bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of a Seed Plate Assay for Evaluating Charcoal Rot Resistance in Soybean and the Relationship to Field Performance
Authors: da Silva Marcos P. , Pereira Andy , Rupe John C. , Bluhm Burt H. , Gbur Edward E. , Wood Lisa , Mozzoni Leandro A. , Chen Pengyin
Published: March 2019

Charcoal rot of soybean, caused by Macrophomina phaseolina, is a disease of economic significance in the United States. Although there are soybean cultivars with moderate resistance, identifying and quantifying resistance is challenging. Existing assays are time consuming, and results are often highly variable. The objectives of this research were to (i) create a reproducible seed plate assay (SPA) for charcoal rot resistance and (ii) correlate field-based disease assessments with SPA results on diverse soybean accessions. To develop the SPA, surface-disinfected seeds from eight soybean genotypes (representing three susceptible and five resistant cultivars) were placed on water agar plates inoculated with M. phaseolina. After incubation at room temperature in darkness for 7 days, percent germination was determined for each cultivar relative to the germination on noninoculated plates. Results from SPA were in general agreement with published responses. None of the soybean genotypes showed complete resistance to M. phaseolina. For the second objective, charcoal rot resistance in 18 soybean accessions was assayed with SPA, and results were analyzed for correlation with field disease assessments from Stuttgart, AR, from 2011 to 2014 and from Rohwer, AR, in 2011 and 2012. SPA consistently categorized soybean genotype resistance compared with field disease assessment averages, and results were consistent with previously published resistance determinations. SPA was significantly correlated with percent height of internal stem discoloration (PHSD) at Stuttgart from 2011 to 2013 and in 2012 at Rohwer, with root and stem severity (RSS) at Rohwer in 2012, and with tap root colonization (CFU) at Stuttgart in 2012. SPA was significantly correlated to yield at Stuttgart in 2011, 2013, and 2014, and in 2011 and 2012 at Rohwer. Yield was not correlated to RSS, PHSD, or CFU at either location or in any year. Therefore, SPA is a reproducible and rapid assay for charcoal rot resistance in soybean and is significantly associated to field performance.
Negative-Pressure Wound Therapy for Managing Complicated Wounds at Extracorporeal Membrane Oxygenation Sites
Authors: Eom Yeseul , Woo Kyong-Je
Published: March 2019

OBJECTIVE:

To evaluate the effectiveness of negative-pressure wound therapy (NPWT) for management of wound complications at extracorporeal membrane oxygenation (ECMO) removal sites.

METHODS:

The authors retrospectively reviewed patients who underwent NPWT at ECMO removal sites followed by the development of wound complications including skin necrosis, lymphorrhea, and femoral vessel exposure. A nonadhesive bacteria-binding mesh was used as a wound contact layer of NPWT application. Patient characteristics and clinical outcomes were evaluated.

RESULTS:

Nine patients underwent NPWT for complicated wounds at ECMO sites. The mean age of patients was 49.2 years (range, 14–64 years). All patients exhibited wound complications with lymphorrhea and skin necrosis. Seven of nine patients had wound cultures that were positive for microorganisms, but culture conversion to negative was achieved after NPWT application for a mean period of 21.2 days (range, 12–30 days). Lymphorrhea was successfully managed, and formation of fresh granulation tissue was observed in all patients. Wound healing either by primary closure, skin graft, or secondary healing was achieved without recurrence of wound complications. There were no cases of femoral vessel injury or aneurysm during NPWT application.

CONCLUSIONS:

Negative-pressure wound therapy appears to be a safe and effective treatment option in the management of complicated wounds at ECMO sites.
EHR quality indicator tracking
Authors: Savas Andrea , Smith Eben , Hay Brittany
Published: March 2019

The Centers for Medicare and Medicaid Services created the Quality Payment Program to award compensation to providers for offering evidence-based, high-value, and efficient care. This article outlines an information technology process improvement pilot project undertaken at a large primary care practice in western Florida to support readiness for Medicare Access and Children's Health Insurance Program (CHIP) Reauthorization Act of 2015 using new EHR quality indicator tracking features.
Acute Kidney Stress and Prevention of Acute Kidney Injury
Authors: Katz Nevin M. , Kellum John A. , Ronco Claudio
Published: March 2019

Critical care physicians continue to be challenged to recognize an environment that has the potential to result in acute kidney injury, with its associated short- and long-term consequences. The recent development of cell cycle arrest biomarkers that signal the potential development of acute kidney injury is part of an evolution in the molecular diagnosis and understanding of acute kidney injury. A preinjury phase that may lead to acute kidney injury has been described as “acute kidney stress.” This concept has the potential to stimulate research and innovation that will lead to early implementation of measures to prevent or reverse acute kidney injury.
Comparison of Two Techniques to Measure Optic Nerve Sheath Diameter in Patients at Risk for Increased Intracranial Pressure
Authors: Agrawal Ashish , Cheng Roger , Tang Julin , Madhok Debbie Y.
Published: March 2019

Objectives:

Intracranial pressure over 20 mm Hg is associated with poor neurologic prognosis, but measuring intracranial pressure directly requires an invasive procedure. Dilation of the optic nerve sheath on axial ultrasound of the eye has been correlated with elevated intracranial pressure, but optimal cutoffs have been inconsistent possibly related to the measurement technique. A coronal technique has been studied on healthy volunteers but not on patients with high intracranial pressure. We compared two measurement techniques (axial and coronal) in patients with suspected high intracranial pressure due to trauma, bleeding, tumor, or infection.

