bluuebunny/crossref_metadata_2025 huggingface dataset:
Bridging the Gap After Physical Therapy: Clinical–Community Linkages With Older Adult Physical Activity Programs
Authors: Fishleder Sarah , Petrescu-Prahova Miruna , Harris Jeffrey R , Steinman Lesley , Kohn Marlana , Bennett Kimberly , Helfrich Christian D
Published: April 2018

Background and Objectives

Many barriers exist to older adult participation in physical activity, despite known benefits. Referrals from physical therapists (PTs) through clinical–community linkages offer novel, promising opportunities to increase older adult engagement in appropriate community-based physical activity programs. We assessed the capacity of PTs to participate in such linkages.

Research Design and Methods

We collected qualitative data using semistructured phone interviews (n = 30) with PTs across 14 states. We conducted thematic analysis using a priori themes based on the 2008 Bridging Model of Etz and colleagues: capacity to assess patient risk, ability to provide brief counseling, capacity and ability to refer, and awareness of community resources.

Results

Risk assessment and counseling were already part of routine practice for our respondents, but counseling could be further facilitated if PTs had more skills to engage less-motivated patients. PTs expressed a desire to refer their patients to community programs; however, barriers to referrals included lack of knowledge of and trust in community programs, and limited infrastructure for communicating with potential partners.

Discussion and Implications

PTs have the capacity to develop patient referral linkages with community-based physical activity programs. PT session length and content facilitates patient risk assessment and behavioral counseling. Integrating motivational techniques can help PTs engage less-motivated patients in physical activity. Systemic improvements should include innovations in communication infrastructure, identifying clinic-level champions, and in-person outreach initiated by organizations that deliver community physical activity programs.
Cosmetics and Cancer: Adverse Event Reports Submitted to the Food and Drug Administration
Authors: Jacob Saya L , Cornell Erika , Kwa Michael , Funk William E , Xu Shuai
Published: April 2018

There have been numerous controversies surrounding cosmetic products and increased cancer risk. Such controversies include associations between parabens and breast cancer, hair dyes and hematologic malignancies, and talc powders and ovarian cancer. Despite the prominent media coverage and numerous scientific investigations, the majority of these associations currently lack conclusive evidence. In 2016, the US Food and Drug Administration (FDA) made publically available all adverse event reports in Center for Food Safety and Applied Nutrition’s Adverse Event Reporting System (CAERS), which includes complaints related to cosmetic products. We mined CAERS for cancer-related reports attributed to cosmetics. Between 2004 and 2017, cancer-related reports caused by cosmetics represented 41% of all adverse events related to cosmetics. This yielded 4427 individual reports of cancer related to a cosmetic product. Of these reports, the FDA redacted the specific product names in 95% of cancer-related reports under the Freedom of Information Act exemptions, most likely due to ongoing legal proceedings. For redacted reports, ovarian cancer reports dominated (n = 3992, 90%), followed by mesothelioma (n = 92, 2%) and malignant neoplasm unspecified (n = 46, 1%). For nonredacted reports, or those reports whose product names were not withheld (n = 218), 70% were related to ovarian cancer attributed to talc powders, followed by skin cancer (11%) and breast cancer (5%) attributed to topical moisturizers. Currently, CAERS is of limited utility, with the available data having been subjected to significant reporter bias and a lack of supportive information such as demographic data, medical history, or concomitant product use. Although the system has promise for safeguarding public health, the future utility of the database requires broader reporting participation and more complete reporting, paired with parallel investments in regulatory science and improved molecular methods.
Clinical and Epidemiologic Profiles for Identifying Norovirus in Acute Gastroenteritis Outbreak Investigations
Authors: Lively Joana Y , Johnson Shacara D , Wikswo Mary , Gu Weidong , Leon Juan , Hall Aron J
Published: April 2018

Background

Noroviruses are the leading cause of acute gastroenteritis (AGE) outbreaks in the United States. However, outbreaks attributed to norovirus often lack confirmation by diagnostic testing. Clinical and epidemiologic profiles, such as the Kaplan criteria (vomiting in >50% cases, mean incubation period of 24–48 hours, mean duration of illness for 12–60 hours, and negative bacterial stool culture), have been used to distinguish norovirus outbreaks from those caused by bacteria.

Methods

Kaplan criteria were evaluated among 10 023 outbreaks reported to the National Outbreak Reporting System (NORS) during 2009–2012. An alternate profile for distinguishing norovirus outbreaks from outbreaks caused by nonviral etiologies was identified using classification and regression tree (CART) modeling. Performance of the Kaplan criteria and alternate profile were compared among laboratory-confirmed outbreaks.

Results

The Kaplan criteria were 63.9% sensitive and 100% specific in discriminating norovirus from nonviral outbreaks, but only 3.3% of norovirus and 1.2% of nonviral outbreaks reported all criteria. Clinical and epidemiologic characteristics identified with CART modeling (ratio of proportion of cases with fever to the proportion of cases with vomiting <1, proportion of cases with bloody stool <0.1, proportion of cases with vomiting ≥0.26) were 85.7% sensitive and 92.4% specific for distinguishing norovirus from nonviral outbreaks and were applicable to more than 8 times as many outbreaks compared with the Kaplan criteria.

