bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative Effectiveness of Low-Volume Time-Efficient Resistance Training Versus Endurance Training in Patients With Heart Failure
Authors: Munch Gregers Winding , Rosenmeier Jaya Birgitte , Petersen Morten , Rinnov Anders Rasmussen , Iepsen Ulrik Winning , Pedersen Bente Klarlund , Mortensen Stefan Peter
Published: January 2018

Purpose:

Cardiorespiratory fitness is positively related to heart failure (HF) prognosis, but lack of time and low energy are barriers for adherence to exercise. We, therefore, compared the effect of low-volume time-based resistance exercise training (TRE) with aerobic moderate-intensity cycling (AMC) on maximal and submaximal exercise capacity, health-related quality of life, and vascular function.

Methods:

Twenty-eight HF patients (New York Heart Association class I-II) performed AMC (n = 14) or TRE (n = 14). Maximal and submaximal exercise capacity, health-related quality of life, and vascular function were evaluated before and after a 6-wk training intervention with 3 training sessions per week. The AMC group and the TRE group trained for 45 and 25 min per training session, respectively. During the training sessions, the TRE and AMC groups trained at 60 ± 4% and 59 ± 2% (mean ± standard deviation) of

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o
2peak, respectively.

Results:

The energy expenditure was significantly greater in AMC than in TRE (P < .05). The

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o
2peak and Wattpeak increased in AMC group (P < .001) and TRE group (P = .001), with no differences between groups. Six-minute walk distance also increased in both groups (AMC, P = .006 and TRE, P = .036), with no difference between groups. Health-related quality of life improved equally in the 2 groups, whereas vascular function did not change in either group.

Conclusion:

These results demonstrate that AMC and TRE equally improved exercise capacity and health-related quality of life in lower New York Heart Association–stage HF patients, despite less time required as well as lower energy expenditure during TRE than during AMC. Therefore, TRE might represent a time-efficient exercise modality for improving adherence to exercise in patients with class I-II HF.
Sexual and reproductive issues and inflammatory bowel disease: a neglected topic in men
Authors: Allocca Mariangela , Gilardi Daniela , Fiorino Gionata , Furfaro Federica , Peyrin-Biroulet Laurent , Danese Silvio
Published: January 2018

There has been considerable literature on sexual issues in women with inflammatory bowel disease (IBD), but relatively little attention has been paid to these aspects in men. To review the available literature and to provide the best management of sexual and reproductive issues in male patients with IBD. The scientific literature on sexual and reproductive issues in men with IBD was reviewed. Several factors, including surgical and medication treatments, disease activity, lifestyle, and psychological factors, may play a role in the development of infertility and sexual dysfunction and may negatively impact pregnancy outcomes. Proctocolectomy with ileal pouch-anal anastomosis increases the risk of erectile and ejaculatory dysfunction by up to 26%. A treatment with sildenafil can be effective. Sperm banking should be advised to young men with IBD before surgery. Both sulfasalazine and methotrexate may be responsible for reversible sexual dysfunction and infertility. Furthermore, sulfasalazine should be switched to mesalazine at least 4 months before conception because of a higher risk of congenital malformations in pregnancies fathered by men treated with this drug. Psychotropic drugs, frequently used in IBD, may cause sexual dysfunction up to 80%. Last but not the least, voluntary childlessness occurs frequently, mainly because of concerns about medication safety in pregnancy and fear of transmitting disease. Accurate counseling, and where necessary, psychological support can decrease any misperceptions and fears. Close collaboration between the gastroenterologist and the patient is recommended for the best management of these relevant, neglected aspects in men with IBD.
Challenges and Perspectives for Immunotherapy in Adenocarcinoma of the Pancreas
Authors: Kieler Markus , Unseld Matthias , Bianconi Daniela , Prager Gerald
Published: January 2018

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a devastating 5-year overall survival of only approximately 7%. Although just 4% of all malignant diseases are accounted to PDAC, it will become the second leading cause of cancer-related deaths before 2030. Immunotherapy has proven to be a promising therapeutic option in various malignancies such as melanoma, non–small cell lung cancer (NSCLC), microsatellite instability-high gastrointestinal cancer, urinary tract cancer, kidney cancer, and others. In this review, we summarize recent findings about immunological aspects of PDAC with the focus on the proposed model of the “cancer immunity cycle”. By this model, a deeper understanding of the underlying mechanism in achieving a T-cell response against cancer cells is provided. There is currently great interest in the field around designing novel immunotherapy combination studies for PDAC based on a sound understanding of the underlying immunobiology.
Pathological and Molecular Aspects to Improve Endoscopic Ultrasonography–Guided Fine-Needle Aspiration From Solid Pancreatic Lesions
Authors: Matsubayashi Hiroyuki , Sasaki Keiko , Ono Sachiyo , Abe Masato , Ishiwatari Hirotoshi , Fukutomi Akira , Uesaka Katsuhiko , Ono Hiroyuki
Published: January 2018