Design:

Prospective blinded observational study.

Setting:

Two tertiary referral center ICUs.

Patients:

Twenty adults admitted to the ICU at risk for increased intracranial pressure expected to receive invasive intracranial monitoring.

Interventions:

Ultrasound measurements of the optic nerve sheath in axial and coronal views either averaged between eyes or the highest in either eye.

Measurements and Main Results:

Coronal measurements showed less variability between each eye than axial measurements (mean difference 0.5 mm vs 1 mm; p = 0.03) and were associated with high intracranial pressure at first measurement and over 24 hours (area under the receiver operating characteristic range 0.7–0.8). Mean and highest axial measurements showed improved association with first (area under the receiver operating characteristic 0.87–0.94) and highest intracranial pressure measurement (area under the receiver operating characteristic 0.89–0.96) within 24 hours. A cutoff of highest axial measurement in either eye greater than 6.2 mm or mean axial measurement between eyes of 5.6 mm had a sensitivity of 100% in predicting high intracranial pressure over the following 24 hours.

Conclusions:

The highest axial measurement of optic nerve sheath diameter in either eye is the most predictive of patients with high intracranial pressure in our population. This comparison of measurement techniques has not previously been described and should be further explored to set test cutoffs for ultrasound of the optic nerve sheath diameter.
Single-center real-life experience with low-dose ipilimumab monotherapy in adjuvant setting for patients with stage III melanoma
Authors: Mangana Joanna , Dimitriou Florentia , Braun Ralph , Ludwig Sabine , Dummer Reinhard , Barysch Marjam J.
Published: March 2019

Ipilimumab is approved for adjuvant melanoma treatment at a dose of 10 mg/kg, but its use is limited owing to high toxicity and treatment-associated costs. We retrospectively analyzed 29 patients who underwent complete resection of stage IIC–III melanoma and were treated with ipilimumab 3 mg/kg in an adjuvant setting. The aim was to assess development of adverse events (primary endpoint) and to evaluate survival outcomes (secondary endpoint) under adjuvant treatment with ipilimumab in a real-life setting. Immune-related adverse events (irAE) of all grades were reported in 72.4% of patients, grade 3 in 5.3% (n = 2), and none for grade 4 or 5. Immune-related hypophysitis resolved in 3/8 (37.5%) and immune-related thyroiditis in 7/10 (70%) cases, whereas the others remained on substitution drugs. The rest irAEs affected the gut (n = 8), skin (n = 5), liver (n = 2), and uvea (n = 2) and resolved completely. Only one patient required tumor necrosis factor-α owing to grade 3 colitis. Hospitalization was required in five cases owing to irAE (four colitis and one hypophysitis). At a median follow-up of 9.7 (1.7–16.8) months, 65.5% of the patients were free of disease. Median progression-free survival was 15.1 months, and median overall survival was not reached yet. Ipilimumab 3 mg/kg for the adjuvant treatment of high-risk patients with fully resected melanoma favors a better safety profile compared with the approved dose of 10 mg/kg in the same setting. Although its limited application owing lately promising data of antiprogrammed cell death protein-1 treatment, it may be considered as additional option or second-line treatment after fully resected disease recurrence under antiprogrammed cell death protein-1 treatment.
NOVEL APPROACH TO SCLERAL FIXATION OF A REPER INTRAOCULAR LENS AND ARTIFICIAL IRIS COMPLEX FOLLOWING PARS PLANA LENSECTOMY AND VITRECTOMY FOR ECTOPIA LENTIS AND CATARACT IN A PATIENT WITH ANIRIDIA AND NYSTAGMUS
Authors: Jiang Shangjun , Baig Kashif , Kalevar Ananda , Choudhry Netan , Gupta R. Rishi
Published: March 2019

Purpose:

Prosthetic iris devices have recently been used to improve cosmesis and reduce glare in aniridia. There is currently no consensus on which prosthetic iris device or which surgical approach is preferred for managing large iris defects.

Methods:

A novel surgical approach with Gore-Tex polytetrafluoroethylene sutures was used to achieve scleral fixation of an intraocular lens and artificial iris complex in a 19-year-old Caucasian female patient with aniridia, nystagmus, cataracts, and ectopia lentis.

Results:

Six weeks postoperatively, the intraocular lens–artificial iris complex remained well centered, and the vision in the left eye improved from 20/400 to 20/70. Two years after prosthetic iris device implantation, there have been no complications.

