bluuebunny/crossref_metadata_2025 huggingface dataset:
When Transfusion Is Not an Option—the Challenges and Rewards
Authors: Schwab Rita , Kosoglow Molly , Philp Frances Hite , Suydam Erin
Published: August 2018

The decision to develop a formal Bloodless Medicine Program to attract and effectively care for patients who decline blood transfusion was made in 1998 by clinical and administrative leaders at our flagship hospital, Allegheny General Hospital, part of the Allegheny Health Network. The Bloodless Medicine Program has more than 20 years of experience in caring for this sometimes challenging patient population and with this experience has provided extensive insight into best practices related to effective, safe, patient blood management. Patient blood management is a patient-centered, evidence-based approach to transfusion that seeks to provide the right care, in the right setting, in the right way, every time. It includes honoring the wishes of patients who decline blood products in their care, that is, “bloodless” medicine. Encouraging patients to participate in their own health care decisions is a vital part of safe, compassionate care. When called upon to provide care to a patient who declines a common therapy such as blood transfusion, clinicians must often develop alternative strategies to achieve the desired results. Their willingness to think creatively and push boundaries has resulted in significant advancement of clinical knowledge and practice related to the use of blood products for all patients. Nurses who advocate for the best care for their patients are a vital component of any successful patient blood management program.
The use of technology in the sexual health education especially among minority adolescent girls in the United States
Authors: Brayboy Lynae M. , McCoy Katryna , Thamotharan Sneha , Zhu Emily , Gil Gabriela , Houck Christopher
Published: August 2018

Purpose of review

The purpose of this review is to examine current sexual health education technologies for adolescents and identify gaps in knowledge. Disparities in sexual health education are prominent and mainly affect young women of color. As a result, the use of technology to reach these marginalized populations could potentially invoke change. Thus, it is crucial to determine the viability of technology as a mechanism to bridge the knowledge gap regarding sexual health for adolescents that are most at risk of sexually transmitted infections and unwanted pregnancies.

Recent findings

With a lack of standardized, evidenced-based sexual health education programs in the United States, the future of comprehensive sexual health education is moving toward smartphone apps. Many sexual health technologies exist that target adolescents, most of which have been proven to demonstrate positive effects. Use of mobile apps, especially for vulnerable populations, can be more effective because of privacy and widespread dissemination.

Ultimately, more research needs to be conducted to determine the most effective content for these sexual health apps. Additionally, more research should be conducted on effective sexual health apps for marginalized populations to determine whether technology is a viable solution.
Pneumococcal Colonization and the Nasopharyngeal Microbiota of Children in Botswana
Authors: Kelly Matthew S. , Surette Michael G. , Smieja Marek , Rossi Laura , Luinstra Kathy , Steenhoff Andrew P. , Goldfarb David M. , Pernica Jeffrey M. , Arscott-Mills Tonya , Boiditswe Sefelani , Mazhani Tiny , Rawls John F. , Cunningham Coleen K. , Shah Samir S. , Feemster Kristen A. , Seed Patrick C.
Published: August 2018

Background:

Nasopharyngeal colonization precedes infections caused by Streptococcus pneumoniae. A more detailed understanding of interactions between S. pneumoniae and the nasopharyngeal microbiota of children could inform strategies to prevent pneumococcal infections.

Methods:

We collected nasopharyngeal swabs from children 1 to 23 months of age in Botswana between August 2012 and June 2016. We tested samples for S. pneumoniae and common respiratory viruses using polymerase chain reaction. We sequenced the V3 region of the bacterial 16S ribosomal RNA gene and used random forest models to identify clinical variables and bacterial genera that were associated with pneumococcal colonization.

Results:

Mean age of the 170 children included in this study was 8.3 months. Ninety-six (56%) children were colonized with S. pneumoniae. Pneumococcal colonization was associated with older age (P = 0.0001), a lack of electricity in the home (P = 0.02) and household use of wood as a cooking fuel (P = 0.002). Upper respiratory symptoms were more frequent in children with S. pneumoniae colonization (60% vs. 32%; P = 0.001). Adjusting for age, nasopharyngeal microbiota composition differed in colonized and noncolonized children (P = 0.001). S. pneumoniae colonization was associated with a higher relative abundance of Moraxella (P = 0.001) and lower relative abundances of Corynebacterium (P = 0.001) and Staphylococcus (P = 0.03). A decision tree model containing the relative abundances of bacterial genera had 81% sensitivity and 85% specificity for the determination of S. pneumoniae colonization status.