Endoscopic ultrasonography–guided fine-needle aspiration (EUS-FNA) has been applied to pancreatic lesions since the 1990s, and its use is now widespread. Improvements in endoscopic devices and sampling techniques have resulted in excellent diagnostic ability for solid pancreatic lesions. However, clinical improvements alone are not responsible for it; pathological aspects have also played important roles. Rapid on-site evaluation minimizes endoscopic procedures, although its value at improving the diagnostic ratio is still debated. Diagnostic efficacy differs by sample preparations (direct smear, cytospin, liquid-based cytology, cell block, and biopsy) and by staining methods (Papanicoloau, Diff-Quik, hematoxylin-eosin, and Giemsa). Several immunocytochemistry protocols aid in diagnosing epithelial components with cytological atypia and in differentiating various tumor types. One cytopathology diagnostic system is telecytology, which uses transmitted digital images and enables real-time diagnosis of EUS-FNA samples by expert cytologists at remote locations. However, EUS-FNA samples are useful for more than just diagnoses, as molecular analysis of these samples allows the identification of prognostic markers, such as genetic alterations in K-ras and EGFR. Expression of drug-metabolizing enzymes, human equilibrative nucleoside transporter 1, correlates with the response to gemcitabine-based chemotherapy. These pathology efforts have enhanced the diagnostic efficacy of EUS-FNA, thereby leading to better outcomes for patients with pancreatic diseases.
Self-Esteem and Anger in Borderline Patients With Self-Injury Behavior
Authors: Almeida Carla Maria , Horta Maria Purificação
Published: January 2018

Anger and low self-esteem characterize borderline individuals, yet little is known about their role and impact in the presence or absence of self-injury behavior. The present study aimed to investigate the impact of anger and self-esteem in borderline patients and whether these variables distinguish these patients with and without self-injury. Patients were recruited from a psychiatric service and were evaluated for self-esteem and anger. Additionally, impulsivity and symptoms were assessed. Two groups were compared, one with self-injurious behavior (n = 18) and another one without it (n = 23). Those who injure themselves seem to have a lower self-esteem (p < 0.001), yet the strengthening of self-esteem seems to have different outcomes, according to the presence or absence of self-injury. Anger and self-esteem seem to influence the severity of diagnosis, but only in patients who self-injure. Anger and self-esteem may influence borderline patients differently according to the presence or absence of self-injury.
Guidance Provided to Authors on Citing and Formatting References in Nursing Journals
Authors: Nicoll Leslie H. , Oermann Marilyn H. , Chinn Peggy L. , Conklin Jamie L. , Amarasekara Sathya , McCarty Midori
Published: January 2018

Reference citations should be accurate, complete, and presented in a consistent format. This study analyzed information provided to authors on preparing citations and references for manuscripts submitted to nursing journals (n = 209). Half of the journals used the American Psychological Association reference style. Slightly more than half provided examples of how to cite articles and books; there were fewer examples of citing websites and online journals. Suggestions on improving accuracy of references are discussed.
Development of a PD-L1 Complementary Diagnostic Immunohistochemistry Assay (SP142) for Atezolizumab
Authors: Vennapusa Bharathi , Baker Brian , Kowanetz Marcin , Boone Jennifer , Menzl Ina , Bruey Jean-Marie , Fine Gregg , Mariathasan Sanjeev , McCaffery Ian , Mocci Simonetta , Rost Sandra , Smith Dustin , Dennis Eslie , Tang Szu-Yu , Damadzadeh Bita , Walker Espen , Hegde Priti S. , Williams J. Andrew , Koeppen Hartmut , Boyd Zachary
Published: January 2018

Cancer immunotherapies, such as atezolizumab, are proving to be a valuable therapeutic strategy across indications, including non–small cell lung cancer (NSCLC) and urothelial cancer (UC). Here, we describe a diagnostic assay that measures programmed-death ligand 1 (PD-L1) expression, via immunohistochemistry, to identify patients who will derive the most benefit from treatment with atezolizumab, a humanized monoclonal anti-PD-L1 antibody. We describe the performance of the VENTANA PD-L1 (SP142) Assay in terms of specificity, sensitivity, and the ability to stain both tumor cells (TC) and tumor-infiltrating immune cells (IC), in NSCLC and UC tissues. The reader precision, repeatability and intermediate precision, interlaboratory reproducibility, and the effectiveness of pathologist training on the assessment of PD-L1 staining on both TC and IC were evaluated. We detail the analytical validation of the VENTANA PD-L1 (SP142) Assay for PD-L1 expression in NSCLC and UC tissues and show that the assay reliably evaluated staining on both TC and IC across multiple expression levels/clinical cut-offs. The reader precision showed high overall agreement when compared with consensus scores. In addition, pathologists met the predefined training criteria (≥85.0% overall percent agreement) for the assessment of PD-L1 expression in NSCLC and UC tissues with an average overall percent agreement ≥95.0%. The assay evaluates PD-L1 staining on both cell types and is robust and precise. In addition, it can help to identify those patients who may benefit the most from treatment with atezolizumab, although treatment benefit has been demonstrated in an all-comer NSCLC and UC patient population.
Chronic Hematoma of the Neck
Authors: Angster Kristen H. , Da Costa Victor
Published: January 2018