Conclusions

Compared with the Kaplan criteria, the CART-derived profile had higher sensitivity and broader application in reported AGE outbreaks. Thus, this alternate profile may provide a more useful tool for identifying norovirus during outbreak investigations.
Characterization and Pathogenicity of Botryosphaeriaceae Fungi Associated with Declining Urban Stands of Coast Redwood in California
Authors: Aćimović Srđan G. , Rooney-Latham Suzanne , Albu Sebastian , Grosman Donald M. , Doccola Joseph J.
Published: April 2018

Coast redwood (Sequoia sempervirens) is among the most widely planted landscape trees in California (CA) but is in decline outside its natural range due to factors including prolonged drought and plant pathogens. We investigated associations of Botryosphaeriaceae fungi with declining coast redwood trees throughout CA. More than 100 samples were collected from 11 coastal and inland locations in CA. Fifty-nine Botryosphaeria-like fungal strains were isolated and 18 were selected for further study. Phylogenetic analysis of ITS and EF-1α sequence data confirmed the presence of Botryosphaeria dothidea, Neofusicoccum australe, N. luteum, N. mediterraneum, and N. parvum. Pathogenicity testing showed that although the Neofusicoccum species vary in virulence, all are more virulent that B. dothidea. N. australe caused the largest lesions, followed by N. luteum, N. parvum, and N. mediterraneum. Of the species recovered, only B. dothidea has been previously confirmed as a pathogen of coast redwood in CA. These results confirm that multiple Botryosphaeriaceae species are associated with branch decline and dieback on coast redwood in CA, which agrees with similar studies on woody agricultural crops. Accurate diagnosis of fungal pathogens of coast redwood is important for the development of disease management strategies and may help improve horticultural practices in maintenance of urban stands.
Complementary medicine for axial spondyloarthritis: is there any scientific evidence?
Authors: Danve Abhijeet , Deodhar Atul A.
Published: April 2018

Purpose of review

Majority of patients with axial spondyloarthritis (axSpA) report use of complementary and alternative medicine (CAM) therapies before and even after the diagnosis, due to perceived efficacy and wide-spread belief that these modalities lack side effects. In this review, we describe the available scientific evidence for the CAM therapies in axSpA.

Recent findings

Clinical trials of the CAM therapies in axSpA are generally hampered by small sample size, short duration, difficulties in blinding, lack of control groups and strong placebo effect. Nonetheless, exercise programs like Pilates and mind–body techniques such as Tai Chi may have favorable effect on the disease activity and function. Although not yet confirmed, the modulation of the microbiome with the help of probiotics or fecal transplant has face validity given the evolving scientific rationale. Diet has only limited role in the management of axSpA. Deep tissue massage, omega-3 fatty acids and Stanger bath were found to be useful in small studies. CAM therapies are not always entirely well tolerated, particularly the manipulative techniques like chiropractic and Tui-na in patients with advanced disease and osteoporosis. There are no trials of yoga in axSpA despite the wider acceptance and use of yoga as an effective mind–body technique.

Larger and better quality clinical trials of CAM therapies are needed to confirm their efficacy and safety in the management of axSpA and to include them in the ‘mainstream’ medicine.
Immune privilege: failure of immunotherapy in controlling metastatic cutaneous melanoma to the eye
Authors: Sia David I.T. , Thaung Caroline , O’Hanlon-Brown Ciara , Cohen Victoria M.L. , Sagoo Mandeep S.
Published: April 2018

This report concerns a 49-year-old female with cutaneous malignant melanoma and systemic metastases. These resolved following combination immunotherapy with ipilimumab and nivolumab. She subsequently experienced unilateral floaters, an increase in iris pigmentation and pigmentary glaucoma. The eye progressively lost vision and became painful due to iris neovascularization. The clinical diagnosis was of cutaneous melanoma metastatic to the vitreous, ciliary body and iris. Enucleation was performed for symptom control, with histopathology confirming the clinical diagnosis. The immune privilege of the eye may preclude ocular metastasis control with immunotherapy. Ocular symptoms in such patients merit referral to an ophthalmologist.
Simulation Model for DMEK Donor Preparation
Authors: Mittal Vikas , Mittal Ruchi , Singh Swati , Narang Purvasha , Sridhar Priti
Published: April 2018

Purpose:

To demonstrate a simulation model for donor preparation in Descemet membrane endothelial keratoplasty (DMEK).

Methods:

The inner transparent membrane of the onion (Allium cepa) was used as a simulation model for human Descemet membrane (DM). Surgical video (see Video, Supplemental Digital Content 1, http://links.lww.com/ICO/A663) demonstrating all the steps was recorded.

Results:

This model closely simulates human DM and helps DMEK surgeons learn the nuances of DM donor preparation steps with ease. The technique is repeatable, and the model is cost-effective.