Conclusions:

S. pneumoniae colonization is associated with characteristic alterations of the nasopharyngeal microbiota of children. Prospective studies should determine if nasopharyngeal microbial composition alters the risk of pneumococcal colonization and thus could be modified as a novel pneumonia prevention strategy.
Randomized Trial of Tablet Computers for Education and Learning in Children and Young People with Low Vision
Authors: Gothwal Vijaya K. , Thomas Rachel , Crossland Michael , Bharani Seelam , Sharma Sujata , Unwin Hilary , Xing Wen , Khabra Komel , Dahlmann-Noor Annegret
Published: August 2018

SIGNIFICANCE

Mobile devices such as tablet computers have become widely available as mainstream devices and are also used in some schools, but there is an absence of robust information regarding the efficacy of any optical/electronic low vision device or tablet computer in supporting education of young people with low vision.

PURPOSE

A randomized controlled trial (RCT) is needed to measure the impact of tablet computers on education, specifically on independent access to educational material, in children and young people with low vision. We conducted a pilot RCT to determine the feasibility of conducting a full-scale trial.

METHODS

This was a randomized multicenter pilot trial across two sites in the United Kingdom and one site in India. Forty children and young people aged 10 to 18 years with low vision (best-corrected visual acuity for distance between <20/60 [0.48 logMAR] and 20/400 [1.30 logMAR] in the better eye) in the United Kingdom (n = 20) and India (n = 20) were randomized to two parallel arms, with a 1:1 allocation ratio, to control (n = 20) or intervention (n = 20). Control group participants received standard low vision care. The intervention group received a tablet computer (iPad) with low vision applications and instruction in its use, including accessibility features. Four primary outcomes included (1) 6-month recruitment rate, (2) retention of participants for 3 months, (3) acceptance/usage of device, and (4) accessibility of device.

RESULTS

Nineteen participants (95%) enrolled within 6 months in the United Kingdom, and 20 participants (100%), in India. Retention at 3 months was 85% (n = 17) in the United Kingdom and 95% (n = 19) in India. More than one half of participants reported using a tablet computer at school at least once every day. The majority (90%) found it easily accessible.

CONCLUSIONS

This study demonstrated that it is feasible to recruit children and young people with low vision into an international multicenter RCT of electronic assistive technology. Regardless of geographical location, children and young people with low vision reported using tablet computers at least once a day at school and accessed them easily.
Pan-Costochondritis Caused by Aspergillus Diagnosed by 18F-FDG PET/CT
Authors: Oliván-Sasot Patricia , Martínez-Sanchis Begoña , Sánchez-Vañó Raquel , Yepes-Agudelo Ana María , Bello-Arques Pilar
Published: August 2018

Thoracic pain is an entity that can be difficult to diagnose etiologically. Once the cardiac origin has been ruled out, the rheumatologic, neoplastic, and infectious causes have to be taken into account. We present the case of a patient with atypical chest pain after triple-bypass surgery in whom 18F-FDG PET/CT scan showed an important uptake of the radiopharmaceutical in costal cartilages, in relation to pan-costochondritis due to Aspergillus.
Central Nervous System Myelomatosis Delineated by High-Resolution Brain Images From Fully Digital 18F-FDG PET
Authors: Bahloul Achraf , Perrin Mathieu , Amlal Samir , Marie Pierre-Yves , Verger Antoine
Published: August 2018

Central nervous system myelomatosis is uncommon and is associated with a particularly poor prognosis. PET images, from a 53-year-old man referred to a fully digital18F-FDG PET for relapsed multiple myeloma, revealed high18F-FDG uptakes located in the cortex and sulci of the right central area and within the meningeal envelopes of the cerebellum, the trigeminal nerves, and on the spinal canal. These particular uptakes gave evidence of a central nervous system myelomatosis subsequently confirmed by plasma cells documented in cerebrospinal fluid. Such interesting images could be obtained owing to the potential of high-resolution images provided by fully digital18F-FDG PET.
Habitat, latitude and body mass influence the temperature dependence of metabolic rate
Authors: DeLong J. P. , Bachman G. , Gibert J. P. , Luhring T. M. , Montooth K. L. , Neyer A. , Reed B.
Published: August 2018

The sensitivity of metabolic rate to temperature constrains the climate in which ectotherms can function, yet the temperature dependence of metabolic rate may evolve in response to biotic and abiotic factors. We compiled a dataset on the temperature dependence of metabolic rate for heterotrophic ectotherms from studies that show a peak in metabolic rate at an optimal temperature (i.e. that describe the thermal performance curve for metabolic rate). We found that peak metabolic rates were lower in aquatic than terrestrial habitats and increased with body mass, latitude and the optimal temperature. In addition, the optimal temperature decreased with latitude. These results support competing hypotheses about metabolic rate adaptation, with hotter being better in the tropics but colder being better towards the poles. Moreover, our results suggest that the temperature dependence of metabolic rate is more complex than previously suggested.
The effects of male harm vary with female quality and environmental complexity in
Drosophila melanogaster
Authors: MacPherson Alison , Yun Li , Barrera Tania S. , Agrawal Aneil F. , Rundle Howard D.
Published: August 2018