Chronic hematomas are defined as hematomas with slow, progressive growth over many weeks. They are an extremely rare cause of acute neck swelling in the pediatric population. They consist of an organized central mass of blood with granulation tissue and fibrotic changes peripherally. The presence of a capsule prevents resorption but allows for intracapsular bleeding with subsequent expansion. We describe a case of a 6-year-old girl who presented to the emergency department with a spontaneously occurring left neck mass in the supraclavicular region. A possible neoplasm was suggested on imaging. The patient was referred to a head and neck surgeon, she underwent a thorough workup, and the mass was ultimately surgically excised. Histologically, the mass was confirmed to be a chronic hematoma. The patient recovered uneventfully, and there has been no recurrence.
Association Between Altered Hip Extension and Kinetic Gait Variables
Authors: Wonsetler Elizabeth C. , Miller Ellie L. , Huey Katherine L. , Frye Sarah E. , Bowden Mark G.
Published: January 2018

Kinematic and kinetic outcome measures are tightly linked in walking. Although altering motor output is a major goal of gait rehabilitation, little is understood regarding the relationship between altering a single kinematic variable and kinetic outcome changes. We designed a strategy to isolate hip extension alterations during walking on a treadmill to assess the change in kinetic outcomes. Ten healthy individuals walked on an instrumented split-belt treadmill with motion capture to calculate hip extension and kinetic outcomes at the following five different randomized cadences: self-selected cadence, self-selected ± 10%, and self-selected ± 20%. The treadmill speed was held constant at the individual's self-selected walking speed, forcing cadence changes to result in successful alterations to hip extension, varying 8.3 degrees from the self-selected −20% to +20% cadence conditions. Kinetic outcomes demonstrated similar alterations. Hip extension changes at each cadence significantly correlated with kinetic changes in propulsive impulse (r = 0.852, P < 0.001), peak ankle power (r = 0.473, P = 0.002), and ankle plantarflexion work (r = 0.762, P < 0.001). These results demonstrate that kinetic outcomes are highly alterable in response to a kinematic gait change. This clinically relevant finding highlights the potential to improve motor output in individuals during rehabilitation by altering gait patterns to achieve more optimal limb positions.
Brief Report: Higher ART Adherence Is Associated With Lower Systemic Inflammation in Treatment-Naive Ugandans Who Achieve Virologic Suppression
Authors: Castillo-Mancilla Jose R. , Morrow Mary , Boum Yap , Byakwaga Helen , Haberer Jessica E. , Martin Jeffrey N. , Bangsberg David , Mawhinney Samantha , Musinguzi Nicholas , Huang Yong , Tracy Russell P. , Burdo Tricia H. , Williams Kenneth , Muzzora Conrad , Hunt Peter W. , Siedner Mark J.
Published: January 2018

Background:

Residual systemic inflammation persists despite suppressive antiretroviral therapy (ART) and is associated with non-AIDS clinical outcomes. We aimed to evaluate the association between ART adherence and inflammation in Ugandans living with HIV who were predominantly receiving nevirapine-based ART with a thymidine analog backbone and were virologically suppressed by conventional assays.

Methods:

Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble (s)CD14, sCD163, and the kynurenine/tryptophan ratio, in addition to CD8+ T-cell activation, were measured at baseline and 6 months after ART initiation in treatment-naive adults who achieved an undetectable plasma HIV RNA (<400 copies/mL) at their 6-month visit. Adherence was measured through medication event monitoring system and calculated as the ratio of observed/prescribed device openings per participant. We fit adjusted linear regression models to estimate the association between ART adherence and the log-transformed plasma concentrations of inflammatory biomarkers.

Results:

We evaluated 282 participants (median age, 35 years; 70% women). The median (interquartile range) adherence was 93% (84–98). In the adjusted analyses, for every 10% increase in average ART adherence, we found a 15% [P < 0.0001; 95% confidence interval (CI), −21.0 to −7.9], 11% (P = 0.017; 95% CI, −18.3 to −2.0), and 3% (P = 0.028; 95% CI, −5.0 to −0.3) decrease in IL-6, D-dimer, and sCD14, respectively.

Conclusions:

Higher ART adherence was associated with lower levels of biomarkers of inflammation, immune activation, and coagulopathy among Ugandans living with HIV who achieved viral suppression shortly after ART initiation. This suggests that ART adherence could have biological consequences beyond viral suppression. Whether ART adherence optimization in virologically suppressed individuals could reduce residual inflammation remains unknown.
Mycobacterium avium complex pulmonary disease: new epidemiology and management concepts
Authors: Lande Leah , George Jason , Plush Theodore
Published: January 2018

Purpose of review

The prevalence of Mycobacterium avium complex (MAC)-related pulmonary disease has been increasing because of environmental factors, changes in organism virulence, and evolving host susceptibility. Treatment is often complicated by adverse effects, development of drug resistance, and refractory disease, with recurrence rates as high as 25–45%.

