bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrasting Perspectives of Practice Leaders and Practice Facilitators May Be Common in Quality Improvement Initiatives
Authors: McHugh Megan , Brown Tiffany , Walunas Theresa L. , Liss David T. , Persell Stephen D.
Published: October 2019

Practice facilitation is an approach for advancing quality improvement (QI), but its success depends on effective relationships and communication among participants. Our goal was to identify patterns of contrasting perspectives on implementation issues between practice leaders and their practice facilitators, and factors that may contribute to them. We conducted individual interviews with practice leaders and the practice facilitators assigned to them as part of a program focused on preventive cardiology within primary care practices. We used summative content analysis to quantify the incidence of contrasting perspectives, and bivariate and qualitative analyses to explore relationships between contrasting perspectives and contextual factors. Among the 16 dyads, contrasting perspectives commonly related to the easiest or hardest QI interventions to implement (8 of 16 dyads) and the practice's success implementing interventions (5 of 16 dyads). There was a nonsignificant, inverse correlation (r = −0.19, p = .47) between the number of in-person QI visits from the facilitator and the total number of contrasting perspectives. Turnover of staff was frequently reported in dyads with contrasting perspectives. Although the impact of contrasting perspectives warrants additional study, planners of QI initiatives using practice facilitation should consider taking steps to minimize contrasting perspectives, or the potential adverse consequences of them, by addressing turnover challenges and encouraging opportunities to share perspectives.
Analysis of Thrombotic Deposits in Extracorporeal Membrane Oxygenators by High-resolution Microcomputed Tomography: A Feasibility Study
Authors: Birkenmaier Clemens , Dornia Christian , Lehle Karla , Müller Thomas , Gruber Michael , Philipp Alois , Krenkel Lars
Published: October 2019

Coagulative disorders, especially clotting during extracorporeal membrane oxygenation, are frequent complications. Direct visualization and analysis of deposits in membrane oxygenators using computed tomography (CT) may provide an insight into the underlying mechanisms causing thrombotic events. However, the already established multidetector CT
1
(MDCT) method shows major limitations. Here, we demonstrate the feasibility of applying industrial micro-CT (µCT) to circumvent these restrictions. Three clinically used membrane oxygenators were investigated applying both MDCT and µCT. The scans were analyzed in terms of clot volume and local clot distribution. As validation, the clot volume was also determined from the fluid volume, which could be filled into the respective used oxygenator compared to a new device. In addition, cross-sectional CT images were compared with crosscut oxygenators. Based on the µCT findings, a morphological measure (sphericity) for assessing clot structures in membrane oxygenators is introduced. Furthermore, by comparing MDCT and µCT results, an augmentation of the MDCT method is proposed, which allows for improved clot volume determination in a clinical setting.
Reasons for early discontinuing or switching of antiplatelet therapy in elderly patients after acute coronary syndrome
Authors: Gimbel Marieke E. , Vos Gerrit J. A. , Nguyen Thuc A. , Kelder Johannes C. , ten Berg Jurriën M.
Published: October 2019

Objective

This study aims to determine frequency and reasons for prematurely discontinuing or switching antiplatelet therapy in elderly patients admitted with non-ST-elevation acute coronary syndrome (NSTE-ACS).

Method

Patients of 75 years or older admitted with suspected NSTE-ACS were included between 2013 and 2016. Information was extracted from the patients’ medical files.

Results

A total of 544 patients were included, 17.3% discontinued aspirin within one year, predominantly (57%) within 30 days. The most common reason was the start of a (non-vitamin-K) oral anticoagulant [(N)OAC], either combined with a P2Y12-inhibitor (43%) or as monotherapy (16%). The P2Y12-inhibitor was discontinued in 31.2% of patients within one year, of which 46% within 30 days. The most common reason was undergoing coronary artery bypass grafting (CABG; 22%). Switching of clopidogrel seldom occurred; however, ticagrelor was switched in 50/179 patients mainly due to dyspnoea (42%). Independent predictors for prematurely discontinuing antiplatelet therapy were undergoing CABG [odds ratio (OR) 3.257 (95% confidence interval [CI] 1.836–5.779)], need for (N)OAC [OR 2.167 (95% CI 1.423–3.300)] and type II ACS as final diagnosis [OR 3.793 (95% CI 1.721–8.361)]. Undergoing percutaneous coronary intervention [OR 0.393 (95% CI 0.243–0.634)] and use of clopidogrel [OR 0.441(95% CI 0.293–0.662)] were independent predictors of continuing antiplatelet therapy.

Conclusion

In elderly patients of at least 75 years with NSTE-ACS, antiplatelet therapy is frequently discontinued prematurely, most often within 30 days. Main reasons for discontinuing are need for (N)OAC, undergoing CABG or type II ACS as final diagnosis and suffering from dyspnoea while on ticagrelor.
Technetium-99m-dimercaptosuccinic acid renal scintigraphy and single photon emission computed tomography/computed tomography in patients with sickle cell disease
Authors: Ramos Celso Dario , Onusic Daniel Massaro , Brunetto Sergio Querino , Amorim Bárbara Juarez , Souza Thiago Ferreira , Saad Sara Teresinha Olalla , Lima Mariana da Cunha Lopes
Published: October 2019

Purpose

Sickle cell disease (SCD) is a common hematologic hereditary disorder characterized by vaso-occlusive episodes affecting multiple organs, and substantially alters renal structure and function. We aimed to evaluate the utility of renal scintigraphy and single photon emission computed tomography/computed tomography (SPECT/CT) with technetium-99m-dimercaptosuccinic acid (99mTc-DMSA) in adult patients with SCD and no clinical evidence of renal insufficiency.