Mate competition provides the opportunity for sexual selection which often acts strongly on males, but also the opportunity for sexual conflict that can alter natural selection on females. Recent attention has focused on the potential of sexual conflict to weaken selection on females if male sexual attention, and hence harm, is disproportionately directed towards high- over low-quality females, thereby reducing the fitness difference between these females. However, sexual conflict could instead strengthen selection on females if low-quality females are more sensitive to male harm than high-quality females, thereby magnifying fitness differences between them. We quantify the effects of male exposure on low- versus high-quality females in
Drosophila melanogaster
in each of two environments (‘simple’ and ‘complex’) that are known to alter behavioural interactions. We show that the effects of male harm are greater for low- compared to high-quality females in the complex but not the simple environment, consistent with mate competition strengthening selection on females in the former but not in the latter environment.
A mechanistic hydro-epidemiological model of liver fluke risk
Authors: Beltrame Ludovica , Dunne Toby , Vineer Hannah Rose , Walker Josephine G. , Morgan Eric R. , Vickerman Peter , McCann Catherine M. , Williams Diana J. L. , Wagener Thorsten
Published: August 2018

The majority of existing models for predicting disease risk in response to climate change are empirical. These models exploit correlations between historical data, rather than explicitly describing relationships between cause and response variables. Therefore, they are unsuitable for capturing impacts beyond historically observed variability and have limited ability to guide interventions. In this study, we integrate environmental and epidemiological processes into a new mechanistic model, taking the widespread parasitic disease of fasciolosis as an example. The model simulates environmental suitability for disease transmission at a daily time step and 25 m resolution, explicitly linking the parasite life cycle to key weather–water–environment conditions. Using epidemiological data, we show that the model can reproduce observed infection levels in time and space for two case studies in the UK. To overcome data limitations, we propose a calibration approach combining Monte Carlo sampling and expert opinion, which allows constraint of the model in a process-based way, including a quantification of uncertainty. The simulated disease dynamics agree with information from the literature, and comparison with a widely used empirical risk index shows that the new model provides better insight into the time–space patterns of infection, which will be valuable for decision support.
A simple, high-resolution, non-destructive method for determining the spatial gradient of the elastic modulus of insect cuticle
Authors: Eshghi S h. , Jafarpour M. , Darvizeh A. , Gorb S. N. , Rajabi H.
Published: August 2018

Nature has evolved structures with high load-carrying capacity and long-term durability. The principles underlying the functionality of such structures, if studied systematically, can inspire the design of more efficient engineering systems. An important step in this process is to characterize the material properties of the structure under investigation. However, direct mechanical measurements on small complex-shaped biological samples involve numerous technical challenges. To overcome these challenges, we developed a method for estimation of the elastic modulus of insect cuticle, the second most abundant biological composite in nature, through simple light microscopy. In brief, we established a quantitative link between the autofluorescence of different constituent materials of insect cuticle, and the resulting mechanical properties. This approach was verified using data on cuticular structures of three different insect species. The method presented in this study allows three-dimensional visualisation of the elastic modulus, which is impossible with any other available technique. This is especially important for precise finite-element modelling of cuticle, which is known to have spatially graded properties. Considering the simplicity, ease of implementation and high-resolution of the results, our method is a crucial step towards a better understanding of material–function relationships in insect cuticle, and can potentially be adapted for other graded biological materials.
Designed for life: biocompatible de novo designed proteins and components
Authors: Grayson Katie J. , Anderson J. L. Ross
Published: August 2018

A principal goal of synthetic biology is the de novo design or redesign of biomolecular components. In addition to revealing fundamentally important information regarding natural biomolecular engineering and biochemistry, functional building blocks will ultimately be provided for applications including the manufacture of valuable products and therapeutics. To fully realize this ambitious goal, the designed components must be biocompatible, working in concert with natural biochemical processes and pathways, while not adversely affecting cellular function. For example, de novo protein design has provided us with a wide repertoire of structures and functions, including those that can be assembled and function
in vivo
. Here we discuss such biocompatible designs, as well as others that have the potential to become biocompatible, including non-protein molecules, and routes to achieving full biological integration.
Newton's financial misadventures in the South Sea Bubble
Authors: Odlyzko Andrew
Published: August 2018