Conclusions:

The described simulation model can assist surgeons and eye bank technicians to learn steps in donor preparation in DMEK.
Overview of Systemic Candida Infections in Hospital Settings and Report of Candida After DMEK Successfully Treated With Antifungals and Partial Graft Excision
Authors: Doshi Himank , Pabon Sheila , Price Marianne O. , Feng Matthew T. , Price Francis W.
Published: April 2018

Purpose:

To report novel surgical and medical management of intraocular and corneal infection with Candida glabrata that manifested 3 months after Descemet membrane endothelial keratoplasty (DMEK) and to review demographic reasons for increasing fungal contamination of donor tissue.

Methods:

Demographics, donor rim cultures, diagnostic tests, management, clinical course, outcomes, and donor mate outcomes are reported for a fungal infection after DMEK.

Results:

The fungal infection was treated for 3 weeks with a combination of intracameral and intracorneal voriconazole and intracameral and topical amphotericin B (off-label use). After initial improvement, the infection appeared to spread to the posterior chamber and the cornea decompensated. Pars plana vitrectomy was performed, and the fungal plaque and underlying area of the graft (approximately 3 mm2 area) were excised with the vitrector. After surgical intervention, the voriconazole and amphotericin B injections were discontinued, and oral posaconazole was prescribed for 2 months (off-label use). This combination of surgical and medical management successfully cleared the infection. Surprisingly, corneal edema completely resolved, and central DMEK endothelial cell density was 2506 cells/mm2 1 month after discontinuing the antifungal injections, which apparently caused reversible endothelial toxicity.

Conclusions:

The incidence of nosocomial fungal infections, particularly non-albicans Candida, is increasing, as are the rates of positive fungal cultures from corneal donor tissue and postkeratoplasty fungal infections. Prospective studies are needed to assess the value of routine donor cultures, compare the safety and efficacy of various prophylactic treatments, and evaluate addition of antifungals to cold storage media.
Population Pharmacokinetics of Intravenous Linezolid in Premature Infants
Authors: Thibault Céline , Kassir Nastya , Goyer Isabelle , Théorêt Yves , Litalien Catherine , Moussa Ahmed , Ovetchkine Philippe , Autmizguine Julie
Published: April 2018

Background:

The emergence of coagulase-negative staphylococci with reduced vancomycin susceptibility in some neonatal intensive care units has resulted in an increase of linezolid use. Linezolid pharmacokinetics (PK) and safety in premature infants still need to be better established.

Methods:

This was a retrospective PK study. All infants who received intravenous linezolid and had linezolid plasma concentrations per standard of care were included. Linezolid concentrations were measured by high performance liquid chromatography. A population PK model was developed using nonlinear mixed effects modeling. Optimal dosing was determined based on achievement of the surrogate pharmacodynamics target for efficacy: a ratio of the area under the concentration–time curve to minimum inhibitory concentration >80. We assessed the occurrence of thrombocytopenia and lactic acidosis in relation with drug exposure.

Results:

A total of 78 plasma concentrations were collected from 26 infants, with a median postnatal age (PNA) of 24 days (8–88) and weight of 1423 g (810–3256). A 1-compartment model described linezolid data well. The final model included PNA and weight on clearance and weight on volume of distribution. Considering an MIC90 of 1 mg/L, all infants reached an area under the concentration–time curve/minimum inhibitory concentration > 80. Although thrombocytopenia and hyperlactatemia occurred frequently, they were not sustained and were not considered related to linezolid.

Conclusion:

and was well tolerated in critically ill premature infants. PNA was the main determinant of clearance.
Distribution of Visits for Chronic Conditions Between Primary Care and Specialist Providers in Medicare Shared Savings Accountable Care Organizations
Authors: Cole Evan S. , Leighton Cassandra , Zhang Yuting
Published: April 2018

Background:

Medicare Shared Savings Program Accountable Care Organizations (ACOs) may focus more on primary care given ACO financial incentives. We examine variation in primary care treatment of 8 prevalent chronic conditions across ACOs and the factors affecting the variation, and compare the role of primary care in ACOs and non-ACOs.

Research Design:

We conduct regression models at the ACO-level to identify factors predicting higher proportions of chronic condition visits delivered by primary care providers (PCPs) using 2013 Medicare claims and enrollment data. We compare the distribution of visits to PCPs, specialists and advanced practice providers between ACO-attributed and non–ACO-attributed beneficiaries.

Results:

At the ACO-level, the proportion of patients who are white and of the local population who are college educated, the complexity of the patient population, and the supply of specialists were negatively associated with the proportion of chronic condition visits delivered by PCPs, whereas the percentage of contracted physicians within the ACO who were PCPs was positively associated. These results varied when subanalyses were conducted for each specific chronic condition. ACO care for chronic conditions was managed similar to that of care for non-ACO Medicare beneficiaries in 2013, but that some ACOs utilize PCPs to manage chronic conditions more than others.