Materials and methods

Twenty-six patients (16 female) aged 23–58 years with SCD and no clinical evidence of renal insufficiency were prospectively studied. Planar and SPECT/CT images were, respectively, obtained after 3 and 4 hours of the injection of 110–180 MBq of 99mTc-DMSA. The relative radiopharmaceutical uptake and renal length were, respectively, determined using SPECT and CT images. Planar and SPECT/CT images were visually analyzed to identify focal areas of 99mTc-DMSA reduced uptake and anatomical deformities of the kidneys.

Results

Focal areas of reduced 99mTc-DMSA uptake with an image aspect of renal scars or inflammation were present in 21/26 patients (81%). In 11/21 (52%) of these patients, the cortical lesions were clearly identified only on SPECT images. Prominent renal columns were observed in 17/26 (65%) patients. The left kidney tended to be more affected than the right kidney. Most patients had enlarged kidneys.

Conclusion

99mTc-DMSA scintigraphy and SPECT/CT identify renal lesions possible related to renal infarcts or infections in most adult patients with SCD and no clinical evidence of renal insufficiency. Prominent renal columns and increased renal size tend to occur in most of these patients.
Comparison of glomerular filtration rates determined using two- and single-blood sample methods with a three-blood sample technique for 2922 paediatric studies
Authors: Bibbo Giovanni , Munn Catherine , Kirkwood Ian
Published: October 2019

Objective

Several different methods for measuring glomerular filtration rates (GFRs) have been developed in search of a more accurate and simplified technique. Currently, the main methods used are the slope-intercept and distribution volume techniques. In this work, 2922 GFR studies have been retrospectively reanalysed as two- and single-blood sample methods and compared with the three-blood sample data.

Patients and Methods

Paediatric GFR data from 1/1/1993 to 4/12/2018 using the three-blood sample technique have been reanalysed as two- and single-blood sample methods. The timing of blood sampling was also reviewed.

Results

Both the two- and the single-sample methods provide accurate estimates of GFR in children for all levels of renal function provided that the blood samples are collected at the appropriate times post administration of the tracer. For the highest accuracy, blood for the two-blood samples method should be collected at 2 and 4 h and at 2 h for the single-blood sample method. The relationship between renal clearance and the 2-h volume of distribution (V120) is linear with a line of best fit: GFR (ml/min) = 3.108 × V
120 − 2.557.

Conclusion

Both the two- and the single-sample techniques can be used to measure GFR in children with the same accuracy as the three-blood sample. With the collection of only a single-blood sample, there are benefits to all involved: patients, families, and nuclear medicine personnel. In addition, institutions have a choice as to which technique to use and for which patients.
Current Practices and Novel Techniques in the Diagnosis and Management of Neuroendocrine Tumors of Unknown Primary
Authors: Hendifar Andrew E. , Ramirez Robert A. , Anthony Lowell B. , Liu Eric
Published: October 2019

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms in which tumor staging/prognosis and response to treatments depend heavily on accurate and timely identification of the anatomic primary site or NET subtype. Despite recent technological advancements and use of multiple diagnostic modalities, 10% to 14% of newly diagnosed NETs are not fully characterized based on subtype or anatomic primary site. Inability to fully characterize NETs of unknown primary may cause delays in surgical intervention and limit potential treatment options. To address this unmet need, clinical validity and utility are being demonstrated for novel approaches that improve NET subtype or anatomic primary site identification. Functional imaging using 68Ga-radiolabeled DOTATATE positron emission tomography/computed tomography has been shown to overcome some false-positive and resolution issues associated with octreotide scanning and computed tomography/magnetic resonance imaging. Using a genomic approach, molecular tumor classification based on differential gene expression has demonstrated high diagnostic accuracy in blinded validation studies of different NET types and subtypes. Given the widespread availability of these technologies, we propose an algorithm for the workup of NETs of unknown primary that integrates these approaches. Including these technologies in the standard workup will lead to better NET subtype identification and improved treatment optimization for patients.
Combined Antiangiogenic Therapy and Immunotherapy Is Effective for Pancreatic Cancer With Mismatch Repair Proficiency but High Tumor Mutation Burden
Authors: Chen Mengni , Yang Shengli , Fan Li , Wu Lu , Chen Renwang , Chang Jian , Hu Jianli
Published: October 2019