A very popular investment anecdote relates how Isaac Newton, after cashing in large early gains, staked his fortune on the success of the South Sea Company of 1720 and lost heavily in the ensuing crash. However, this tale is based on only a few items of hard evidence, some of which are consistently misquoted and misinterpreted. A superficially plausible contrarian argument has also been made that he did not lose much in that period, and John Maynard Keynes even claimed Newton successfully surmounted the South Sea Bubble. This paper presents extensive new evidence that while Newton was a successful investor before this event, the folk tale about his making large gains but then being drawn back into that mania and suffering large losses is almost certainly correct. It probably even understates the extent of his financial miscalculations. Incidental to the clarification of this prominent issue, a controversy between Dale
et al
. and Shea about an aspect of market rationality during that bubble is settled. Some new information is also presented about Thomas Guy, famous for making a fortune out of the Bubble that paid for the establishment of Guy's Hospital, and other investors. The work reported here suggests new research directions and perspectives on bubbles.
Accessory parameters in conformal mapping: exploiting the isomonodromic tau function for Painlevé VI
Authors: Anselmo Tiago , Nelson Rhodri , Carneiro da Cunha Bruno , Crowdy Darren G.
Published: August 2018

We present a novel method to solve the accessory parameter problem arising in constructing conformal maps from a canonical simply connected planar region to the interior of a circular arc quadrilateral. The Schwarz–Christoffel accessory parameter problem, relevant when all sides have zero curvature, is also captured within our approach. The method exploits the isomonodromic tau function associated with the Painlevé VI equation. Recently, these tau functions have been shown to be related to certain correlation functions in conformal field theory and asymptotic expansions have been given in terms of tuples of the Young diagrams. After showing how to extract the monodromy data associated with the target domain, we show how a numerical approach based on the known asymptotic expansions can be used to solve the conformal mapping accessory parameter problem. The viability of this new method is demonstrated by explicit examples and we discuss its extension to circular arc polygons with more than four sides.
TreeBASEdmp: A Toolkit for Phyloinformatic Research
Authors: Piel William H. , Vos Rutger A.
Published: August 2018

Over the last 20 years, TreeBASE has acquired a substantial body of phylogenetic data, including more than 20,000 published phylogenies. Given latency issues and limited options when it comes to querying the database remotely, a simplified and consolidated version of the database, here called TreeBASEdmp, is made available for download, allowing biologists to design custom analyses of the data on their local computers. The database is indexed to support searching for phylogenetic topologies using nested sets and closure tables. Here we propose a new approach to find broadly-defined phylogenetic patterns, a method we callGeneric Topological Querying, which allows the user to find hypotheses of relationship without being constrained to use particular sets of specific taxa. Additionally, we normalize as many leaf nodes as possible to an equivalent species rank identifier to assist in supertree synthesis. Our example script rapidly assembles sets of trees and generates a matrix representation of them for subsequent supertree generation.
Prediction of Choice From Competing Mechanosensory and Choice-Memory Cues During Active Tactile Decision Making
Authors: Dario Campagner , Mathew Evans H , Katarina Chlebikova , Andrea Colins-Rodriguez , Michaela Loft S E , Sarah Fox , David Pettifer , Mark Humphries D , Karel Svoboda , Rasmus Petersen S
Published: August 2018

Perceptual decision making is an active process where animals move their sense organs to extract task-relevant information. To investigate how the brain translates sensory input into decisions during active sensation, we developed a mouse active touch task where the mechanosensory input can be precisely measured and that challenges animals to use multiple mechanosensory cues. Mice were trained to localise a pole using a single whisker and to report their decision by selecting one of three choices. Using high-speed imaging and machine vision we estimated whisker-object mechanical forces at millisecond resolution. Mice solved the task by a sensory-motor strategy where both the strength and direction of whisker bending were informative cues to pole location. We found competing influences of immediate sensory input and choice memory on mouse choice. On correct trials, choice could be predicted from the direction and strength of whisker bending, but not from previous choice. In contrast, on error trials, choice could be predicted from previous choice but not from whisker bending. This study shows that animal choices during active tactile decision making can be predicted from mechanosenory and choice-memory signals; and provides a new task, well-suited for future study of the neural basis of active perceptual decisions.

SIGNIFICANCE STATEMENT

Due to the difficulty of measuring the sensory input to moving sense organs, active perceptual decision making remains poorly understood. The whisker system provides a way forward since it is now possible to measure the mechanical forces due to whisker-object contact during behaviour. Here we train mice in a novel behavioural task that challenges them to use rich mechanosensory cues, but can be performed using one whisker and enables task-relevant mechanical forces to be precisely estimated. This approach enables rigorous study of how sensory cues translate into action during active, perceptual decision making. Our findings provide new insight into active touch and how sensory/internal signals interact to determine behavioural choices.
Comparing the efficacy of cancer therapies between subgroups in basket trials
Authors: Palmer Adam C. , Plana Deborah , Sorger Peter K.
Published: August 2018