Conclusions:

Many ACOs may underutilize PCPs, and thus could actively shift care to less expensive primary care for potential savings to payers. Barriers to that shift could include low numbers of PCPs contracted in the ACO, and existing referral patterns and patient relationships with specialists.
Non-Parametric Mixture Modelling and its Application to Disease Progression Modelling
Authors: Firth Nicholas C. , Oxtoby Neil P. , Primativo Silvia , Brotherhood Emilie , Young Alexandra L. , Yong Keir X.X. , Crutch Sebastian J. , Alexander Daniel C.
Published: April 2018

Dementia is characterised by its progressive degeneration of cognitive abilities. In research cohorts, detailed neuropsychological test batteries are often administered to better understand how cognition changes over time. Understanding cognitive changes in dementia is of great importance, particularly in determining how structural changes in the brain may affect cognition and in facilitating earlier detection of symptomatic changes. Disease progression models are often applied to these data to understand how a disease changes over time from cross-sectional data or to disease trajectories from large numbers of individuals. Previous disease progression models used to build longitudinal models from cross-sectional data have focused on brain imaging data; however, these models are not directly applicable to cognitive data. Here we use the novel, non-parametric, Kernel Density Estimation Mixture Modelling (KDEMM) approach and demonstrate accurate modelling of the progression of cognitive test data. We found that using KDEMM resulted in more accurate models of disease progression in simulated data compared to Gaussian Mixture Models (GMMs) for the majority of parameters used to simulate the data. When comparing KDEMM and GMM to cognitive data collected in different Alzheimers Disease subtypes, we found the KDEMM resulted in a model much more in line with clinical phenotype. We anticipate that the KDEMM will be used to integrate cognitive test data, and other non-normally distributed datasets into complex disease progression models.
Cascading Effects of Shrimp Trawling: Increased Benthic Biomass and Increase in Net Primary Production
Authors: Joseph John Luczkovich , Rebecca A Deehr , Hart Kevin J , Clough Lisa M , Johnson Jeffrey C
Published: April 2018

Trawling has been shown to cause high mortality of discarded species (bycatch) and short-term ecological disturbance to bottom communities in coastal systems, resulting in lowered benthic biomass. Here we report evidence of a trawling-induced trophic cascade resulting in an increase in biomass of benthic polychaetes after the end of the shrimp trawling season in areas open to trawling in North Carolina (USA). Using comparative measurements of abundance of bycatch species and benthos in open and closed trawling management areas and Ecopath network modeling, we show that trawling in the open area has led to increases in deposit-feeding polychaetes and decreases in bycatch species (fish and crabs) that are benthic predators on the polychaetes. We conclude that proposed management actions to reduce the shrimp trawl fishery effort will influence other net and trap fisheries for southern flounder and blue crabs indirectly, as revealed by our network models, and the proposed trawling ban may lead to improvements in other valuable fisheries.
A generalized theory of somatic evolution
Authors: Rozhok Andrii , DeGregori James
Published: April 2018

The modern Multi-Stage Model of Carcinogenesis (MMC) was developed in the 1950s through the ‘70s and postulated carcinogenesis as a process of rounds of Darwinian selection favoring progressively more malignant cell phenotypes. Through this period, almost nothing was known about driver mutations in cancers. Also, stem cells and cellular tissue organization were poorly characterized. The general multi-stage process was later confirmed by experimental studies, and cancer risk and incidence has been explained as primarily a function of mutation occurrence. However, the MMC has never been formally tested for its ability to account for current knowledge about cancer evolution. In particular, different numbers of cancer drivers required for different cancers and vast discrepancies in the organization of stem cell compartments for different tissues appear inconsistent with the very similar age distribution of the vast majority of cancers. In this regard, the initial theoretical idea underlying MMC is often over-interpreted with little connection to modern evidence, and a general theory of somatic evolution still does not exist. In this study, we applied Monte Carlo modeling and demonstrated the effect of various parameters, such as mutation rate, mutation effects and cell division, on the MMC performance. Our modeling demonstrates that the MMC requires considerable modification in order to describe cancer incidence. We elucidate the required conditions for how somatic cell selection should operate within the MMC in order to explain modern data on stem cell clonality and cancer, and propose a generalized theory of somatic evolution based on these results.
Low nutrient levels reduce the fitness cost of MexCD-OprJ efflux pump overexpression in ciprofloxacin-resistant Pseudomonas aeruginosa
Authors: Lin Wenfang , Wan Kun , Zeng Jie , Li Jingjing , Li Xi , Yu Xin
Published: April 2018