Immunotherapy has been recommended as a second-line treatment only for high microsatellite instability or DNA mismatch repair deficiency advanced pancreatic cancer in National Comprehensive Cancer Network guidelines. Here, we report a case with a good response to immunotherapy in pancreatic cancer with mismatch repair proficiency. A 55-year-old woman diagnosed with pancreatic cancer cT4N1M1 (liver, lung) who harbored ERBB2 mutations with high tumor mutation burden (TMB) underwent multiple therapies and survived 19 months. A partial response in pancreatic cancer was observed when the patient was treated with combined antiangiogenic therapy and immunotherapy after a series of ineffective treatments. Neutrophil-to-lymphocyte ratio (NLR), a predictive marker of efficacy of immunotherapy, confirmed that immunotherapy resulted in the partial response in pancreatic cancer. To our knowledge, this is the first to report advanced pancreatic cancer with mismatch repair proficiency had a good response to immunotherapy, and this is the first to report an association between high blood-based TMB or NLR and improved clinical outcomes in pancreatic cancer. Therefore, TMB may also be a biomarker for immunotherapy of pancreatic cancer, and NLR may be a prospective predictive marker for efficacy of immunotherapy in pancreatic cancer.
Vasoactive Intestinal Peptide–Secreting Tumors
Authors: Siddappa Pradeep Kumar , Vege Santhi Swaroop
Published: October 2019

Vasoactive intestinal peptide–secreting tumors (VIPomas) are a group of rare neuroendocrine tumors, which cause a typical syndrome of watery diarrhea. Most of these tumors are found in the pancreas and are usually detected at a later stage. Although curative resection is not possible in most of these tumors, both symptom and tumor control can be achieved by a multidimensional approach, to enable a long survival of most patients. There are no clear-cut guidelines for the management of VIPomas because of the rarity of this neoplasm and lack of prospective data. In this review, we discuss the available evidence on the clinical features and management of these rare tumors.
Health and Disability Among Young Black Men
Authors: Ricks Tiffany N. , Frederick Angela , Harrison Tracie
Published: October 2019

Background

Black men experience the highest rate of disability compared to White, Asian, and Hispanic men. Yet, we know little about how Black men with disabilities experience the embodiment of their gender, race, social class, and disability positionalities and how they draw from their cultural backgrounds as they engage in health-seeking behaviors.

Objectives

The purpose of this study was to explore how young Black men experienced the onset of chronic disabling conditions while negotiating health-promoting activities in the context of gender, race, social class, disability positionalities, and culture.

Methods

This descriptive study used hermeneutic phenomenology to achieve study objectives. This study’s research questions were answered using audiotaped, one-on-one qualitative interviews, along with detailed field notes. Each participant was interviewed twice at a mutually decided upon location to ensure their privacy and comfort.

Results

In relation to their embodied interactions of self in the context of disability, these men described their health-related decisions using four themes: maintaining manhood, economic constraints, the “risk” of healthcare, and health promotion.

Conclusions

By examining the experiences of young adult Black men living with disabilities, knowledge of their perspectives and experiences at earlier stages in their life course contributes to the understanding of their personal challenges, health needs, and their perspectives of health-promoting strategies.
Frequency and Identification of Risk Factors of Uveitis in Juvenile Idiopathic Arthritis
Authors: Conti Giovanni , Chirico Valeria , Porcaro Federica , Fede Claudia , Vitale Agata , Fede Antonio , Castagna Irene , Fede Carmelo
Published: October 2019

Background

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease of childhood. The JIA–associated uveitis represents the most common extra-articular manifestation.

Objectives

The main aim of this study was to evaluate frequency and risk factors of uveitis in a pediatric population affected by JIA.

Methods

One hundred eight Italian children with JIA were followed during a follow-up period of 13 years. Association between uveitis, antinuclear antibodies (ANAs), and subtype of arthritis has been estimated, and Kaplan-Meier curves were generated to assess the probability of ocular complications during the follow-up period.

Results

Twenty-one patients developed uveitis, after 96.5 ± 50.4 months from the enrollment. According to JIA subtypes, the oligoarthritis subtype was characterized by the highest prevalence (39%) of uveitis. The greatest risk of uveitis has been detected in oligoarthritis patients associated to ANA positivity (risk ratio, 8.6; 95% confidence interval, 2.27–32.9; χ2 = 20.4), whereas the worst evolution was revealed in patients with oligoarthritis and high levels of ANAs, with a progression time of 36 months (log-rank χ2 = 16.39; p < 0.0001; risk ratio, 18; 95% confidence interval, 7.3–44.2).

Conclusions

Patients with early-onset ANA-positive oligoarticular JIA have the highest risk of developing uveitis. A routine ophthalmological follow-up is required at regular intervals, even though the joint disease is clinically quiescent.
Nontraumatic Subperiosteal Orbital Hematoma in a Patient With Behcet Disease
Authors: Seo Ji Won , Kim Eung Hyun , Han So-Eun
Published: October 2019

Orbital subperiosteal hematomas are commonly caused by facial trauma. Nontraumatic subperiosteal orbital hematomas (NTSOHs) are rare but may occur in patients with underlying medical diseases. A 71-year-old woman presented to the emergency department with a 5-day history of left periorbital pain and proptosis. She was known to have Behcet disease and presented with no recent trauma. Clinical features and computed tomography findings aided in establishing the diagnosis of an NTSOH. The hematoma was evacuated via sub brow incision. After surgery, the patient's clinical symptoms resolved and did not recur during the 12-month follow-up period. On the basis of the findings of this case, the authors conclude that patients diagnosed with diseases such as bleeding disorders or autoimmune vasculitis should consider visual symptoms as a sign of an NTSOH. Patients who diagnosed with disease experience visual disturbance, periorbital pain, or periorbital swelling should undergo early surgical treatment for spontaneous NTSOH to avoid permanent visual loss.
A Rarely Seen Mass of Nasal Cavity: Seromucinous Hamartoma
Authors: Şahin Bayram , Sönmez Said , Kara Hakan , Aydemir Levent , Çomoğlu Şenol
Published: October 2019