Conclusion:

This case demonstrates a promising proof-of-concept for long-term management of complicated aniridia cases using an intraocular lens and artificial iris complex prosthetic iris devices. Gore-Tex sutures may be preferable to conventional polypropylene sutures because of their improved durability.
Frequencies of 4 Distinct Patterns of Glaucomatous Disc Appearance and Their Clinical Associations in Japanese Population-based Studies
Authors: Iwase Aiko , Araie Makoto , Kuwayama Yasuaki , Murata Hiroshi , Yamamoto Tetsuya
Published: March 2019

Purpose:

To study the frequencies and factors associated with 4 disc patterns in primary open-angle glaucoma (POAG) identified in population-based studies: focal glaucomatous (FG type), generalized enlargement of cup (GE type), myopic glaucomatous (MG type), and senile sclerotic glaucomatous (SS type) patterns.

Subjects:

In total, 270 disc photographs of acceptable quality were extracted from the records of 270 definitive POAG cases diagnosed according to the International Society of Geographical and Epidemiological Ophthalmology Criteria in 2 Japanese population-based glaucoma surveys. One randomly chosen eye from the bilateral POAG cases was included.

Results:

Using a method of κ coefficient of reproducibility of classification of 0.80 according to a preliminary study, 143 discs were classified as FG, GE, MG, or SS types with respective frequencies of 57% (95% confidence interval [CI], 48-66), 33% (95% CI, 25-42), 7% (95% CI, 3-13), and 3% (95% CI, 0-7), and 127 discs as the miscellaneous type. Multinomial logistic regression analysis showed that the MG type was associated (P=0.052, 0.025, 0.019, and 0.018) with younger age, lower body mass index (BMI), and greater disc area and ovality, and the GE type was associated (P<0.001, 0.036, and 0.056) with greater disc area, corneal radius, and hyperopic refraction than the FG type.

Conclusions:

The FG type occurs most frequently in Japanese POAG followed by the GE type. The MG and SS types occurred much less often than previously reported in Japanese. Associations with age, BMI, disc area and ovality, refraction, and corneal radius differed among the FG, GE, and MG types.
The Effect of Cochlear Coverage on Auditory and Speech Performance in Cochlear Implant Patients
Authors: Doubi Aseel , Almuhawas Fida , Alzhrani Farid , Doubi Motaz , Aljutaili Hamad , Hagr Abdulrahman
Published: March 2019

Objective:

To determine the effect of cochlear coverage on audiological and speech parameters in patients with cochlear implants. Previous work has investigated the effect of tailoring electrode size to a cochlear implant recipient's individual cochlear duct length (CDL). However, no clear relationship has been found between speech development and the extent of electrode insertion, and the benefits of apical stimulation are not yet clear.

Methodology:

In this retrospective study, we assessed the effect of cochlear coverage on audiological and speech performance. Participants were prelingually deaf children who received cochlear implants between June 2013 and December 2014 under the care of a single cochlear implant surgeon. Cochlear coverage was estimated for each ear according to electrode type, depth of insertion, and the number of active electrodes. Electrode type and length were determined by the individual's CDL, measured by computed tomography (CT), and full insertion was documented intraoperatively. The number of active electrodes was recorded using intraoperative audiological response telemetry. Audiological assessments were obtained 6 months and 1 year postoperatively. Results of the categories of auditory performance-II and speech intelligibility rating scales were obtained after 3 years. Patients were divided into two groups based on their cochlear coverage and their audiological and speech outcomes were compared.

Results:

Of the 97 children recruited, 47 were girls. Temporal bone CT scans showed the right and left mean CDLs among girls were 27.7 and 27.9 mm, respectively, and 29.2 mm for both ears in boys. For each sex, the right and left CDLs did not differ significantly (p = 0.07). Twenty patients were lost to follow-up, leaving 77 patients (120 ears), which were divided into groups according to cochlear coverage (complete vs. incomplete). Significant between-group differences were not found in assessments of audiology, categories of auditory performances, or speech intelligibility ratings after 3 years.

Conclusion:

Audiological parameters do not differ according to the degree of cochlear coverage, specifically for low-frequency tones. Speech parameters are also comparable. Therefore, complete cochlear coverage does not appear to provide significant benefit over incomplete coverage for prelingually deaf cochlear implant recipients.
Multiplication product of Model for End-stage Liver Disease and Donor Risk Index as predictive models of survival after liver transplantation
Authors: Khalaileh Abed , Khoury Tawfik , Harkrosh Subhi , Nowotny Yakob , Massarwa Mohamad , Safadi Rifaat , Mor Eytan , Nakache Richard , Abu Gazala Samir , Merhav Hadar
Published: March 2019

Background

Liver transplantation (LT) is the treatment of choice for most end-stage liver diseases. This treatment increases survival rates and improves quality of life. Because of the shortage of organ donors, as opposed to waiting patients, the need to optimize the matching of donors to recipients for maximum utility is crucial.

Aim

The aim of this study was to examine a predictive model based on the combination of donor and recipient risk factors using the liver Donor Risk Index (DRI) and recipient Model of End-stage Liver Disease (MELD) to predict patients’ survival following LT.

Patients and methods

The charts of 289 adult primary LT patients, who had undergone transplantation in Israel between 2010 and 2015, were studied retrospectively using prospectively gathered data.