The long-term persistence of antibiotic resistance in the environment is a public health concern. Expression of an efflux pump, an important mechanism of resistance to antibiotics, is usually associated with a fitness cost in bacteria. In this study, we aimed to determine why antibiotic resistance conferred by overexpression of an efflux pump persists in environments such as drinking and source water in which antibiotic selective pressure may be very low or even absent. Competition experiments between wild-type Pseudomonas aeruginosa and ciprofloxacin-resistant mutants revealed that the fitness cost of ciprofloxacin resistance (strains cip_1, cip_2, and cip_3) significantly decreased (P < 0.05) under low-nutrient (0.5 mg/l total organic carbon (TOC)) relative to high-nutrient (500 mg/l TOC) conditions. Mechanisms underlying this fitness cost were analyzed. MexD gene expression in resistant bacteria (cip_3 strain) was significantly lower (P < 0.05) in low-nutrient conditions, with 10 mg/l TOC (8.01 ± 0.82-fold), than in high-nutrient conditions, with 500 mg/l TOC (48.89 ± 4.16-fold). Moreover, rpoS gene expression in resistant bacteria (1.36 ± 0.13-fold) was significantly lower (P < 0.05) than that in the wild-type strain (2.78 ± 0.29-fold) under low-nutrient conditions (10 mg/l TOC), suggesting a growth advantage. Furthermore, the difference in metabolic activity between the two competing strains was significantly smaller (P < 0.05) in low-nutrient conditions (5 and 0.5 mg/l TOC). These results suggest that nutrient levels are a key factor in determining the persistence and spread of antibiotic resistance conferred by efflux pumps in the natural environment with trace amounts or no antibiotics.

Importance

The widespread of antibiotic resistance has led to an increasing concern about the environmental and public health risks. Mechanisms associated with antibiotic resistance including efflux pumps often increase bacterial fitness cost. Our study showed that the fitness cost of ciprofloxacin resistance conferred by overexpression of MexCD-OprJ efflux pump significantly decreased under low-nutrient relative to high-nutrient conditions. The significance of our research is to reveal that nutrient levels are key factor in determining the persistence of antibiotic resistance conferred by efflux pumps under conditions with trace amounts or no antibiotics, which can be mediated by some mechanisms including MexD gene expression, SOURs differences, and rpoS gene regulation.
Over 2000-fold increased production of the leaderless bacteriocin garvicin KS by genetic engineering and optimization of culture conditions
Authors: Telke Amar A. , Ovchinnikov Kirill V. , Vuoristo Kiira S. , Mathiesen Geir , Thorstensen Tage , Diep Dzung B.
Published: April 2018

The leaderless bacteriocin Garvicin KS (GarKS) is a potent antimicrobial, being active against a wide range of important pathogens. GarKS production by the native producerLactococcus garvieaeKS1546 was however relatively low (80 BU/ml) under standard laboratory growth conditions (batch culture in GM17 at 30°C). To improve the production of GarKS, we systematically evaluated the impact of different media and media components on bacteriocin production. Based on the outcomes a new medium formulation was made to greatly improve bacteriocin production. The new medium composed of pasteurized milk and tryptone (PM-T), increased GarKS production about 60-fold compared to that achieved in GM17. GarKS production was increased further 4-fold (i.e., to 20,000 BU/ml) by increasing gene dose of the bacteriocin gene cluster (gak) in the native producer. Finally, a combination of the newly composed medium (PM-T), an increased gene dose and a cultivation at a constant pH 6 and a 50-60% dissolved oxygen level in growth medium, gave rise to a GarKS production of 164,000 BU/ml. This high production, which is about 2000-fold higher compared to that initially achieved in GM17, corresponds to a GarKS production of 1.2 g/L. To our knowledge, this is one of the highest bacteriocin production reported hitherto.

Importance

Low bacteriocin production is a well-known bottle-neck in developing bacteriocins into large-scaled and useful applications. The present study shows different approaches that significantly improve bacteriocin production. This is an important research field to better exploit the antimicrobial potential of bacteriocins, especially with regard to the decreasing effect of antibiotics in infection treatments due to the global emergence of antibiotic resistance.
Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis
Authors: Piton Jérémie , Vocat Anthony , Lupien Andréanne , Foo Caroline , Riabova Olga , Makarov Vadim , Cole Stewart T.
Published: April 2018

Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1 thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ back-up program we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulphonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ and covalent adducts with the active site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 as compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.
TNF-α induces reactivation of human cytomegalovirus independently of myeloid cell differentiation following post-transcriptional establishment of latency
Authors: Forte Eleonora , Swaminathan Suchitra , Schroeder Mark W. , Kim Jeong Yeon , Terhune Scott S. , Hummel Mary
Published: April 2018

We used the Kasumi-3 model to study HCMV latency and reactivation in myeloid progenitor cells. Kasumi-3 cells were infected with HCMV strain TB40/Ewt-GFP, flow sorted for GFP+ cells, and cultured for various times to monitor establishment of latency, as judged by repression of viral gene expression (RNA/DNA ratio) and loss of virus production. We found that, in the vast majority of cells, latency was established post-transcriptionally in the GFP+ infected cells: transcription was initially turned on, and then turned off. We also found that some of the GFP-cells were infected, suggesting that latency might be established in these cells at the outset of infection. We were not able to test this hypothesis because some GFP-cells expressed lytic genes, and thus, it was not possible to separate them from GFP-quiescent cells. In addition, we found that the pattern of expression of lytic genes that have been associated with latency, including UL138, US28, and RNA2.7, was the same as that of other lytic genes, indicating that there was no preferential expression of these genes once latency is established. We confirmed previous studies showing that TNF-α induced reactivation of infectious virus, and by analyzing expression of the progenitor cell marker CD34 as well as myeloid cell differentiation markers in IE+ cells after treatment with TNF-α, we showed that TNF-α induced transcriptional reactivation of IE gene expression independently of differentiation. TNF-α-mediated reactivation in Kasumi-3 cells was correlated with activation of NF-κB, KAP-1 and ATM.