Seromucinous hamartoma (SH) is a rarely seen benign polypoid mass of the sinonasal tract. Although the most common presentation symptom is nasal obstruction, most of the patients are asymptomatic. In this paper, the authors present an additional case of SH and discuss its differential diagnosis. A 34-year-old male patient presented with progressive nasal obstruction and serous nasal discharge for several months. A well-defined polypoid mass was detected in the left nasal cavity during the endoscopic assessment. Preoperative biopsy was reported as benign polypoid lesion. The mass was resected via transnasal endoscopic approach and final pathological examination was notified as SH.

The SH is an uncommon tumor, originates from nasal septum in the most cases and presents as a well-circumscribed polypoid mass. Radiological imaging modalities and biopsy should be performed to distinguish from the sinonasal malignancies. Complete surgical excision is recommended treatment and recurrence is almost never.
Causes of Horner Syndrome: A Study of 318 Patients
Authors: Sabbagh Mohammad Amr , De Lott Lindsey B. , Trobe Jonathan D.
Published: October 2019

Background:

Some reports have indicated that when a cause for Horner syndrome can be determined, it is most often chest and neck tumors and stroke. Others have suggested that Horner syndrome is more frequently caused by surgical procedures in the neck and chest. These differences may be explained by disparate accrual methods. Therefore, we decided to compare the cause of Horner syndrome in cases where the diagnosis was confirmed by apraclonidine testing conducted by ophthalmologists to cases in which the diagnosis was made entirely on clinical grounds mostly by nonophthalmologists.

Methods:

We applied a new search engine to the inpatient and outpatient electronic medical records text at the University of Michigan Medical Center from 1996 to 2018 for Horner syndrome with and without pharmacologic confirmation through ocular instillation of apraclonidine 0.5%. Among apraclonidine-confirmed cases, 159 met inclusion criteria. Among apraclonidine-unconfirmed cases, more than 2,000 cases were identified, so that we included only the first 159 cases that met inclusion criteria. In these 318 cases, we documented patient demographics, ophthalmologic features, imaging, underlying cause, and whether the cause was discovered before or after the diagnosis of Horner syndrome.

Results:

In the cohort of 159 apraclonidine-confirmed cases of Horner syndrome, a cause was identified in 97 (61%). Procedures in the neck, chest, skull base, and paraspinal region accounted for most of the identified causes, with cervical carotid dissection the next most common cause. In a cohort of 159 cases of Horner syndrome not tested with apraclonidine because the clinical diagnosis appeared firm, procedures again accounted for the largest percentage, but tumor was the next most common cause. In both groups, when a cause for Horner syndrome could be identified, that cause was nearly always known before Horner syndrome was identified. However, in an important minority of cases, mostly involving carotid dissection or tumor, the identification of Horner syndrome was critical to the discovery of those conditions.

Conclusions:

The prevalence of causes of Horner syndrome depends on the accrual method. Among pharmacologically-confirmed cases, the cause was often undetermined or due to a preceding neck or chest procedure. Among pharmacologically-unconfirmed cases, a substantial proportion had also been caused by neck and chest procedures, but tumors in that region were also common. When a cause of Horner syndrome was found in both cohorts, it was usually known before Horner syndrome was discovered, making Horner syndrome an afterthought. However, in an important minority of cases where the cause was not yet known, the identification of Horner syndrome was valuable in leading to important diagnoses such as carotid dissection and tumor.
Modelling and prediction of the peak-radiated sound in subsonic axisymmetric air jets using acoustic analogy-based asymptotic analysis
Authors: Afsar Mohammed Z. , Sescu Adrian , Leib Stewart J.
Published: October 2019

This paper uses asymptotic analysis within the generalized acoustic analogy formulation (Goldstein 2003
JFM
488
, 315–333. (
doi:10.1017/S0022112003004890
)) to develop a noise prediction model for the peak sound of axisymmetric round jets at subsonic acoustic Mach numbers (Ma). The analogy shows that the exact formula for the acoustic pressure is given by a convolution product of a propagator tensor (determined by the vector Green's function of the adjoint linearized Euler equations for a given jet mean flow) and a generalized source term representing the jet turbulence field. Using a low-frequency/small spread rate asymptotic expansion of the propagator, mean flow non-parallelism enters the lowest order Green's function solution via the streamwise component of the mean flow advection vector in a hyperbolic partial differential equation. We then address the predictive capability of the solution to this partial differential equation when used in the analogy through first-of-its-kind numerical calculations when an experimentally verified model of the turbulence source structure is used together with Reynolds-averaged Navier–Stokes solutions for the jet mean flow. Our noise predictions show a reasonable level of accuracy in the peak noise direction at Ma = 0.9, for Strouhal numbers up to about 0.6, and at Ma = 0.5 using modified source coefficients. Possible reasons for this are discussed. Moreover, the prediction range can be extended beyond unity Strouhal number by using an approximate composite asymptotic formula for the vector Green's function that reduces to the locally parallel flow limit at high frequencies.