An increase in the number of targeted anti-cancer drugs and growing genomic stratification of patients has led to the development of basket clinical trials in which a single drug is tested simultaneously in multiple tumor subtypes under a master protocol. Basket trials typically involve few patients per type, making it difficult to rigorously compare responses across types. We describe the use of permutation testing to analyze tumor volume changes and Progression Free Survival across subtypes in basket trials for neratinib, larotrectinib, pembrolizumab, and imatinib. Permutation testing is a complement to the standard Simon’s two-stage binomial approach and can test for differences among subgroups using empirical null distributions while controlling for multiple hypothesis testing. This approach uncovers examples of therapeutic benefit missed by a binomial test; in the case of the SUMMIT trial, our analysis identifies an overlooked opportunity for use of neratinib in lung cancers carrying ERBB2 Exon 20 mutations.
The interaction between ORF18 and ORF30 is required for late gene expression in Kaposi’s sarcoma-associated herpesvirus
Authors: Castañeda Angelica F , Glaunsinger Britt A
Published: August 2018

In the beta- and gammaherpesviruses, a specialized complex of viral transcriptional activators (vTAs) coordinate to direct expression of virus-encoded late genes, which are critical for viral assembly and whose transcription initiates only after the onset of viral DNA replication. The vTAs in Kaposi’s sarcoma-associated herpesvirus (KSHV) are ORF18, ORF24, ORF30, ORF31, ORF34, and ORF66. While the general organization of the vTA complex has been mapped, the individual roles of these proteins, and how they coordinate to activate late gene promoters, remains largely unknown. Here, we performed a comprehensive mutational analysis of the conserved residues in ORF18, which is a highly interconnected vTA component. Surprisingly, the mutants were largely selective for disrupting the interaction with ORF30 but not the other three ORF18 binding partners. Furthermore, disrupting the ORF18-ORF30 interaction weakened the vTA complex as a whole, and an ORF18 point mutant that failed to bind ORF30 was unable to complement an ORF18 null virus. Thus, contacts between individual vTAs are critical, as even small disruptions in this complex result in profound defects in KSHV late gene expression.
Basolateral localization of MMP14 drives apicobasal polarity change during EMT independently of its catalytic activity
Authors: Andrieu Cyril , Montigny Audrey , Alfandari Dominique , Theveneau Eric
Published: August 2018

The transmembrane Matrix Metalloproteinase MMP14/MT1-MMP is known to promote cell migration by cleavage of the extracellular matrix. To initiate migration, epithelial cells need to gain mesenchymal attributes. They reduce cell-cell junctions and apicobasal polarity and gain migratory capabilities. This process is named epithelial-mesenchymal transition (EMT). MMP14’s implication in EMT is still ill-defined. We used chick neural crest (NC) cells as a model to explore the function of MMP14 in physiological EMT. Our results show that MMP14 is expressed by chick NC cells. However, it is its subcellular localization, rather than its expression, that correlates with EMT. MMP14 is first apical and switches to basolateral domains during EMT. Loss of function and rescue experiments show that MMP14 is involved in EMT independently of its catalytic activity. It lies downstream of pro-EMT genes and upstream of cell polarity. We found that basolateral localization of MMP14 is required and sufficient to induce polarity change in NC cells and neuroepithelial cells, respectively. These effects on polarity occur without impact on cell-cell adhesion or the extracellular matrix. Overall, our data points to a new function of MMP14 in EMT that will need to be further explored in other systems such as cancer cells.
Activation mechanism of ATP-sensitive K+channels explored with real-time nucleotide binding
Authors: Puljung Michael C. , Vedovato Natascia , Usher Samuel , Ashcroft Frances M.
Published: August 2018

The response of ATP-sensitive K+channels (KATP) to cellular metabolism is coordinated by three classes of nucleotide binding site (NBS). We used a novel approach involving labeling of intact channels in a native, membrane environment with a non-canonical fluorescent amino acid and measurement (using FRET with fluorescent nucleotides) of steady-state and time-resolved nucleotide binding to dissect the role of NBS2 of the accessory SUR1 subunit of KATPin channel gating. Binding to NBS2 was Mg2+-independent, but Mg was required to trigger a conformational change in SUR1. Mutation of a lysine (K1384A) in NBS2 that coordinates bound nucleotides increased the EC50for trinitrophenyl-ADP binding to NBS2, but only in the presence of Mg2+, indicating that this mutation disrupts the ligand-induced conformational change. Comparison of nucleotide-binding with ionic currents suggests a model in which each nucleotide binding event to NBS2 of SUR1 is independent and promotes KATPactivation by the same amount.
GI-16 lineage (624/I or Q1), there and Back Again: the history of one of the major threat for poultry farming of our era
Authors: Franzo Giovanni , Cecchinato Mattia , Tosi Giovanni , Fiorentini Laura , Faccin Francesca , Tucciarone Claudia Maria , Trogu Tiziana , Barbieri Ilaria , Massi Paola , Moreno Ana
Published: August 2018