IMPORTANCE

HCMV is an important human pathogen that establishes lifelong latent infection in myeloid progenitor cells, and reactivates frequently to cause significant disease in immunocompromised people. Our observation that viral gene expression is first turned on, and then turned off to establish latency suggests that there is a host defense, which may be myeloid-specific, responsible for transcriptional silencing of viral gene expression. Our observation that TNF-α induces reactivation independently of differentiation provides insight into molecular mechanisms that control reactivation.
Epilepsy gene therapy using non-integrating lentiviral delivery of an engineered potassium channel gene
Authors: Snowball Albert , Chabrol Elodie , Wykes Robert C. , Lieb Andreas , Hashemi Kevan S. , Kullmann Dimitri M. , Walker Matthew C. , Schorge Stephanie
Published: April 2018

Refractory focal neocortical epilepsy is a devastating disease for which there is frequently no effective treatment. Gene therapy represents a promising alternative, but treating epilepsy in this way involves irreversible changes to brain tissue, so vector design must be carefully optimized to guarantee safety without compromising efficacy. We set out to develop an epilepsy gene therapy vector optimized for clinical translation. The gene encoding the voltage-gated potassium channel Kv1.1, KCNA1, was codon-optimized for human expression and mutated to accelerate the channels’ recovery from inactivation. For improved safety, this engineered potassium channel (EKC) gene was packaged into a non-integrating lentiviral vector under the control of a cell type-specific CAMK2A promoter. In a blinded, randomized, placebo-controlled pre-clinical trial, the EKC lentivector robustly reduced seizure frequency in a rat model of focal neocortical epilepsy characterized by discrete spontaneous seizures. This demonstration of efficacy in a clinically relevant setting, combined with the improved safety conferred by cell type-specific expression and integration-deficient delivery, identify EKC gene therapy as ready for clinical translation in the treatment of refractory focal epilepsy.
A cell-based probabilistic approach unveils the concerted action of miRNAs
Authors: Mahlab-Aviv Shelly , Linial Nathan , Linial Michal
Published: April 2018

Mature microRNAs (miRNAs) regulate most human genes through direct base-pairing with mRNAs. We investigate some underlying principles of such regulation. To this end, we overexpressed miRNAs in different cell types and measured the mRNA decay rate under transcriptional arrest. Parameters extracted from these experiments were incorporated into a computational stochastic framework which was developed to simulate the cooperative action of miRNAs in living cells. We identified gene sets that exhibit coordinated behavior with respect to all major miRNAs, over a broad range of overexpression levels. While a small set of genes is highly sensitive to miRNA manipulations, about 180 genes are insensitive to miRNA manipulations as measured by their degree of mRNA retention. The insensitive genes are associated with the translation machinery. We conclude that the stochastic nature of miRNAs reveals an unexpected robustness of gene expression in living cells. Moreover, the use of a systematic probabilistic approach exposes design principles of cells’ states and in particular, the translational machinery.

Highlights

A probabilistic-based simulator assesses the cellular response to thousands of miRNA overexpression manipulations

The translational machinery displays an exceptional resistance to manipulations of miRNAs.

The insensitivity of the translation machinery to miRNA manipulations is shared by different cell types

The composition of the most abundant miRNAs dominates cell identity
A parsimonious software sensor for estimating the individual dynamic pattern of methane emissions from cattle
Authors: Muñoz-Tamayo R. , Ramírez Agudelo J. F. , Dewhurst R. J. , Miller G. , Vernon T. , Kettle H.
Published: April 2018

Large efforts have been deployed in developing methods to estimate methane emissions from cattle. For large scale applications, accurate and inexpensive methane predictors are required. Within a livestock precision farming context, the objective of this work was to integrate real-time data on animal feeding behaviour with anin silicomodel for predicting the individual dynamic pattern of methane emission in cattle. The integration of real-time data with a mathematical model to predict variables that are not directly measured constitutes a software sensor. We developed a dynamic parsimonious grey-box model that uses as predictor variables either dry matter intake (DMI) or the intake time (IT). The model is described by ordinary differential equations. Model building was supported by experimental data of methane emissions from respiration chambers. The data set comes from a study with finishing beef steers (cross-bred Charolais and purebred Luing finishing). DMI and IT were recorded with load cells. A total of 37 individual dynamic patterns of methane production were analysed. Model performance was assessed by concordance analysis between the predicted methane output and the methane measured in respiration chambers. The model predictors DMI and IT performed similarly with a Lin’s concordance correlation coefficient (CCC) of 0.78 on average. When predicting the daily methane production, the CCC was 0.99 for both DMI and IT predictors. Consequently, on the basis of concordance analysis, our model performs very well compared with reported literature results for methane proxies and predictive models. Since IT measurements are easier to obtain than DMI measurements, this study suggests that a software sensor that integrates ourin silicomodel with a real-time sensor providing accurate IT measurements is a viable solution for predicting methane output in a large scale context.