Recent findings

Aerosolization of water, soil, or dusts are the likely sources of MAC-related pulmonary disease in susceptible individuals. The management of MAC-related pulmonary disease requires a multimodality approach, including antimicrobial therapy in appropriate patients, employment of mucus clearance techniques, instituting changes in the individual's home environment and personal habits to reduce environmental exposure to MAC, prevention of reflux, and maintenance of a healthy body weight. When the standard treatment for MAC-related pulmonary disease is not possible because of drug intolerance, antibiotic resistance, or progression of disease, second-line agents such as inhaled amikacin, clofazimine, bedaquiline, and delamanid must be considered, despite limited experience and few studies to guide their use.

Individuals who have proven to be susceptible to MAC-related pulmonary disease should institute measures to reduce exposure to environmental sources of infection. Further research is needed to assess the impact of such preventive strategies on the incidence of new infection and disease recurrence. The efficacy of new medications for MAC-related pulmonary disease and their use in different combinations also requires further study.
The role of tedizolid in skin and soft tissue infections
Authors: Bouza Emilio , Muñoz Patricia , Burillo Almudena
Published: January 2018

Purpose of review

Tedizolid is a second-generation oxazolidinone with activity against Gram-positive bacteria, including MRSA isolates resistant to linezolid. Pivotal clinical trials showed that tedizolid at 200 mg once-daily for 6 days is not inferior to linezolid 600 mg twice daily for 10 days in patients with SSTI. The comparison of adverse events is favorable to tedizolid under the circumstances of the clinical trials. This is a review of recent literature on tedizolid, its use in special populations and potential adverse effects.

Recent findings

Findings suggest that tedizolid can be used in SSTI in adolescents, those older than 65 years, obese individuals and patients with diabetic foot infections. Forthcoming research to determine the future uses of this drug in other clinical syndromes requires demonstration of tolerance whenever tedizolid is administered for longer than 6 days.

We also speculate on missing data and potential future indications of tedizolid in the highly competitive field of the treatment of severe Gram-positive infections other than SSTI.

Tedizolid is a second-generation oxazolidinone, very convenient for treatment of SSTI, in search for other indications including nosocomial pneumonia and bone and joint infections.

Video abstract

http://links.lww.com/COID/A22
A Validation Argument for a Simulation-Based Training Course Centered on Assessment, Recognition, and Early Management of Pediatric Sepsis
Authors: Geis Gary L. , Wheeler Derek S. , Bunger Amy , Militello Laura G. , Taylor Regina G. , Bauer Jerome P. , Byczkowski Terri L. , Kerrey Benjamin T. , Patterson Mary D.
Published: January 2018

Introduction

Early recognition of sepsis remains one of the greatest challenges in medicine. Novice clinicians are often responsible for the recognition of sepsis and the initiation of urgent management. The aim of this study was to create a validity argument for the use of a simulation-based training course centered on assessment, recognition, and early management of sepsis in a laboratory-based setting.

Methods

Five unique simulation scenarios were developed integrating critical sepsis cues identified through qualitative interviewing. Scenarios were piloted with groups of novice, intermediate, and expert pediatric physicians. The primary outcome was physician recognition of sepsis, measured with an adapted situation awareness global assessment tool. Secondary outcomes were physician compliance with pediatric advanced life support (PALS) guidelines and early sepsis management (ESM) recommendations, measured by two internally derived tools. Analysis compared recognition of sepsis by levels of expertise and measured association of sepsis recognition with the secondary outcomes.

Results

Eighteen physicians were recruited, six per study group. Each physician completed three sepsis simulations. Sepsis was recognized in 19 (35%) of 54 simulations. The odds that experts recognized sepsis was 2.6 [95% confidence interval (CI) = 0.5–13.8] times greater than novices. Adjusted for severity, for every point increase in the PALS global performance score, the odds that sepsis was recognized increased by 11.3 (95% CI = 3.1–41.4). Similarly, the odds ratio for the PALS checklist score was 1.5 (95% CI = 0.8–2.6). Adjusted for severity and level of expertise, the odds of recognizing sepsis was associated with an increase in the ESM checklist score of 1.8 (95% CI = 0.9–3.6) and an increase in ESM global performance score of 4.1 (95% CI = 1.7–10.0).

Conclusions

Although incomplete, evidence from initial testing suggests that the simulations of pediatric sepsis were sufficiently valid to justify their use in training novice pediatric physicians in the assessment, recognition, and management of pediatric sepsis.
Preparing Physiotherapy Students for Clinical Placement
Authors: Dalwood Narelle , Maloney Stephen , Cox Narelle , Morgan Prue
Published: January 2018

Introduction

Simulation is increasingly used in health care education, yet the organizational and financial costs can be prohibitive. This study aimed to investigate whether peer simulation is perceived by third-year undergraduate physiotherapy students as valuable for clinical placement preparation.

Methods

Third-year undergraduate physiotherapy students participated in a 9-week peer simulation program, using each other as patients, and were invited to complete two surveys evaluating perceptions of the program. The program consisted of weekly patient interactions during which students were required to assess and treat a “patient” under strict simulation guidelines and in accordance with stated learning objectives. Items rated included self-perceived skills, confidence, time management, and clinical placement readiness and included collection of qualitative responses. Surveys were released at commencement and completion of the simulation program.