This article is part of the theme issue ‘Frontiers of aeroacoustics research: theory, computation and experiment’.
Analysis of fan-stage gap-flow data to inform simulation of fan broadband noise
Authors: Grace Sheryl , Gonzalez-Martino Ignacio , Casalino Damiano
Published: October 2019

Time-resolved simulations present a new opportunity for studying the disturbances responsible for the broadband interaction noise created by the fan stage. In this paper, two vane configurations from the source diagnostic test at the approach rotor speed were computed with PowerFLOW's very large-eddy simulation (VLES) method using two solution strategies: a coarser mesh near the rotor and a trip to trigger turbulent transition on the rotor; and a much finer mesh near the rotor with no trip. The simulated data allow for an investigation of the potential effect from the vane configuration and an in-depth study of the mean and turbulent flow in the interstage gap. A challenge related to post-processing of high-resolution simulations is discussed. Comparison of the flow quantities with previously obtained Reynolds Averaged Navier–Stokes simulation results indicates that little advantage is gained by running a lattice Boltmann method (LBM)/VLES to simply recover the gap flow parameters for use with a lower-order fan broadband interaction noise calculation method. The true benefit of the LBM/VLES is that the noise calculation can be directly and simultaneously completed with the flow simulation.

This article is part of the theme issue ‘Frontiers of aeroacoustics research: theory, computation and experiment’.
Modelling of jet noise: a perspective from large-eddy simulations
Authors: Brès Guillaume A. , Lele Sanjiva K.
Published: October 2019

In the last decade, many research groups have reported predictions of jet noise using high-fidelity large-eddy simulations (LES) of the turbulent jet flow and these methods are beginning to be used more broadly. A brief overview of the publications since the review by Bodony & Lele (2008,
AIAA J.
56
, 346–380) is undertaken to assess the progress and overall contributions of LES towards a better understanding of jet noise. In particular, we stress the meshing, numerical and modelling advances which enable detailed geometric representation of nozzle shape variations intended to impact the noise radiation, and sufficiently accurate capturing of the turbulent boundary layer at the nozzle exit. Examples of how LES is currently being used to complement experiments for challenging conditions (such as highly heated pressure-mismatched jets with afterburners) and guide jet modelling efforts are highlighted. Some of the physical insights gained from these numerical studies are discussed, in particular on crackle, screech and shock-associated noise, impingement tones, acoustic analogy models, wavepackets dynamics and resonant acoustic waves within the jet core. We close with some perspectives on the remaining challenges and upcoming opportunities for future applications.

This article is part of the theme issue ‘Frontiers of aeroacoustics research: theory, computation and experiment’.
Effect of fluid injection on turbulence and noise reduction of a supersonic jet
Authors: Prasad Chitrarth , Morris Philip
Published: October 2019

Supersonic jets, such as the ones used in high-performance military aircraft, have both downstream and upstream noise components due to the large-scale turbulent structures and the presence of shock cells in the jet plume. The fluid insert technology is a noise reduction method that has been shown to effectively reduce both these noise components. This paper analyses the unsteady flow changes associated with different fluid insert configurations with a goal of helping to understand the detailed noise reduction mechanisms. Using direct cross-correlations of the near-field data with the far-field microphone signals, it is found that even the use of a single injector as a fluid insert helps break up the large-scale structures of the flow. However, a more azimuthally distributed blowing is required to reduce the upstream broadband shock-associated noise (BBSAN). Addition of upstream injectors at each azimuthal location further enhances the BBSAN reduction. Decomposition of the jet flow-field into hydrodynamic and acoustic modes shows that fluid insert nozzles reduce the amplitude and convection speed of the coherent acoustic mode in the plane of highest noise reduction.

This article is part of the theme issue ‘Frontiers of aeroacoustics research: theory, computation and experiment’.
Murine cytomegalovirus disseminates independently of CX3CR1, CCL2 or its m131/m129 chemokine homologue
Authors: Farrell Helen E. , Bruce Kimberley , Redwood Alec J. , Stevenson Philip G.
Published: October 2019

Cytomegaloviruses (CMVs) use myeloid cells to move within their hosts. Murine CMV (MCMV) colonizes the salivary glands for long-term shedding, and reaches them via CD11c+ infected cells. A need to recruit patrolling monocytes for systemic spread has been proposed, based on poor salivary gland infection in fractalkine receptor (CX3CR1)-deficient mice. We found no significant CX3CR1 dependence of salivary gland infection. CCL2 and the viral m131/m129 chemokine homologue were also redundant for acute MCMV spread, arguing against a need for inflammation or infection to recruit additional monocytes to the entry site. M131/m129 promoted salivary gland infection, but only after the initial seeding of infected cells to this site. Our data support the idea that MCMV disseminates by infecting and mobilizing tissue-resident dendritic cells.
LncRNA de novo discovery reveals noncoding RNAs as major molecular mechanism associating coronary artery disease GWAS variants with causal genes to confer disease risk
Authors: Pjanic Milos , Zhao Quanyi , Cheng Paul , Nguyen Trieu , Wirka Robert C. , Kim Juyong Brian , Miller Clint L. , Quertermous Thomas
Published: October 2019