The genetic variability of Infectious bronchitis virus (IBV) is one of the main challenges for its control, hindering not only the development of effective vaccination strategies but also its classification and, consequently, epidemiology understanding. The 624/I and Q1 genotypes, now recognized to be part of the GI-16 lineage, represent an excellent example of the practical consequences of IBV molecular epidemiology limited knowledge. In fact, being their common origin unrecognized for a long time, independent epidemiological pictures were drawn for the two genotypes. To fix this misinterpretation, the present study reconstructs the history, population dynamics and spreading patterns of GI-16 lineage as a whole using a phylodynamic approach. A collection of worldwide available hypervariable region 1 and 2 (HVR12) and 3 (HVR3) sequences of the S1 protein was analysed together with 258 HVR3 sequences obtained from samples collected in Italy (the country where this genotype was initially identified) since 1963. The results demonstrate that after its emergence at the beginning of the XX century, GI-16 was able to persist until present days in Italy. Approximately in the late 1980s, it migrated to Asia, which became the main nucleus for further spreading to Middle East, Europe and especially South America, likely through multiple introduction events. A remarkable among-country diffusion was also demonstrated in Asia and South America. Interestingly, although most of the recent Italian GI-16 strains originated from ancestral viruses detected in the same country, a couple were closely related to Chinese ones, supporting a backward viral flow from China to Italy.

Besides to the specific case-study results, this work highlights the misconceptions that originate from the lack of a unified nomenclature and poor molecular epidemiology data generation and sharing. This shortcoming appears particularly relevant since the described scenario could likely be shared by many other IBV genotypes and pathogens in general.
Extracellular matrix stiffness regulates force transmission pathways in multicellular ensembles of human airway smooth muscle cells
Authors: Polio Samuel R. , Stasiak Suzanne E , Krishnan Ramaswamy , Parameswaran Harikrishnan
Published: August 2018

For an airway or a blood vessel to narrow, there must be a connected path that links the smooth muscle (SM) cells with each other, and transmits forces around the organ, causing it to constrict. Currently, we know very little about the mechanisms that regulate force transmission pathways in a multicellular SM ensemble. Here, we used extracellular matrix (ECM) micropatterning to study force transmission in a two-cell ensemble of SM cells. Using the two-SM cell ensemble, we demonstrate (a) that ECM stiffness acts as a switch that regulates whether SM force is transmitted through the ECM or through cell-cell connections. (b) Fluorescent imaging for adherens junctions and focal adhesions show the progressive loss of cell-cell borders and the appearance of focal adhesions with the increase in ECM stiffness (confirming our mechanical measurements). (c) At the same ECM stiffness, we show that the presence of a cell-cell border substantially decreases the overall contractility of the SM cell ensemble. Our results demonstrate that connectivity among SM cells is a critical factor to consider in the development of diseases such as asthma and hypertension.
Evolution of Bacterial Gene Transfer Agents
Authors: Redfield Rosemary J. , Soucy Shannon M.
Published: August 2018

Bacterial gene transfer agents (GTAs) are small virus-like particles that package DNA fragments and inject them into cells. They are encoded by gene clusters resembling defective prophages, with genes for capsid head and tail components. These gene clusters are usually assumed to be maintained by selection for the benefits of GTA-mediated recombination, but this has never been tested. We rigorously examined the potential benefits of GTA-mediated recombination, considering separately transmission of GTA-encoding genes and recombination of all chromosomal genes. In principle GTA genes could be directly maintained if GTA particles spread them to GTA−cells often enough to compensate for the loss of GTA-producing cells. However careful bookkeeping showed that losses inevitably exceed gains for two reasons. First, cells must lyse to release particles to the environment. Second, GTA genes are not preferentially replicated before DNA is packaged. A simulation model was then used to search for conditions where recombination of chromosomal genes makes GTA+populations fitter than GTA−populations. Although the model showed that both synergistic epistasis and some modes of regulation could generate fitness benefits large enough to overcome the cost of lysis, these benefits neither allowed GTA+cells to invade GTA−populations, nor allowed GTA+populations to resist invasion by GTA−cells. Importantly, the benefits depended on highly improbable assumptions about the efficiencies of GTA production and recombination. Thus, the selective benefits that maintain GTA gene clusters over many millions of years must arise from consequences other than transfer of GTA genes or recombination of chromosomal genes.
A quantitative and predictive model for RNA binding by human Pumilio proteins
Authors: Jarmoskaite Inga , Denny Sarah K. , Vaidyanathan Pavanapuresan P. , Becker Winston R. , Andreasson Johan O.L. , Layton Curtis J. , Kappel Kalli , Shivashankar Varun , Sreenivasan Raashi , Das Rhiju , Greenleaf William J. , Herschlag Daniel
Published: August 2018