Results

Of 79 third-year students, 63% completed survey 1 and 66% completed survey 2. Students had high expectations of the program and these were consistently met. Peer simulation rated highly for all items, including identifying knowledge and skill deficits, and improving confidence, clinical reasoning, time management, and communication. Simulation was considered safe, supportive, engaging, and valuable for clinical placement preparation. Students identified some lack of authenticity when working with peers.

Conclusions

Peer simulation was perceived by students as valuable in preparing them for clinical placement, despite a perceived lack of realism. These findings support the use of peer simulation as an alternative to the use of more formalized standardized patients in an undergraduate physiotherapy program. Further investigation is required to establish a detailed cost analysis of the program and to determine the amount of realism required to optimize the benefits of this promising educational strategy.
Validating Lung Models Using the ASL 5000 Breathing Simulator
Authors: Dexter Amanda , McNinch Neil , Kaznoch Destiny , Volsko Teresa A.
Published: January 2018

Objective

This study sought to validate pediatric models with normal and altered pulmonary mechanics.

Methods

PubMed and CINAHL databases were searched for studies directly measuring pulmonary mechanics of healthy infants and children, infants with severe bronchopulmonary dysplasia and neuromuscular disease. The ASL 5000 was used to construct models using tidal volume (V
T), inspiratory time (T
I), respiratory rate, resistance, compliance, and esophageal pressure gleaned from literature. Data were collected for a 1-minute period and repeated three times for each model. t tests compared modeled data with data abstracted from the literature. Repeated measures analyses evaluated model performance over multiple iterations. Statistical significance was established at a P value of less than 0.05.

Results

Maximum differences of means (experimental iteration mean − clinical standard mean) for T
I and V
T are the following: term infant without lung disease (T
I = 0.09 s, V
T = 0.29 mL), severe bronchopulmonary dysplasia (T
I = 0.08 s, V
T = 0.17 mL), child without lung disease (T
I = 0.10 s, V
T = 0.17 mL), and child with neuromuscular disease (T
I = 0.09 s, V
T = 0.57 mL). One-sample testing demonstrated statistically significant differences between clinical controls and V
T and T
I values produced by the ASL 5000 for each iteration and model (P < 0.01). The greatest magnitude of differences was negligible (V
T < 1.6%, T
I = 18%) and not clinically relevant.

Conclusions

Inconsistencies occurred with the models constructed on the ASL 5000. It was deemed accurate for the study purposes. It is therefore essential to test models and evaluate magnitude of differences before use.
Deep learning with EEG spectrograms in rapid eye movement behavior disorder
Authors: Ruffini Giulio , Ibañez David , Castellano Marta , Dubreuil Laura , Gagnon Jean-François , Montplaisir Jacques , Soria-Frisch Aureli
Published: January 2018

REM Behavior Disorder (RBD) is now recognized as the prodromal stage of α-synucleinopathies such as Parkinson’s disease (PD). In this paper, we describe deep learning models for diagnosis/prognosis derived from a few minutes of eyes-closed resting electroencephalography data (EEG) collected from idiopathic RBD patients (n=121) and healthy controls (HC, n=91). A few years after the EEG acquisition (4 ± 2 years), a subset of the RBD patients eventually developed either PD (n=14) or Dementia with Lewy bodies (DLB, n=13), while the rest remained idiopathic. We describe first a simple convolutional neural network (DCNN) with a five-layer architecture combining filtering and pooling, which we train using stacked multi-channel EEG spectrograms. We treat the data as in audio or image classification problems where deep networks have proven highly successful by exploiting compositional and translationally invariant features in the data. For comparison, we study an even simpler deep recurrent neural network using three stacked Long Short Term Memory network (LSTM) cells or gated-recurrent unit (GRU) cells—with very similar results. The performance of these networks typically reaches 80% (±1%) classification accuracy in the balanced HC vs. PD-outcome classification problem. In particular, using data from a single EEG channel we obtain an area under the curve (AUC) of 87% (±1%) while avoiding spectral feature selection. The trained classifier can also be used to generate synthetic spectrograms to study what spectrogram features are relevant for classification, pointing to the presence of theta band bursts and a decrease of power in the alpha band in future PD or DLB patients compared to HCs. We conclude that deep networks may provide a key tool for the analysis of EEG dynamics even from relatively small datasets and enable the delivery of new biomarkers.
A structural mechanism for directing inverse agonism of PPARγ
Authors: Brust Richard , Shang Jinsai , Fuhrmann Jakob , Bass Jared , Cano Andrew , Heidari Zahra , Chrisman Ian M. , Blayo Anne-Laure , Griffin R. Patrick , Kamenecka Theodore M. , Hughes Travis S. , Kojetin Douglas
Published: January 2018