This paper has been removed owing to copyright violation.
Novel insights into expansion and functional diversification of MIR169 family in tomato
Authors: Rao Sombir , Balyan Sonia , Jha Sarita , Mathur Saloni
Published: October 2019

MIR169 family is an evolutionarily conserved miRNA family in plants. A systematic in-depth analysis of MIR169 family in tomato is lacking. We report eighteen miR169 precursors, annotating new loci for MIR169a, b and d, as well as four novel mature isoforms (MIR169f/g/h/i). The family has expanded by both tandem- and segmental-duplication events during evolution. A tandem-pair ‘MIR169b/b-1 and MIR169b-2/h’ is polycistronic in nature coding for three MIR169b isoforms and a new variant miR169h, that is evidently absent in the wild relatives S. pennellii and S. pimpinellifolium. Seven novel miR169 targets including RNA-binding-protein, protein-phosphatase, aminotransferase, chaperone, tetratricopeptide-repeat-protein, and transcription factors ARF-9B and SEPELLATA-3 were established by efficient target cleavage in presence of specific precursors as well as increased target abundance upon miR169 chelation by short-tandem-target-mimic construct in transient assays. Comparative antagonistic expression profiles of MIR169:target pairs suggest MIR169 family as ubiquitous regulator of various abiotic stresses (heat, cold, dehydration and salt) and developmental pathways. This regulation is partly brought about by acquisition of new promoters as demonstrated by promoterMIR169:GUS-reporter assays as well as differential processivity of different precursors and miRNA cleavage efficiencies. Thus, the current study augments the functional horizon of MIR169 family with applications for stress tolerance in crops.

Highlight

Expansion of MIR169 members by duplication and new mature forms, acquisition of new promoters, differential precursor-miRNA processivity and engaging novel targets increases the functional diversification of MIR169 in tomato. (29/30)
Channel Capacity Computations for Unregulated and Autoregulated Gene Expression
Authors: Vahdat Zahra , Nienałtowski Karol , Farooq Zia , Komorowski Michał , Singh Abhyudai
Published: October 2019

How living cells can reliably process biochemical cues in the presence of molecular noise is not fully understood. Here we investigate the fidelity of information transfer in the expression of a single gene. We use the established model of gene expression to examine how precisely the protein levels can be controlled by two distinct mechanisms: (i) the transcription rate of the gene, or (ii) the translation rate for the corresponding mRNA. The fidelity of gene expression is quantified with the information-theoretic notion of information capacity. Derived information capacity formulae reveal that transcriptional control generally provides a tangibly higher capacity as compared to the translational control. We next introduce negative feedback regulation in gene expression, where the protein directly inhibits its own transcription. While negative feedback reduces noise in the level of the protein for a given input signal, it also decreases the input-to-output sensitivity. Our results show that the combined effect of these two opposing forces is a reduced capacity in the presence of feedback. In summary, our analysis presents the first analytical quantification of information transfer in simple gene expression models, which provides insight into the fidelity of basic gene expression control mechanisms.
Decisions bias future choices by modifying hippocampal associative memories
Authors: Luettgau Lennart , Tempelmann Claus , Kaiser Luca Franziska , Jocham Gerhard
Published: October 2019

Decision making is guided by memories of option values. However, retrieving items from memory renders them malleable. Here, we show that merely retrieving values from memory and making a choice between options is sufficient both to induce changes to stimulus-reward associations in the hippocampus and to bias future decision making. After allowing participants to make repeated choices between reward-conditioned stimuli, in the absence of any outcome, we observed that participants preferred stimuli they had previously chosen, and neglected previously unchosen stimuli, over otherwise identical-valued options. Using functional brain imaging, we show that decisions induced changes to hippocampal representations of stimulus-outcome associations. These changes were correlated with future decision biases. Our results indicate that choice-induced preference changes are partially driven by choice-induced modification of memory representations and suggest that merely making a choice - even without experiencing any outcomes - induces associative plasticity.
Amphetamine disrupts haemodynamic correlates of prediction errors in nucleus accumbens and orbitofrontal cortex
Authors: Werlen Emilie , Shin Soon-Lim , Gastambide Francois , Francois Jennifer , Tricklebank Mark D , Marston Hugh M , Huxter John R , Gilmour Gary , Walton Mark E
Published: October 2019