Results

Two variables, DRI and MELD, were found to significantly affect post-transplant patient survival. DRI negatively affected survival in a continuous fashion, whereas MELD had a significantly negative effect only at MELD more than 30. Both female sex and the presence of hepatocellular carcinoma were associated with increased patient survival.

Conclusion

According to our findings, the model described here is a novel prediction tool for the success of orthotopic LT and can thus be considered in liver allocation.
Charting Cognitive Growth of Nursing Students Using Linguistic Software
Authors: DeBlieck Conni J. , Summers Linda C. , Saiki Lori S. , Kuchler Elizabeth , Noe Shelly , Lynch Stephanie , Reinhardt Anita C. , Keller Teresa
Published: March 2019

Background

Students' word choice when writing in a reflective journal may reveal their emotional development, sense of belonging, cognitive processing, and ability to appraise their own growth and understanding. New linguistic analysis software can scan and categorize these journals for the use of pronouns, positive and negative emotions, and cognitive keywords.

Methods

A retrospective study design evaluated student journaling from a psychiatric clinical course. Journal entries from weeks 1 and 12 were compared by z-score analysis.

Findings

Significant increases were found in the use of “we” (P = .001), positive emotions (P < .001), inclusion words (P < .001), and insight words (P = .004), whereas the use of cause and self-discrepancy words were not significantly different.

Conclusion

Identification of learning as expressed in words could have an impact on how student assignments are designed by including the use of the Linguistic Inquiry and Word Count software to assess changes in student cognition.
A Qualitative Analysis of Outpatient Medication Use in Community Settings: Observed Safety Vulnerabilities and Recommendations for Improved Patient Safety
Authors: Lyson Helena C. , Sharma Anjana E. , Cherian Roy , Patterson Emily S. , McDonald Kathryn M. , Lee Shin-Yu , Sarkar Urmimala
Published: March 2019

Objective

The aim of the study was to analyze diverse patients’ experiences throughout the medication use process to inform the development of overarching interventions that support safe medication use in community settings.

Methods

Using a qualitative observational approach, we conducted approximately 18 hours of direct observation of the medication use process across multiple settings for a sample of vulnerable, high-risk patients. Observers recorded detailed field notes during the observations. To enrich the observational findings, we also conducted six semistructured interviews with medication safety experts representing a diversity of perspectives. Barriers and facilitators to safe medication use were identified based on inductive coding of the data.

Results

A variety of safety vulnerabilities plague all stages of the medication use process and many of the well-established evidence-based interventions aimed at improving the safety of medication use at key stages of the process have not been widely implemented in community settings observed in this study. Key safety vulnerabilities identified include: limited English proficiency, low health literacy, lack of clinician continuity, incomplete medication reconciliation and counseling, unsafe medication storage and disposal habits, and conflicting healthcare agendas with caregivers.

Conclusions

Our findings underscore a need for overarching, comprehensive interventions that span the entire process of medication use, including integrated communication systems between clinicians, pharmacies, and patients, and a “patient navigator” program that assists patients in navigating the entire medication-taking process. Collective ownership of the medication management system and mutual motivation for devising collaborative solutions is needed among key sectors.
Is Physician Mentorship Associated With the Occurrence of Adverse Patient Safety Events?
Authors: Harrison Reema , Sharma Anurag , Lawton Rebecca , Stewart Kevin
Published: March 2019

Background

Mentorship has been identified as a beneficial practice for doctors and key aspect of continuing professional development, associated with a number of potential clinical and nonclinical gains. The likely contribution of mentorship to enhancing patient safety is acknowledged, but there is a dearth of empirical studies that attempt to make associations between the impact of mentorship for physicians on patient safety outcomes. This article begins to fill this gap by exploring whether a physician with a mentor reports having fewer near-misses or adverse events, compared with a physician with no mentor.

Methods

An online survey was administered to fellows and members of the Royal College of Physicians London using their membership database in April 2013. Adverse events and near misses are modeled as two separate binary variables using a logit regression framework with “having a mentor” being the main covariate. The marginal effect of this covariate captures the effect of mentorship on adverse events.

Results

A total of 1755 doctors (37% female) responded who represented all internal medical specialties. Our results show that compared with physicians with no mentor, the probability of getting involved in an adverse event or near miss is reduced by 12.69% (95% confidence interval = −17.41 to −7.98) and 11.12% (95% confidence interval = −15.84 to −6.41) for physicians with a mentor.

Conclusions

Having a mentor may contribute toward minimizing preventable harm to patients, which is a priority for health systems internationally, but longer-term studies of mentorship are necessary to determine the aspects of mentorship that are particularly important for enhancing patient safety outcomes.
Ecstasy Abuse and Its Effects on the Oral Mucosa
Authors: Biancardi Mariel Ruivo , Silveira Heitor Albergoni da , Fernandes Darcy , Almeida Luciana Yamamoto de , Ortega Rose Mara , León Jorge Esquiche , Bufalino Andreia
Published: March 2019