Implications

Reducing methane emissions from ruminants is a major target for sustainable and efficient livestock farming. For the animal, methane production represents a loss of feed energy. For the environment, methane exerts a potent greenhouse effect. Methane mitigation strategies require accurate, non-invasive and inexpensive techniques for estimating individual methane emissions on farm. In this study, we integrate measurements of feeding behaviour in cattle and a mathematical model to estimate individual methane production. Together, model and measurements form a software sensor that efficiently predicts methane output. Our software sensor is a promising approach for estimating methane emissions at large scale.
Telomere length set point regulation in human pluripotent stem cells critically depends on the shelterin protein TPP1
Authors: Boyle John M. , Hennick Kelsey M. , Regalado Samuel G. , Vogan Jacob M. , Zhang Xiaozhu , Collins Kathleen , Hockemeyer Dirk
Published: April 2018

Telomere maintenance is essential for the long-term proliferation of human pluripotent stem cells, while their telomere length set point determines the proliferative capacity of their differentiated progeny. The shelterin protein TPP1 is required for telomere stability and elongation, but its role in set point establishment remains elusive. Here, we characterize the contribution of TPP1 isoforms and residues outside the TEL patch, TPP1’s telomerase interaction domain, to telomere length control. We demonstrate that TPP1L, the longer minor isoform of TPP1, can partially compensate for loss of the more abundant shorter isoform, TPP1S. Both TPP1S knockout and complete TPP1 knockout cell lines (TPP1 KO) show telomere shortening. However, TPP1S KO cells are able to stabilize short telomeres while TPP1 KO cells do not and die. We compare these phenotypes with that of TPP1L104A/L104A mutant cells that like the TPP1S KO have short stable telomeres. In contrast to TPP1S KO, TPP1L104A/L104A cells respond to increased telomerase. However, TPP1L104A/L104A’s sensitivity to shelterin-mediated feedback is altered, revealing TPP1L104A/L104A as a new type of shelterin mutant with aberrant set point regulation.
Mechanosensation Dynamically Coordinates Polar Growth and Cell Wall Assembly to Promote Cell Survival
Authors: Davì Valeria , Tanimoto Hirokazu , Ershov Dmitry , Haupt Armin , De Belly Henry , Le Borgne Remi , Couturier Etienne , Boudaoud Arezki , Minc Nicolas
Published: April 2018

How growing cells cope with size expansion while ensuring mechanical integrity is not known. In walled cells, such as those of microbes and plants, growth and viability are both supported by a thin and rigid encasing cell wall (CW). We deciphered the dynamic mechanisms controlling wall surface assembly during cell growth, using a novel sub-resolution microscopy approach to monitor CW thickness in live rod-shaped fission yeast cells. We found that polar cell growth yielded wall thinning, and that thickness negatively influenced growth. Thickness at growing tips exhibited oscillating behavior with thickening phases followed by thinning phases, indicative of a delayed feedback promoting thickness homeostasis. This feedback was mediated by mechanosensing through the cell wall integrity pathway, which probes strain in the wall to adjust synthase localization and activity to surface growth. Mutants defective in thickness homeostasis lysed by rupturing the wall demonstrating its essential role for walled cell survival.
Participatory budgeting as a form of dialogic accounting in Russia
Authors: Aleksandrov Evgenii , Bourmistrov Anatoli , Grossi Giuseppe
Published: April 2018

Purpose

The purpose of this paper is to investigate how participatory budgeting (PB), as a form of dialogic accounting, is produced in practice.

Design/methodology/approach

This is a qualitative case study of PB development for the period 2013-2016 in one Russian municipality. Based on triangulation of in-depth semi-structured interviews, documentary analysis, videotape data and netnographic observation, the authors employ ideas of dialogic accounting and institutional work.

Findings

The study shows that the PB experiment, which began with dialogic rhetoric, in reality, had very limited dialogic effects. However, the authors also observed that the PB dynamics over time made the practice neither inherently monologic nor dialogic. The authors explained such transformations by the way in which the individual reflexivity of actors altered when carrying out institutional work. Curiosity reflexivity was the most essential, triggering different patterns of institutional work to set up the PB experiment. However, further, the authors demonstrated that, over the course of the experiment’s development, the institutional work was trapped by various actors’ individual reflexivity forms and in this way limited PB’s dialogic potential.

Originality/value

The study shows the importance of understanding and managing individuals’ reflexivity, as it shapes the institutional work performed by different actors and, therefore, influences the direction of both the design and materialization of dialogic accounting experiments such as PB. In a broader sense, this also influences the way in which democratic governance is developed, losing democratization potential.
The use and non-use of the government financial report by Maltese Members of Parliament
Authors: Caruana Josette , Farrugia Brady
Published: April 2018

Purpose

The purpose of this paper is to examine the use and non-use of the Government Financial Report by Maltese Members of Parliament (MPs). It refers to information overload theory to analyse the gap between financial reports and their relevance for decision making.