In an uncertain world, the ability to predict and update the relationships between environmental cues and outcomes is a fundamental element of adaptive behaviour. This type of learning is typically thought to depend on prediction error, the difference between expected and experienced events, and in the reward domain this has been closely linked to mesolimbic dopamine. There is also increasing behavioural and neuroimaging evidence that disruption to this process may be a cross-diagnostic feature of several neuropsychiatric and neurological disorders in which dopamine is dysregulated. However, the precise relationship between haemodynamic measures, dopamine and reward-guided learning remains unclear. To help address this issue, we used a translational technique, oxygen amperometry, to record haemodynamic signals in the nucleus accumbens (NAc) and orbitofrontal cortex (OFC) while freely-moving rats performed a probabilistic Pavlovian learning task. Using a model-based analysis approach to account for individual variations in learning, we found that the oxygen signal in the NAc correlated with a reward prediction error, whereas in the OFC it correlated with an unsigned prediction error or salience signal. Furthermore, an acute dose of amphetamine, creating a hyperdopaminergic state, disrupted rats’ ability to discriminate between cues associated with either a high or a low probability of reward and concomitantly corrupted prediction error signalling. These results demonstrate parallel but distinct prediction error signals in NAc and OFC during learning, both of which are affected by psychostimulant administration. Furthermore, they establish the viability of tracking and manipulating haemodynamic signatures of reward-guided learning observed in human fMRI studies using a proxy signal for BOLD in a freely behaving rodent.
Under-ice mesocosms reveal the primacy of light but the importance of zooplankton in winter phytoplankton dynamics
Authors: Hrycik Allison R. , Stockwell Jason D.
Published: October 2019

Factors that regulate planktonic communities under lake ice may be vastly different than the open-water season. However, under-ice food webs in temperate lakes are poorly understood, despite expected changes in light availability, ice cover, and snowfall associated with climate change. We hypothesized that light limitation (bottom-up control) outweighs zooplankton grazing (top-down control) on phytoplankton biovolume and community structure under ice in a north temperate lake. Using in situ under-ice mesocosms, we found that light had stronger effects on phytoplankton abundance than zooplankton, as expected. Specifically, low light limited growth of diatoms, cryptophytes, chrysophytes, and chlorophytes. Zooplankton, however, also significantly affected phytoplankton by decreasing diatoms and cryptophytes, in contrast to the common assumption that zooplankton grazing has negligible effects under ice. Ammonia and soluble reactive phosphorus decreased in high light treatments presumably through uptake by phytoplankton, whereas ammonia and soluble reactive phosphorus increased in high zooplankton treatments, likely through excretion. In situ experimental studies are commonly applied to understand food web dynamics in open-water conditions, but are extremely rare under ice. Our results suggest that changes in the light environment under ice have significant, rapid effects on phytoplankton growth and community structure and that zooplankton may play a more active role in winter food webs than previously thought. Changes in snow and ice dynamics associated with climate change may alter the light environment in ice-covered systems and significantly influence community structure.
Active zone compaction in presynaptic homeostatic potentiation
Authors: Mrestani Achmed , Kollmannsberger Philip , Pauli Martin , Repp Felix , Kittel Robert J. , Eilers Jens , Doose Sören , Sauer Markus , Sirén Anna-Leena , Heckmann Manfred , Paul Mila M.
Published: October 2019

Brain function relies on neurotransmission which is stabilized by presynaptic homeostatic potentiation (PHP). PHP operates on time scales ranging from minute- to life-long adaptations and likely involves reorganization of presynaptic active zones (AZs). At Drosophila melanogaster neuromuscular junctions, earlier work ascribed AZ enlargement by incorporating more Bruchpilot (Brp) scaffold protein a central mechanistic role in PHP.

We used localization microscopy (direct stochastic optical reconstruction microscopy, dSTORM) and hierarchical density-based spatial clustering of applications with noise (HDBSCAN) to study AZ plasticity during PHP. We found that both acute, philanthotoxin (PhTx)-induced and chronic, genetically-induced PHP lead to compaction of individual AZs without altering Brp copy numbers per AZ. This compaction even occurs within Brp subclusters of the AZ scaffold which also move towards AZ centers. Furthermore, lowering imaging resolution revealed how AZ compaction in PHP translates into apparent increases in AZ area and Brp protein content as implied earlier. Our results suggest AZ compaction in PHP as an effective mechanism to raise presynaptic protein density and transmitter release.

SIGNIFICANCE STATEMENT

Homeostatic plasticity stabilizes chemical synaptic transmission in multiple organisms ranging from insects to humans. Changes in active zones (AZs), membrane specializations of the presynapse where synaptic vesicles are discharged, are thought to be crucial in homeostatic adaptations. AZ growth by protein incorporation was proposed as a core mechanism in presynaptic homeostatic potentiation (PHP). Localization microscopy of an abundant AZ scaffold protein uncovered that instead of growing, AZs are compacted in acute and chronic PHP. At lower imaging resolution, however, AZs appear larger and brighter although protein numbers are not increased. In summary, our findings suggest AZ compaction as new and effective mechanism to raise presynaptic protein density and transmitter release in PHP.
High Affinity binding of Yeast Nucleolin Nsr1 to Co-transcriptionally Formed G4 DNA Obstructs Replication and Elevates Genome Instability
Authors: Singh Shivani , Berroyer Alexandra , Kim Minseon , Kim Nayun
Published: October 2019