Ecstasy is an illicit drug that has been increasingly abused by young people. This synthetic drug has both stimulant and hallucinogenic effects and is usually consumed in a tablet. The side effects of ecstasy use include nausea, muscle cramping, fever, and symptoms mostly linked to muscular tension including jaw pain, facial pain, and headaches. There are few studies assessing the ecstasy effects on the oral mucosa, both clinically and histopathologically. The authors report 2 young women (22- and 27-year-old) who presented multifocal oral erosions and ulcerations. The lesions were painful and covered by a yellow-white pseudomembrane with a bright erythematous halo. By microscopy, it was observed superficial ulceration surrounded by acanthotic squamous epithelium with marked spongiosis, interstitial edema within the corion and perivascular lyphoid infiltrate, suggesting drug-induced oral mucositis. In conclusion, ecstasy use may be associated with the development of oral ulcers, which should be considered in the differential diagnosis when assessing multifocal oral ulcerations, especially in young people.
Filling in the Details: A Review of Lipofilling of Radiated Tissues in the Head and Neck
Authors: Hammond Sarah E. , Samuels Stuart , Thaller Seth
Published: March 2019

Adipose tissue is considered by many to be an ideal filler. Fat is the model filler in that it is biocompatible, autologous tissue which typically incorporates into the host tissue with minimal complications. Along with the increasing use of fat as a soft tissue filler has come a growing interest in the development of standardized technical protocols and indications for lipofiller use. In this review, we will examine the current literature regarding lipofilling techniques, explore the potential benefits of fat grafting in radiated tissue, and discuss recent scientific advancements to optimize fat graft survival and outcomes.
Risks of Postendoscopic Retrograde Cholangiopancreatography Pancreatitis and Hyperamylasemia After Endoscopic Papillary Balloon Dilation: A Retrospective Analysis
Authors: Liu Shan-Shan , Chang Xiao-Hua , Song Ji-Tao , Chen Jing , Wen Ji-Feng , Hu Ying , Huang Qian-qian , Guan Jing-ming , Xu Jun
Published: March 2019

It is currently unclear whether endoscopic papillary balloon dilation (EPBD) is associated with increased severe postendoscopic retrograde cholangiopancreatography pancreatitis (PEP)-related morbidity owing to conflicting reports. This study aimed to investigate whether EPBD increases the risk of PEP and hyperamylasemia. Clinical data of patients with choledocholithiasis, treated at the Second Affiliated Hospital of Harbin Medical University from January 2015 to December 2016 were analyzed. Patients were divided into the EPBD group and endoscopic sphincterotomy (EST)+EPBD group, and their characteristics and PEP and hyperamylasemia incidences were compared. Incidences related to dilated balloon diameter were also analyzed. There were no significant differences in patient characteristics and the incidences of PEP (2.6% vs. 0%; P=0.257) and hyperamylasemia (4.4% vs. 5.6%; P=0.954) between the 2 groups. Results were similar even with different balloon dilatations. EPBD without endoscopic sphincterotomy did not increase the risk of PEP and hyperamylasemia. It is a safe option for choledocholithiasis patients.
A comprehensive map of the dendritic cell transcriptional network engaged upon innate sensing of HIV
Authors: Johnson Jarrod S. , Veaux Nicholas De , Rives Alexander W. , Lahaye Xavier , Lucas Sasha Y. , Pérot Brieuc , Luka Marine , Amon Lynn M. , Watters Aaron , Aderem Alan , Manel Nicolas , Littman Dan R. , Bonneau Richard , Ménager Mickaël M.
Published: March 2019

Transcriptional programming of the innate immune response is pivotal for host protection. However, the transcriptional mechanisms that link pathogen sensing with innate activation remain poorly understood. During infection with HIV-1, human dendritic cells (DCs) can detect the virus through an innate sensing pathway leading to antiviral interferon and DC maturation. Here, we developed an iterative experimental and computational approach to map the innate response circuitry during HIV-1 infection. By integrating genome-wide chromatin accessibility with expression kinetics, we inferred a gene regulatory network that links 542 transcription factors with 21,862 target genes. We observed that an interferon response is required, yet insufficient to drive DC maturation, and identified PRDM1 and RARA as essential regulators of the interferon response and DC maturation, respectively. Our work provides a resource for interrogation of regulators of HIV replication and innate immunity, highlighting complexity and cooperativity in the regulatory circuit controlling the DC response to infection.

Graphical Abstract
Ultrasound Imaging of Gene Expression in Mammalian Cells
Authors: Farhadi Arash , Ho Gabrielle H. , Sawyer Daniel P. , Bourdeau Raymond W. , Shapiro Mikhail G.
Published: March 2019

The study of cellular processes occurring inside intact organisms and the development of cell-based diagnostic and therapeutic agents requires methods to visualize cellular functions such as gene expression in deep tissues. Ultrasound is a widely used biomedical technology enabling deep-tissue imaging with high spatial and temporal resolution. However, no genetically encoded molecular reporters are available to connect ultrasound contrast to gene expression in mammalian cells. To address this limitation, we introduce the first mammalian acoustic reporter genes. Starting with an eleven-gene polycistronic gene cluster derived from bacteria, we engineered a eukaryotic genetic program whose introduction into mammalian cells results in the expression of a unique class of intracellular air-filled protein nanostructures called gas vesicles. The scattering of ultrasound by these nanostructures allows mammalian cells to be visualized at volumetric densities below 0.5%, enables the monitoring of dynamic circuit-driven gene expression, and permits high-resolution imaging of gene expression in living animals. These mammalian acoustic reporter genes enable previously impossible approaches to monitoring the location, viability and function of mammalian cellsin vivo.
A simple model of a quadruped discovers single-foot walking and trotting as energy optimal strategies
Authors: Polet Delyle T. , Bertram John E. A.
Published: March 2019