High-throughput methodologies have enabled routine generation of RNA target sets and sequence motifs for RNA-binding proteins (RBPs). Nevertheless, quantitative approaches are needed to capture the landscape of RNA/RBP interactions responsible for cellular regulation. We have used the RNA-MaP platform to directly measure equilibrium binding for thousands of designed RNAs and to construct a predictive model for RNA recognition by the human Pumilio proteins PUM1 and PUM2. Despite prior findings of linear sequence motifs, our measurements revealed widespread residue flipping and instances of positional coupling. Application of our thermodynamic model to published in vivo crosslinking data reveals quantitative agreement between predicted affinities and in vivo occupancies. Our analyses suggest a thermodynamically driven, continuous Pumilio binding landscape that is negligibly affected by RNA structure or kinetic factors, such as displacement by ribosomes. This work provides a quantitative foundation for dissecting the cellular behavior of RBPs and cellular features that impact their occupancies.
Brain connectivity dynamics: Multilayer network switching rate predicts brain performance
Authors: Pedersen Mangor , Zalesky Andrew , Omidvarnia Amir , Jackson Graeme D.
Published: August 2018

Large-scale brain dynamics measures repeating spatiotemporal connectivity patterns that reflect a range of putative different brain states that underlie the dynamic repertoire of brain functions. The role of transition between brain networks is poorly understood and whether switching between these states is important for behavior has been little studied. Our aim here is to model switching between functional brain networks using multilayer network methods and test for associations between model parameters and behavioral measures. We calculated time-resolved functional MRI (fMRI) connectivity from one-hour long data recordings in 1003 healthy human adults from the Human Connectome Project. The time-resolved fMRI connectivity data was used to generate a spatiotemporal multilayer modularity model enabling us to quantifynetwork switchingwhich we define as the rate at which each brain region transits between different fMRI networks. We found i) an inverse relationship between network switching and connectivity dynamics –defined as the difference in variance between time-resolved fMRI connectivity signals and phase randomized surrogates–; ii) brain connectivity was lower during intervals of network switching; iii) brain areas with frequent network switching had greater temporal complexity; iv) brain areas with high network switching were located in association cortices; and v) using cross-validated Elastic Net regression, network switching predicted inter-subject variation in working memory performance, planning/reasoning and amount of sleep. Our findings shed new light on the importance of brain dynamics predicting task performance and amount of sleep. The ability to switch between network configurations thus appears to be a fundamental feature of optimal brain function.
SIS-seq, a molecular ‘time machine’, connects single cell fate with gene programs
Authors: Tian Luyi , Schreuder Jaring , Zalcenstein Daniela , Tran Jessica , Kocovski Nikolce , Su Shian , Diakumis Peter , Bahlo Melanie , Sargeant Toby , Hodgkin Phillip D. , Ritchie Matthew E. , Naik Shalin H.
Published: August 2018

Conventional single cell RNA-seq methods are destructive, such that a given cell cannot also then be tested for fate and function, without a time machine. Here, we develop a clonal method SIS-seq, whereby single cells are allowed to divide, and progeny cells are assayed separately in SISter conditions; some for fate, others by RNA-seq. By cross-correlating progenitor gene expression with mature cell fate within a clone, and doing this for many clones, we can identify the earliest gene expression signatures of dendritic cell subset development. SIS-seq could be used to study other populations harboring clonal heterogeneity, including stem, reprogrammed and cancer cells to reveal the transcriptional origins of fate decisions.
Construction and Characterization of a Synthetic Baculovirus-inducible 39K Promoter
Authors: Dong Zhan-Qi , Hu Zhi-Gang , Li Hai-Qing , Jiang Ya-Ming , Cao Ming-Ya , Chen Peng , Lu Cheng , Pan Min-Hui
Published: August 2018

The low expression activity and specificity of natural promoters limit the applications of genetic engineering. To construct a highly efficient synthetic inducible promoter in the Bombyx mori (Lepidoptera), we analyzed the regulatory elements and functional regions of the B. mori nucleopolyhedrovirus (BmNPV) 39K promoter. The results of truncated mutation analysis of the 39K promoter showed that the transcriptional regulatory region spanning positions -573 to -274 and +1 to +62 is essential for virus-inducible promoter activity. Further investigation using electrophoretic mobility shift assay (EMSA) revealed that the baculovirus IE-1 protein binds to the 39K promoter at the -310 to -355 region, and transcription activates the expression of 39K promoter assay. Finally, we successfully constructed a synthetic inducible promoter that increase the virus-inducing activity of other promoters using the baculovirus-inducible transcriptional activation region that binds to specific core elements of 39K (i.e., spanning the region -310 to -355). In summary, we describes a novel, synthetic, and highly efficient biological tool, namely, a virus-inducible 39K promoter, which provides endless possibilities for future gene function research, gene therapy, and pest control in genetic engineering.
Antimicrobial Susceptibility Testing ofChlamydophila pneumoniae: Pilot Study for Alternative Methods that Address the Complex Chlamydial Life Cycle
Authors: Stewart Laura S. , Alvarez-Macias Sandra , McHenry Rendie , Chappell James D. , Stratton Charles W.
Published: August 2018