Small chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms can be difficult to predict from static crystal structures alone. Here we show how a simple phenyl-to-pyridyl substitution between two common covalent orthosteric ligands targeting peroxisome proliferator-activated receptor gamma (PPARγ) converts a transcriptionally neutral antagonist (GW9662) into an inverse agonist (T0070907). X-ray crystallography, molecular dynamics simulations, and mutagenesis coupled to activity assays reveal a water-mediated hydrogen bond network linking the T0070907 pyridyl group to Arg288 that is essential for inverse agonism. NMR spectroscopy reveals that PPARγ exchanges between two long-lived conformations when bound to T0070907 but not GW9662, including a conformation that prepopulates a corepressor-bound state, priming PPARγ for high affinity corepressor binding. Our findings demonstrate that ligand engagement of Arg288 may provide new routes for developing PPARγ inverse agonist.
PDE5 inhibition improves symptom-free survival and restores transverse tubule loss and catecholamine responsiveness in heart failure
Authors: Lawless Michael , Caldwell Jessica L. , Smith Charlotte E.R. , Radcliffe Emma J. , Madders George W.P. , Hutchings David C. , Woods Lori S. , Church Stephanie J. , Unwin Richard D. , Kirkwood Graeme J. , Becker Lorenz K. , Pearman Charles M. , Taylor Rebecca F. , Eisner David A. , Dibb Katharine M. , Trafford Andrew. W
Published: January 2018

Heart failure is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for heart failure are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of advanced heart failure, we show that tadalafil treatment results in a marked improvement in symptom-free survival, reverses transverse tubule loss and restore cardiac myocyte systolic calcium transient amplitude and the hearts chronotropic and contractile response to catecholamines. These effects are independent of changes in myocardial cGMP content and are associated with upregulation of both monomeric and dimerized forms of protein kinase G and of the cGMP hydrolyzing phosphodiesterase 2 and 3. We propose that the molecular switch for the loss of transverse tubules in heart failure and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1) and the restoration of catecholamine sensitivity is through reductions in G-protein receptor kinase 2, protein phosphatase 1 and protein phosphatase 2A abundance following phosphodiesterase 5 inhibition.
Dynamic action of the Sec machinery during initiation, protein translocation and termination revealed by single molecule fluorescence
Authors: Fessl Tomas , Watkins Daniel , Oatley Peter , Allen William J. , Corey Robin A. , Horne Jim E. , Baldwin Steve A. , Radford Sheena E. , Collinson Ian , Tuma Roman
Published: January 2018

Protein translocation across cell membranes is a ubiquitous process required for protein secretion and membrane protein insertion. This is mediated, for the majority of proteins, by the highly conserved Sec machinery. The bacterial translocon – SecYMKEG – resides in the plasma membrane, where translocation is driven through rounds of ATP hydrolysis by the cytoplasmic SecA ATPase, and the proton motive force (PMF). We have used single molecule Förster resonance energy transfer (FRET) alongside a combination of confocal and total internal reflection microscopy to gain access to SecY pore dynamics and translocation kinetics on timescales spanning milliseconds to minutes. This allows us to dissect and characterise the translocation process in unprecedented detail. We show that SecA, signal sequence, pre-protein and ATP hydrolysis each have important and specific roles in unlocking and opening the Sec channel, priming it for transport. After channel opening, translocation proceeds in two phases: an initiation phase independent of substrate length, and a length-dependent transport phase with an intrinsic translocation rate of ~ 40 amino acids per second for the model pre-protein substrate proOmpA. The initiation and translocation phases are both coupled to ATP hydrolysis while termination is ATP-independent. Distributions of translocation rates reflect the stochastic nature of the translocation process and are consistent with the recently proposed Brownian ratchet model [Allenet al.doi: 10.7554/eLife.15598]. The results allow us unparalleled access to the kinetics of the complex reaction and provide a framework for understanding the molecular mechanism of protein secretion.
Loss of Trem2 in microglia leads to widespread disruption of cell co-expression networks in mouse brain
Authors: Carbajosa Guillermo , Malki Karim , Lawless Nathan , Wang Hong , Ryder John W. , Wozniak Eva , Wood Kristie , Mein Charles A. , Dobson Richard J.B. , Collier David A. , O’Neill Michael J. , Hodges Angela K. , Newhouse Stephen J.
Published: January 2018

Rare heterozygous coding variants in the Triggering Receptor Expressed in Myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months. Using brain cell type markers and ontology enrichment, we found subnetworks with cell type and/or functional identity. We primarily discovered changes in an endothelial-gene enriched subnetwork at 4 months, including a shift towards a more central role for the Amyloid Precursor Protein (App) gene, coupled with widespread disruption of other cell-type subnetworks, including a subnetwork with neuronal identity. We reveal an unexpected potential role of Trem2 in the homeostasis of endothelial cells that goes beyond its known functions as a microglial receptor and signalling hub, suggesting an underlying link between immune response and vascular disease in dementia.
Enhanced photon collection enables four dimensional fluorescence nanoscopy of living systems
Authors: Masullo Luciano A. , Bodén Andreas , Pennacchietti Francesca , Coceano Giovanna , Ratz Michael , Testa Ilaria
Published: January 2018