It is widely held that quadrupeds choose steady gaits that minimize their energetic cost of transport, but it is difficult to explore the entire range of possible footfall sequences empirically. We present a simple model of a quadruped that can spontaneously produce any of the 2300+ planar footfall sequences available to quadrupeds. Through trajectory optimization of a work and force-rate cost, and a large sample of random initial guesses, we provide stronger evidence towards the global optimality of symmetrical four-beat walking at low speeds and two beat running (trotting) at intermediate speeds. Using input parameters based on measurements in dogs (Canis lupus familiaris), the model predicts the correct phase offset in walking and a realistic walk-trot transition speed. It also spontaneously reproduces the double-hump ground reaction force profile observed in walking, and the smooth single-hump profile observed in trotting, despite the model’s lack of springs. However, the model incorrectly predicts duty factor at the slowest speeds, and does not choose galloping as globally optimal at high speeds. These limitations might point to missing levels of complexity that could be added to future quadrupedal models, but the present results suggest that massive legs, elastic components, head-neck oscillations and even multi-linked legs are not critical determiners for the optimality of natural quadrupedal walking and trotting.

Author summary

Why do quadrupedal mammals move in consistent ways, when so many options are available? We tackled this problem by determining energetically-optimal gaits using a simple computational model of a four-legged animal. The model can use virtually any pattern of movement (physics-permitting!) but selects natural movement strategies as energetically optimal. The similarities between the computer-based predictions and natural animal movement are striking, and suggest mammals utilize movement strategies that optimize energy use when they move.
LNISKS: Reference-free mutation identification for large and complex crop genomes
Authors: Suchecki Radosław , Sandhu Ajay , Deschamps Stéphane , Llaca Victor , Wolters Petra , Watson-Haigh Nathan S. , Pallotta Margaret , Whitford Ryan , Baumann Ute
Published: March 2019

Mutation discovery is often key to the identification of genes responsible for major phenotypic traits. In the context of bulked segregant analysis, common reference-based computational approaches are not always suitable as they rely on a genome assembly which may be incomplete or highly divergent from the studied accession. Reference-free methods based on short sequences of lengthk(k-mers), such as NIKS, exploit redundancy of information across pools of recombinant genomes. Building on concepts from NIKS we introduce LNISKS, a mutation discovery method which is suited for large and repetitive crop genomes. In our experiments, it rapidly and with high confidence, identified mutations from over 700 Gbp of bread wheat genomic sequence data. LNISKS is publicly available athttps://github.com/rsuchecki/LNISKS.
T-cell activation is modulated by the 3D mechanical microenvironment
Authors: Majedi Fatemeh S. , Hasani-Sadrabadi Mohammad Mahdi , Thauland Timothy J. , Li Song , Bouchard Louis-S. , Butte Manish J.
Published: March 2019

T cells recognize mechanical forces through a variety of cellular pathways, including mechanical triggering of the T-cell receptor (TCR) and mechanical triggering of the integrin LFA-1. We show here that T cells can recognize forces arising from the rigidity of the microenvironment. We fabricated 3D hydrogels with mechanical stiffness tuned to 4 kPa and 40 kPa and specially engineered be microporous independent of stiffness. We cultured T cells and antigen presenting cells within the matrices and studied activation by flow cytometry and live imaging. We found there was an augmentation of T-cell activation in the context of mechanically stiffer 3D material as compared to the softer material. In contrast, proliferation, activation markers, and migration were all diminished in T cells cultured in the softer material. These results show that T cells can sense their mechanical environment and amplify responses in the context of mechanical stiffness.
Enhanced autophagic-lysosomal activity and increased BAG3-mediated selective macroautophagy as adaptive response of neuronal cells to chronic oxidative stress
Authors: Chakraborty Debapriya , Felzen Vanessa , Hiebel Christof , Stürner Elisabeth , Perumal Natarajan , Manicam Caroline , Sehn Elisabeth , Grus Franz , Wolfrum Uwe , Behl Christian
Published: March 2019

