonance Imaging Predicts Early Treatment Response in Schizophrenia with Radiomics Strategy
Authors: Cui Long-Biao , Fu Yu-Fei , Liu Lin , Wei Yongbin , Wu Xu-Sha , Xi Yi-Bin , Wang Hua-Ning , Qin Wei , Yin Hong
Published: February 2020

Multimodal neuroimaging features might enable accurate classification and provide personalized treatment options in psychiatric domain. We conducted a retrospective study to investigate whether structural and functional features for predicting response to overall treatment of schizophrenia at the end of the first or a single hospitalization and in addition cross validate the results. This structural and functional magnetic resonance imaging (MRI) study included 85 and 63 patients with schizophrenia at baseline in dataset 1 and 2, respectively. After treatment, patients were classified as responders and non-responders. Features of gray matter and functional connectivity were extracted. Radiomics analysis was used to explore the predictive performance. Prediction models were based on structural features, functional features, and combined features. We found that the prediction accuracy was 80.38% (sensitivity: 87.28%; specificity 82.47%) for the model using functional features, and 69.68% (sensitivity: 83.96%; specificity: 72.41%) for the model using structural features. Our model combined both structural and functional features accurately predicted 92.04% responder and 80.23% non-responders to overall treatment, with an accuracy of 85.03%. These results highlight the power of structural and functional MRI-derived radiomics features to predict early response to treatment in schizophrenia. Prediction models of the very early treatment response in schizophrenia could augment effective therapeutic strategies.
Activator protein-1 transactivation of the major immediate early locus is a determinant of cytomegalovirus reactivation from latency
Authors: Krishna Benjamin A. , Wass Amanda B. , O’Connor Christine M.
Published: February 2020

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that latently infects hematopoietic cells and has the ability to reactivate when triggered by immunological stress. This reactivation causes significant morbidity and mortality in immune-deficient patients, who are unable to control viral dissemination. While a competent immune system helps prevent clinically detectable viremia, a portrait of the factors that induce reactivation following the proper cues remains incomplete. Our understanding of the complex molecular mechanisms underlying latency and reactivation continue to evolve. We previously showed the HCMV-encoded G-protein coupled receptorUS28is expressed during latency and facilitates latent infection by attenuating the activator protein-1 (AP-1) transcription factor subunit, c-fos, expression and activity. We now show AP-1 is a critical component for HCMV reactivation. Pharmacological inhibition of c-fos significantly attenuates viral reactivation. In agreement, infection with a virus in which we disrupted the proximal AP-1 binding site in the major immediate early (MIE) enhancer results in inefficient reactivation compared to wild type. Concomitantly, AP-1 recruitment to the MIE enhancer is significantly decreased following reactivation of the mutant virus. Further, AP-1 is critical for de-repression of MIE-driven transcripts and downstream early and late genes, while immediate early genes from other loci remain unaffected. Our data also reveal MIE transcripts driven from the MIE promoter, the distal promoter, and the internal promoter, iP2, are dependent upon AP-1 recruitment, while iP1-driven transcripts are AP-1-independent. Collectively, our data demonstrate AP-1 binding to and activation of the MIE enhancer is a key molecular process controlling reactivation from latency.

Significance Statement

Human cytomegalovirus (HCMV) is a common pathogen that infects the majority of the population for life. This infection poses little threat in immunologically healthy individuals, but can be fatal in people with compromised immune systems. Our understanding of the mechanisms underlying latency and reactivation remains incomplete. Here, we show the cellular transcription factor, AP-1, is a key to regulating HCMV reactivation. Our findings reveal AP-1 binding to the major immediate early enhancer/promoter is critical for switching this locus from one that is repressed during latency to one that is highly active following reactivation. Our work provides a novel mechanism HCMV exploits to reactivate, highlighting AP-1 as a potential target to prevent HCMV reactivation.
Efficiency of biological and chemical inducers for controlling Septoria tritici leaf blotch (STB) on wheat (Triticum aestivumL.)
Authors: Bellameche Fares , Pedrazzini Chiara , Mauch-Mani Brigitte , Mascher Fabio
Published: February 2020

The hemibiotrophic fungusZymoseptoria triticiis the causative agent of Septoria tritici leaf blotch (STB) disease of wheat (Triticum aestivumL.), the economically most damaging disease of wheat in Europe. Today, ecofriendly plant protection methods compatible with sustainable agriculture are strongly desirable. Here, we applied the two chemical inducers β-aminobutyric acid (BABA) and benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester (BTH) and the two biotic inducersPseudomonas protegensCHA0 (CHA0) andP. chlororaphisPCL1391 (PCL) on the roots of wheat seedlings in order to test their ability to induce resistance against STB. At 21 days after inoculation, only plants treated with BABA showed a smaller area covered by lesions and less pycnidia compared to the untreated control plants. We evaluated spore germination and fungal development on inoculated wheat leaves at early infection stages using calcofluor white staining. Overall, spores ofZ. triticigerminated less on plants soil-drenched with BABA and BTH and their hyphal growth was significantly delayed. On the contrary, CHA0 and PCL seed treatments did not affect fungal growth in wheat leaves. In conclusion, BABA efficiently enhanced plant resistance toZ. tritici, BTH delayed fungal development at early stages while the two biotic inducers did not enhance resistance against STB disease.