Design/methodology/approach

A mix of qualitative (interviews) and quantitative (questionnaire) research tools are applied, with the Maltese MPs being the research participants. This method is acclaimed to be comprehensive, but this study highlights certain disadvantages when applied in the political arena.

Findings

The characteristics of the information itself could be the main cause of information overload, resulting in the non-use of the financial report for decision making. Politicians refer to financial data for their decision making, but not to the data presented in the financial report. Irrespective of the politician’s professional background, the data in the financial report is perceived as incomplete and outdated.

Practical implications

The cause of information overload and its effects are important considerations for preparers of financial information and accounting standard setters, if they wish that their production is relevant for decision makers.

Originality/value

There is an increase in research concerning politicians’ use of budgetary and performance information, at local and regional levels of government. This study investigates exclusively the use of the financial report by politicians at central level, in a politically stable environment.
Connecting local and global technological knowledge sourcing
Authors: Cantwell John , Zaman Salma
Published: April 2018

Purpose

Through increasing globalization, cities are becoming increasingly interconnected with each other. To remain competitive, it is necessary for cities to combine complementary non-local sources of knowledge with local knowledge sources. The authors contend that an increase in non-local knowledge sourcing tends to enhance local knowledge sourcing too. The purpose of this study is to examine the influence of international knowledge sources on the capacity to build upon local knowledge sources in a city region. In addition, the authors investigate whether information and communication technologies (ICT) knowledge sources have a bigger impact than do other fields of knowledge on local knowledge connectivity.

Design/methodology/approach

Using the US Patent and Trademark Office data, the authors study knowledge sourcing trends for the years 1980-2016 across 33 global cities. Backward patent citations from these granted patents are used to identify the location of inventors of prior knowledge sources, and the geography of knowledge building connections over time is assessed by using the inventor locations of cited (source) and citing (recipient) patents.

Findings

The authors show that international knowledge sourcing is highly connected with local knowledge sourcing. The authors also find that ICT have a significant effect on this relationship. However, there are significant differences across cities in the extent and nature of this relationship.

Originality/value

This study contributes to the literature on the changing geography of knowledge connections. It provides a detailed picture of changing knowledge sourcing trends at a city region level, and it improves our understanding of the role played by a variety of knowledge connections in helping a city remain competitive.
A test method for evaluation of colourfastness of textiles to perfumes
Authors: Krishnamoorthi Kavitha , Jagannathan Srinivasan
Published: April 2018

Purpose

The purpose of this paper is to present a laboratory-based test method to evaluate colourfastness of silk fabrics when perfumes are applied on it.

Design/methodology/approach

Three different simple methods like simple spray method, rubbing and perspirometer were used. In simple spray method, standard quantity was sprayed from constant distance. In rubbing fastness tester, perfume sprayed fabric was subjected to rubbing. Similarly, perfume sprayed fabric was kept in perspirometer similar to perspiration fastness testing method. As a new method, perfume applied fabric was again treated with perspiration solution and colour change and staining were observed.

Findings

On comparing the different methods, it is suggested that method using fabric applied with both perfume and perspiration solution kept in perspirometer will simulate actual wearing condition and will give the actual effect of Perfume on fabric colour.

Originality/value

So far, no standard method is available. Hence, this test method will enable fabric manufacturers, perfume manufacturers and customers to be aware of effect of perfumes on fabric colour and aesthetics.
Effect of strain rate on the tensile performance of woven para-aramid fabrics
Authors: Seretis Georgios V. , Theodorakopoulos Ioannis D. , Manolakos Dimitrios E. , Provatidis Christopher G.
Published: April 2018

Purpose

Para-aramid fabrics see service in a great variety of applications, such as heavy weight lifting applications, penetration protective multilayer panels, etc. It is, therefore, increasingly important to understand the strain rate range at which the fabric has optimum mechanical properties. Although this is a field that has not been studied before, it is of great significance since it allows for the determination of the fabric’s layer location within the multilayered structure which offers maximum overall performance. The paper aims to discuss this issue.

Design/methodology/approach

Rectangular strips of PARAX 300 S8 woven para-aramid fabric underwent uniaxial tensile tests at various extension rates. The angle between two fibers at the center of each specimen was measured after the fabrics were elongated at different tensile extensions. This recovery angle was determined by visual analysis of the test video recordings after specimen unloading. Based on this, the recovery of the weaving form after unloading was also estimated for each tensile extension. A recovery degree based deformation characterization of the sections of a typical load/extension curve has been introduced.

Findings

The fabric does not appear to be strain rate sensitive for a strain rate range of 0.03 s-1 to 0.53 s-1, and its load/extension characteristics are generally not affected by the extension rate. However, break load and maximum elongation values appear reduced at actuator velocity of 2,400 mm/min and enhanced at 3,600 mm/min. Finally, the effect of extension rate on the different deformation zones of the material is reported and discussed.

Originality/value

The current research work offers a novel approach for the investigation of non-standard response of woven para-aramid fabrics when subjected to tensile loading under various strain rates. Additionally, a new approach is introduced to explain in detail the deformation zones based on the recovery degree of the fiber orientation angle after unloading.