Oxidative stress and a disturbed cellular protein homeostasis (proteostasis) belong to the most important hallmarks of aging and of neurodegenerative disorders. The proteasomal and autophagic-lysosomal degradation pathways are key measures to maintain proteostasis. Here, we report that hippocampal cells selected for full adaptation and resistance to oxidative stress induced by hydrogen peroxide (oxidative stress-resistant cells, OxSR cells) showed a massive increase in the expression of components of the cellular autophagic-lysosomal network and a significantly higher overall autophagic activity. A comparative expression analysis revealed that distinct key regulators of autophagy are upregulated in OxSR cells. The observed adaptive autophagic response was found to be independent of the upstream autophagy regulator mTOR but is accompanied by a significant upregulation of further downstream components of the canonical autophagy network such as Beclin1, WIPI1 and the transmembrane ATG9 proteins. Interestingly, the expression of the HSP70 co-chaperone BAG3, mediator ofBAG3-mediated selective macroautophagyand highly relevant for the clearance of aggregated proteins in cells was found to be increased in OxSR cells that were consequently able to effectively overcome proteotoxic stress. Overexpression of BAG3 in oxidative stress-sensitive HT22 wildtype cells partly established the vesicular phenotype and the enhanced autophagic flux seen in OxSR cells suggesting that BAG3 takes over a key part in the adaptation process. A full proteome analysis demonstrated additional changes in the expression of mitochondrial proteins, metabolic enzymes and different pathway regulators in OxSR cells as consequence of the adaptation to oxidative stress in addition to autophagy-related proteins. Taken together, this analysis revealed a wide variety of pathways and players that act as adaptive response to chronic redox stress in neuronal cells.
Elimination of Egfr-Overexpressing Cancer Cells by CD32 Chimeric Receptor T Cells in Combination with Cetuximab or Panitumumab
Authors: Caratelli Sara , Arriga Roberto , Sconocchia Tommaso , Ottaviani Alessio , Lanzilli Giulia , Pastore Donatella , Cenciarelli Carlo , Venditti Adriano , Del Principe Maria Ilaria , Lauro Davide , Landoni Elisa , Du Hongwei , Savoldo Barbara , Ferrone Soldano , Dotti Gianpietro , Sconocchia Giuseppe
Published: March 2019

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). While the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects a poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on NK cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32) to a similar extent. Here, we have compared the ability of T cells, engineered with a novel low-affinity CD32131R-chimeric receptor (CR), and those engineered with the low-affinity CD16158F–CR T cells in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. Following T cell transduction, the percentage of CD32131R-CR T cells was (74±10) significantly higher than that of CD16158F-CR T cells (46±15). Only CD32131R-CR T cells bound panitumumab. CD32131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116FcγR+cells, in a reverse ADCC assayin vitro. Cross-linking of CD32131R-CR on T cells by cetuximab or panitumumab and CD16158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and secretion of IFN gamma (IFNγ) and tumor necrosis factor alpha (TNFα). Neither cetuximab nor panitumumab induced Fcγ-CR T anti-tumor activity against KRAS-mutated HCT116, non-small-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. ADCC of Fcγ-CR T cells was significantly associated with the over-expression of EGFR on ECCs. In conclusion, CD32131R-CR T cells are efficiently redirected by cetuximab or panitumumab against BC cells overexpressing EGFR.

Article category

Tumor Immunology and Microenvironment

Novelty and Impact

Monoclonal antibody-redirected Fcγ-CR T cell immunotherapy represents a promising approach in the fight against cancer. Here, we expand the application of this methodology to TNBC overexpressing the EGFR utilizing a novel CD32A131R-CR in combination with anti-EGFR mAbs. Our study supports the use of CD32A131R-CR T cells combined with panitumumab or cetuximab for targeting TNBC cells overexpressing the EGFR. Our results may be utilized as a platform for the rational design of therapies targeting TNBC overexpressing EGFR.
ROS accumulation and associated cell death mediates susceptibility to Alternaria brassicae in Arabidopsis accessions
Authors: Mandal Sayanti , Rajarammohan Sivasubramanian , Kaur Jagreet
Published: March 2019

Alternaria brassicae is a necrotrophic fungal pathogen capable of infecting most of the agriculturally important Brassica species. The mechanisms underlying invasion of A. brassicae and host responses are unknown. In the present study, we exploited the natural variation in Arabidopsis to understand the molecular and cellular mechanisms underlying resistance to A. brassicae. Using a subset of resistant (Ei-2, Ull2-3, Lz-0, and Cvi-0) and susceptible (Gre-0, Est-1, and Zdr1) accessions, we show that the susceptibility to A. brassicae is associated with higher ROS accumulation and cell death. Susceptibility to A. brassicae was reduced in the rboh (D, E and F) mutants that are incapable of producing ROS, suggesting that RBOH D, E and F may act as negative regulators of defence against this pathogen. Additionally, our data also supports the hypothesis that the Jasmonic acid (JA), Ethylene (ET) and Abscisic acid (ABA) signalling pathways positively contribute to resistance against necrotrophic pathogens. In summary, these results reveal the central role of ROS and cell death in the pathogenesis of A. brassicae and expand our understanding of plant-necrotroph interactions.
Labour sharing promotes coexistence in atrazine degrading bacterial communities
Authors: Billet Loren , Devers Marion , Rouard Nadine , Martin-Laurent Fabrice , Spor Aymé
Published: March 2019