The theoretically unlimited spatial resolution of fluorescence nanoscopy often comes at the expense of time, contrast and increased dose of energy for recording. Here, we developed MoNaLISA, for Molecular Nanoscale Live Imaging with Sectioning Ability, a nanoscope capable of imaging structures at a scale of 45–65 nm within the entire cell volume at low light intensities (W–kW/cm2). Our approach, based on reversibly switchable fluorescent proteins, features three distinctly modulated illumination patterns crafted and combined in a novel way to gain fluorescence ON-OFF switching cycles and image contrast. By maximizing the detected photon flux MoNaLISA enables prolonged (40–50 frames) and large (50 x 50 μm2) recordings at 0.3–1.3 Hz with enhanced optical sectioning ability. We demonstrated the general use of our approach by 4D imaging of organelles and fine structures in epithelial human cells, colonies of mouse embryonic stem cells, brain cells, and organotypic tissues.
A novel system for online fertility monitoring based on milk progesterone
Authors: Adriaens Ines , Saeys Wouter , Huybrechts Tjebbe , Lamberigts Chris , François Liesbeth , Geerinckx Katleen , Leroy Jo , De Ketelaere Bart , Aernouts Ben
Published: January 2018

Timely identification of a cow’s reproduction status is essential to minimize fertilityrelated losses on dairy farms. This includes optimal estrus detection, pregnancy diagnosis and the timely recognition of early embryonic death and ovarian problems. On farm milk progesterone (P4) analysis could indicate all of these fertility events simultaneously. However, milk P4 measurements are subject to a large variability both in terms of measurement errors and absolute values between cycles. In this study, an innovative monitoring system based on milk P4 using the principles of synergistic control is presented. Instead of using filtering techniques and fixed thresholds, the present system employs an individually updated online model to describe the P4 profile, combined with a statistical process control chart to identify the cow’s fertility status. The inputs for the latter are the residuals of the online model, corrected for the concentration-dependent variability which is typical for milk P4 measurements. The objective of this paper is to present the developed methodology and give an indication of its use on farm. To this end, the system was validated on the P4 profiles of 38 dairy cows. The positive predictive value for luteolysis followed by estrus was 100%, meaning that the monitoring system picked up all estrous periods identified by the experts. Pregnancy or embryonic mortality was characterized by the absence or detection of luteolysis following an insemination, respectively. For thirteen cows, no luteolysis was detected by the system within the 25-32 days after insemination, indicating pregnancy, which was confirmed later by rectal palpation. It was also shown that the system is able to cope with deviating P4 profiles having prolonged follicular or luteal phases, which may suggest the occurrence of cysts. Future research is recommended for optimizing sampling frequency, prediction of the optimal insemination window and the establishment of rules to detect problems based on deviating P4 patterns.

INTERPRETIVE SUMMARY. Progestrone-based online fertility monitoring. Adriaens.

Milk progesterone based monitoring systems can be valuable for indicating fertility events in dairy cows, as the evolution of the milk progesterone levels can be related to acyclicity, estrus, pregnancy, and ovarian problems. We developed a system to translate raw progesterone measurements into clear information for the farmer, based on a mathematical model and a statistical control chart. In this way, a detailed image of a cow’s reproduction status on-farm can be obtained and fertility-related losses minimized.
Diverse spatial organization of photosynthetic membranes among purple nonsulfur bacteria
Authors: LaSarre Breah , Kysela David T. , Stein Barry D. , Ducret Adrien , Brun Yves V. , McKinlay James B.
Published: January 2018

In diverse bacteria, proper cellular physiology requires the utilization of protein- or membrane-bound compartments that afford specific metabolic capabilities. One such compartment is the light-harvesting intracytoplasmic membrane (ICM) of purple nonsulfur bacteria (PNSB). Here we reveal that ICMs are subject to differential spatial organization among PNSB. We visualized ICMs in live cells of fourteen PNSB species by exploiting the natural autofluorescence of the photosynthetic machinery. We then quantitatively characterized ICM localization using automated computational analysis of autofluorescence patterns within single cells across the population. Our studies revealed that ICMs are localized in distinct subcellular patterns that differ between species; some PNSB elaborate ICMs throughout the cell, while others spatially restrict ICM to varying degrees. The most highly-restricted ICMs were localized in a specific pattern corresponding to progression of cell growth and division. An identical pattern of ICM restriction was conserved across at least two genera. Phylogenetic and phenotypic comparisons established that ICM localization and ICM architecture are not strictly interdependent and that neither trait fully correlates with the evolutionary relatedness of the species. This discovery of new diversity in bacterial cell organization has implications for understanding both the mechanisms underpinning spatial arrangement of bacterial compartments and the potential benefits of adopting different spatiotemporal patterns.
Higher performers upregulate brain signal variability in response to more feature-rich visual input
Authors: Garrett Douglas D. , Epp Samira , Kleemeyer Maike , Lindenberger Ulman , Polk Thad A.
Published: January 2018