A significant increase in genome instability is associated with the conformational shift of a guanine-run-containing DNA strand into the four-stranded G-quadruplex (G4) DNA. The mechanism underlying the recombination and genome rearrangements following the formation of G4 DNAin vivohas been difficult to elucidate but has become better clarified by the identification and functional characterization of several key G4 DNA-binding proteins. Mammalian nucleolin NCL is a highly specific G4 DNA-binding protein with a well-defined role in the transcriptional regulation of genes with associated G4 DNA-forming sequence motifs at their promoters. The consequence of thein vivointeraction between G4 DNA and nucleolin in respect to the genome instability has not been previously investigated. We show here that G4 DNA-binding is a conserved function in the yeast nucleolin Nsr1. Furthermore, we demonstrate that the Nsr1-G4 DNA complex formation results in replication obstruction and is a major factor in inducing the genome instability associated with the co-transcriptionally formed G4 DNA in the yeast genome. The G4-associated genome instability and the G4 DNA-bindingin vivorequires the arginine-glycine-glycine (RGG) repeats located at the C-terminus of the Nsr1 protein. Nsr1 with the deletion of RGG domain supports normal cell growth and is sufficient for its pre-rRNA processing function. However, the truncation of RGG domain of Nsr1 significantly weakens its interaction with G4 DNAin vitroandin vivoand restores unhindered replication, overall resulting in a sharp reduction in the G4-associated genome instability. Our data suggest that the interaction between Nsr1 with the intact RGG repeats and G4 DNA impairs genome stability by precluding the access of G4-resolving proteins and obstructing replication.

AUTHOR SUMMARY

Genome instability is uniquely elevated at sequences containing multiple runs of guanines, which can fold into the unusual, four-stranded G-quadruplex (G4) DNA. In this study, we report a novel finding that a highly conserved G4 DNA binding protein Nsr1 can elevate the rate of recombination and chromosomal rearrangement occurring at a G4 DNA-forming sequence in the genome ofSaccharomyces cerevisiae. The elevated genome instability requires the C-terminally located RGG domain of Nsr1, which supports the high-affinity interaction between the protein and G4 DNA. The connection between G4-specific genome instability and the function of Nsr1 to form stable complex with G4 DNA led to the hypothesis that the high-affinity Nsr1-G4 DNA complexes can become a barrier to replication. We demonstrate here that the presence of Nsr1 in fact slows the replication past a G4 DNA-containing genomic site and that the RGG domain is required to facilitate such replication block.
A dual functioning small RNA/Riboswitch controls the expression of the methionine biosynthesis regulator SahR inDesulfovibrio vulgarisHildenborough
Authors: Kempher M. L. , Burns A. S. , Novichkov P. S. , Bender K. S.
Published: October 2019

Riboswitches arecis-acting RNA regulatory elements that control expression of a downstream gene(s) by directly binding to a specific metabolite. Here we report aS-adenosylmethionine (SAM)-I riboswitch in the sulfate-reducing bacteriumDesulfovibrio vulgarisHildenborough (DvH) that plays an additional regulatory role as atranssmall noncoding RNA (sRNA) targeting the methionine biosynthesis cycle transcriptional regulator SahR. Sequence and expression analyses indicated that DseA (Desulfovibrio SAMelementA) is located upstream of a small hypothetical protein DVU1170 and that the two are co-transcribed. Multiple techniques were used to verify the riboswitch activity of DseA and its activity as a transcriptional terminator in response to SAM. While determining a potential role for DseA in the methionine biosynthesis pathway, a mRNA target encoding SahR was identified. Subsequent electrophoretic mobility shift assays confirmed the ability of DseA to bind thesahRtranscript and qRT-PCR analysis of a DseA deletion strain suggested a negative regulatory role. This study presents the first regulatory role for a newly discovered sRNA inDesulfovibrio. Additionally, this study suggests that DseA acts not only as a riboswitch, but also as atransregulatory molecule.

IMPORTANCE

Sulfate-reducing bacteria (SRB) are important contributors to global geochemical cycles while also causing major issues for the petroleum and oil industry due to biocorrosion and souring of oil wells. Despite their significance, gene regulatory networks and pathways remain poorly understood in SRB. Here, we report atransacting small noncoding RNA that plays a dual role as a SAM sensing riboswitch that controls the expression of a small hypothetical protein. Our findings provide important insights into the regulatory repertoire of sulfate-reducing bacteria.
CCmed: cross-condition mediation analysis for identifying robust trans-eQTLs and assessing their effects on human traits
Authors: Yang Fan , Gleason Kevin J. , Wang Jiebiao ,   The GTEx consortium, Duan Jubao , He Xin , Pierce Brandon L , Chen Lin S
Published: October 2019

Trans-eQTLs collectively explain a substantial proportion of expression variation, yet are challenging to detect and replicate since their effects are individually weak. Many trans-effects are mediated by cis-gene expression and some of those effects are shared across tissue types/conditions. To detect robust cis-mediated trans-associations at the gene-level and for specific single nucleotide polymorphisms (SNPs), we proposed two Cross-Condition Mediation methods – CCmedgene and CCmedGWAS, respectively. We analyzed data from 13 brain tissue types from the Genotype-Tissue Expression (GTEx) project, and identified trios with cis-eQTLs of a cis-gene having associations with a trans-gene, many of which show evidence of replication in other datasets. By applying CCmedGWAS, we identified trans-genes associated with known schizophrenia susceptibility loci. We further conducted validation analyses assessing the schizophrenia-risk-associations of the identified trans-genes, by harnessing GWAS summary statistics from the Psychiatric Genomics Consortium and multitissue eQTL statistics from GTEx.