Microbial communities exert a pivotal role in the biodegradation of xenobiotics including pesticides1. In the case of atrazine, multiple studies have shown that its degradation involved a consortia rather than a single species2,3,4,5, but little is known about how interdependency between the species composing the consortium is set up. The Black Queen Hypothesis (BQH) formalized theoretically the conditions leading to the evolution of dependency between species6: members of the community called ‘helpers’ provide publicly common goods obtained from the costly degradation of a compound, while others called ‘beneficiaries’ take advantage of the public goods, but lose access to the primary resource through adaptive degrading gene loss. Here, we test whether liquid media supplemented with the herbicide atrazine could support coexistence of bacterial species through BQH mechanisms. We observed the establishment of dependencies between species through atrazine degrading gene loss. Labour sharing between members of the consortium led to coexistence of multiple species on a single resource and improved atrazine degradation potential. Until now, pesticide degradation has not been approached from an evolutionary perspective under the BQH framework. We provide here an evolutionary explanation that might invite researchers to consider microbial consortia, rather than single isolated species, as an optimal strategy for isolation of xenobiotics degraders. Also, we anticipate that future research should focus on the bioaugmentation with stabilized and tightly structured microbial degrading consortia as an effective solution forin situbioremediation of sites polluted with recalcitrant compounds.
Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1
Authors: Tricaud Nicolas , Gautier Benoit , Van Hameren Gerben , Berthelot Jade , Gonzalez Sergio , Chrast Roman
Published: March 2019

The maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.
Insight into the genetic aetiology of retinal detachment by combining small clinical and large population-based datasets
Authors: Boutin Thibaud S. , Charteris David G. , Chandra Aman , Campbell Susan , Hayward Caroline , Campbell Archie ,   UK Biobank Eye & Vision Consortium, Nandakumar Priyanka , Hinds David ,   23andMe Research Team, Mitry Danny , Vitart Veronique
Published: March 2019

Idiopathic retinal detachment is a serious common condition, but genetic studies to date have been hampered by the small size of the assembled cohorts. Genetic correlations between retinal detachment and high myopia or cataract operation were high, respectively 0.46 (SE=0.08) and 0.44 (SE=0.07), in the UK Biobank dataset and in line with known epidemiological associations. Meta-analysis of genome-wide association studies using UK Biobank retinal detachment cases (N=3977) and two cohorts, each comprising ∼1000 rhegmatogenous retinal detachment patients, uncovered 11 genome-wide significant association signals, near or withinZC3H11B, BMP3, COL22A1, DLG5, PLCE1, EFEMP2, TYR, FAT3, TRIM29, COL2A1andLOXL1.Replication in the 23andMe dataset, where retinal detachment is self-reported by participants, firmly establishes association at six lociFAT3, COL22A1, TYR, BMP3, ZC3H11BandPLCE1.The former two seem to particularly impact on retinal detachment, the latter three shed light on shared aetiologies with cataract, myopia and glaucoma.

Author Summary

Retinal detachments are common conditions that may lead to permanent severe sight reduction or blindness; they are a major cause of emergency eye surgery. The most common type of retinal detachment follows a break in the retina and is thought to be in part genetically determined but little is known about the contributing individual genetic risk variants. The condition prevalence increases with age and with common eye conditions such as myopia, cataract or glaucoma. We showed that the retinal detachment cases derived from self-report or hospitalisation records in the large UK Biobank dataset show very similar characteristics to samples of carefully clinically evaluated retinal detachment with break cases and therefore could be used to perform genetic analysis of the condition. Association studies require large sample of cases and by pooling Biobank and clinical cases, this study identifies 11 novel significant associations, six of which were further replicated in an independent population-based dataset (23andMe). Two of the replicated findings seem to specifically underline retinal detachment risk while three others highlight shared genetic risk with myopia, cataract and/or glaucoma, paving the way to better understanding of these conditions and of their overlap.
DNA methylation, microRNA expression profiles and their relationships with transcriptome in grass-fed and grain-fed Angus Cattle rumen tissue
Authors: Li Yaokun , Carrillo José A. , Ding Yi , He Yanghua , Zhao Chunping , Liu Jianan , Zan Linsen , Song Jiuzhou
Published: March 2019

Rumen is a critical organ for supplying nutrients for the growth and production of bovine, which might function differently under grass-fed and grain-fed regimens considering the association of gene expression, DNA methylation, and microRNA expression. The objective of this study was to explore the potential mechanism influencing rumen function of grass-fed and grain-fed animals. Methylated DNA binding domain sequencing (MBD-Seq) and microRNA-Seq were respectively utilized to detect the DNA methylation and microRNA expression in rumen tissue of grass-fed and grain-fed Angus cattle. Integration analysis revealed that the expression of the differentially expressed genes ADAMTS3 and ENPP3 was correlated with the methylation abundance of the corresponding DMRs inside these two genes, and these two genes were reported to be respectively involved in biosynthesis and regulation of glycosyltransferase activity; the differentially expressed microRNA bta-mir-122 was predicted to possibly target the differentially expressed genes OCLN and RBM47, potentially affecting the rumen function; the microRNA bta-mir-655 was exclusively detected in grain-fed group; its targets were involved in the significantly enriched insulin and TGF-beta signaling pathways, which might worked together to regulate the function of rumen, resulting in different characteristics between grass-fed and grain-fed cattle. Collectively, our results provided insights into understanding the mechanisms determining rumen function and unraveled the biological basis underlying the economic traits to improve the productivity of animals.