The extent to which brain responses differ across varying cognitive demands is referred to as “neural differentiation,” and greater neural differentiation has been associated with better cognitive performance in older adults. An emerging approach has examined within-person neural differentiation using moment-to-moment brain signal variability. A number of studies have found that brain signal variability differs by cognitive state; however, the factors that cause signal variability to rise or fall on a given task remain understudied. We hypothesized that top performers would modulate signal variability according to the complexity of sensory input, upregulating variability when processing more feature-rich stimuli. In the current study, 46 older adults passively viewed face stimuli and house stimuli during fMRI. Low-level analyses of our stimuli showed that house images were more feature-rich than faces, and subsequent computational modelling of ventral visual stream responses (HMAX) revealed that houses were more feature-rich especially in V1/V2-like model layers. Notably, we then found that participants exhibiting greater face-to-house upregulation of brain signal variability in V1/V2 (higher for house relative to face stimuli) also exhibited more accurate, faster, and more consistent behavioral performance on a battery of offline visuo-cognitive tasks. Further, control models revealed that face-house modulation of mean brain signal was relatively insensitive to offline cognition, providing further evidence for the importance of brain signal variability for understanding human behavior. We conclude that the ability to align brain signal variability to the complexity of perceptual input may mark heightened trait-level behavioral performance in older adults.
Substrate deformations induce directed keratinocyte migration
Authors: Zarkoob Hoda , Chinnathambi Sathivel , Selby John C. , Sander Edward A.
Published: January 2018

Cell migration is an essential part of many (patho)physiological processes in the body, including keratinocyte re-epithelialization of healing wounds. Recent interest in the mechanobiology of tissues suggests that physical forces and mechanical cues from the wound bed (in addition to biochemical signals) may also play an important role in the healing process. Previously, we explored this possibility and found that polyacrylamide (PA) gel stiffness affected primary human keratinocyte behavior and that mechanical deformations in soft (~1.2 kPA) PA gels produced by neighboring cells appeared to influence the process ofde novoepithelial sheet formation. In order to clearly demonstrate that keratinocytes do respond to such deformations, we conducted a series of experiments where we observed the response of single keratinocytes to a prescribed local substrate deformation that mimicked a neighboring cell or evolving multicellular aggregate via a servo-controlled microneedle. We also examined the effect of adding either Y27632, a rho kinase inhibitor, or blebbistatin, a non-muscle myosin II inhibitor, on the response of the cells to PA gel deformations. The results of this study indicate that keratinocytes do sense and respond to mechanical signals comparable to those that originate from substrate displacements imposed by neighboring cells, a finding that could have important implications for the process of keratinocyte re-epithelialization that takes place during normal and pathologic wound healing. Furthermore, the Rho/ROCK pathway and the engagement of NM II are both essential to the observed process of substrate deformation-directed keratinocyte migration.
Structure of the Core of the Type Three Secretion System Export Apparatus
Authors: Kuhlen Lucas , Abrusci Patrizia , Johnson Steven , Gault Joseph , Deme Justin , Caesar Joseph , Dietsche Tobias , Mebrhatu Mehari Tesfazgi , Ganief Tariq , Macek Boris , Wagner Samuel , Robinson Carol V. , Lea Susan M.
Published: January 2018

Export of proteins through type three secretion systems is critical for bacterial motility and virulence of many major bacterial pathogens. Three putative integral membrane proteins (FliP/FliQ/FliR) are suggested to form the core of an export gate in the inner membrane, but their structure, assembly and location within the final nanomachine remain unclear. We here present the structure of this complex at 4.2 Å by cryo-electron microscopy. None of the subunits adopt canonical integral membrane protein topologies and common helix-turn-helix structural elements allow them to form a helical assembly with 5:4:1 stoichiometry. Fitting of the structure into reconstructions of intact secretion systems localize the export gate as a core component of the periplasmic portion of the machinery, and cross-linking experiments confirm this observation. This study thereby identifies the export gate as a key element of the secretion channel and implies that it primes the helical architecture of the components assembling downstream.

One Sentence Summary

The core of the T3SS export gate forms a supra-membrane helical assembly
Enabling the hypothesis-driven prioritization of ligand candidates in big databases: Screenlamp and its application to GPCR inhibitor discovery for invasive species control
Authors: Raschka Sebastian , Scott Anne M. , Liu Nan , Gunturu Santosh , Huertas Mar , Li Weiming , Kuhn Leslie A.
Published: January 2018

While the advantage of screening vast databases of molecules to cover greater molecular diversity is often mentioned, in reality, only a few studies have been published demonstrating inhibitor discovery by screening more than a million compounds for features that mimic a known three-dimensional ligand. Two factors contribute: the general difficulty of discovering potent inhibitors, and the lack of free, user-friendly software to incorporate project-specific knowledge and user hypotheses into 3D ligand-based screening. The Screenlamp modular toolkit presented here was developed with these needs in mind. We show Screenlamp’s ability to screen more than 12 million commercially available molecules and identify potentin vivoinhibitors of a G protein-coupled bile acid receptor within the first year of a discovery project. This pheromone receptor governs sea lamprey reproductive behavior, and to our knowledge, this project is the first to establish the efficacy of computational screening in discovering lead compounds for aquatic invasive species control. Significant enhancement in activity came from selecting compounds based on one of the hypotheses: that matching two distal oxygen groups in the three-dimensional structure of the pheromone is crucial for activity. Six of the 15 most active compounds met these criteria. A second hypothesis – that presence of an alkyl sulfate side chain results in high activity – identified another 6 compounds in the top 10, demonstrating the significant benefits of hypothesis-driven screening.