Conventional susceptibility testing ofChlamydophila pneumoniaedoes not account for the complex life cycle that takes place in an obligatory intracellular niche and involves multiple morphological forms. Some of these forms (elementary bodies and cryptic bodies) cause persistence and are not susceptible to antimicrobial agents. Therefore, we describe a pilot study for alternative methods of susceptibility testing ofC. pneumoniae. These methods include delaying the addition of antimicrobial agents to cell cultures for 48 hours to allow the development of an established chlamydial infection as well as the use of reverse transcriptase quantitative PCR [RT-qPCR] to measure messenger RNA. Using these methods, susceptibility testing of an established infection in Hep2 cells was compared with conventional susceptibility testing ofC. pneumoniae.

Conventional antimicrobial susceptibility testing ofC. pneumoniaeresults in MICs and MBCs that would suggest that recommended treatment regimens of 2 to 3 weeks of antibiotics such as doxycycline, clarithromycin, levofloxacin, and rifabutin would be sufficient. However, susceptibility testing using an established chlamydial infection in HEp2 cells reveals that none of these agents are as inhibitory and/or bactericidal as indicated by conventional methods. The resultsof this pilot study suggest that further evaluation of chlamydial susceptibility testing methods using established infection in cell cultures and RT-qPCR to measure messenger RNA are needed to optimize treatment recommendations for chronicC. pneumoniaeinfections.
Acetylation of nuclear localization signal controls importin-mediated nuclear transport of Ku70
Authors: Fujimoto H , Ikuta T , Koike A , Koike M
Published: August 2018

Ku70 participates in various intra-and extra-nucleic processes. For multifunctional control, machinery that precisely regulates the intracellular localization of Ku70 is essential. Recently, it was reported that acetylation of Ku70 regulates its function. Here, we demonstrate that specific lysine residues in Ku70 that are targets of acetylation are critical for regulating nuclear transportin vivo. Ku70-GFP fusion proteins transiently expressed in cultured cells localized in the nucleus, whereas mimicking acetylation of K553 or K556 in the Ku70 nuclear localization signal (NLS) by substituting these lysine residues with glutamine markedly decreased the nuclear localization of Ku70. Moreover, the Ku70-importin interaction was suppressed in the K553Q and K556Q mutants. Theoretical estimations indicated that the binding energy between the Ku70 NLS and importin-α decreases with acetylation of lysine residues in the Ku70 NLS, similar to the case when these lysine residues are substituted with glutamine. These results suggest that acetylation of specific lysine residues in the Ku70 NLS is a key switch that controls the localization of Ku70 by modulating interactions between Ku70 and nuclear transport factors.
Identification of a genetic element required for spore killing in Neurospora
Authors: Rhoades Nicholas A. , Harvey Austin M. , Samarajeewa Dilini A. , Svedberg Jesper , Yusifov Aykhan , Abusharekh Anna , Manitchotpisit Pennapa , Brown Daren W. , Sharp Kevin J. , Rehard David G. , Peters Joshua , Ostolaza-Maldonado Xavier , Stephenson Jackson , Shiu Patrick K. T. , Johannesson Hanna , Hammond Thomas M.
Published: August 2018

Meiotic drive elements likeSpore killer-2(Sk-2) in Neurospora are transmitted through sexual reproduction to the next generation in a biased manner.Sk-2achieves this biased transmission through spore killing. Here, we identifyrfk-1as a gene required for the spore killing mechanism. Therfk-1gene is associated with a 1,481 bp DNA interval (calledAH36) near the right border of the 30 cMSk-2element, and its deletion eliminates the ability ofSk-2to kill spores. Therfk-1gene also appears to be sufficient for spore killing because its insertion into a non-Sk-2isolate disrupts sexual reproduction after the initiation of meiosis. Although the completerfk-1transcript has yet to be defined, our data indicate thatrfk-1encodes a protein of at least 39 amino acids and thatrfk-1has evolved from a partial duplication of genencu07086. We also present evidence thatrfk-1’s location near the right border ofSk-2is critical for the success of spore killing. Increasing the distance ofrfk-1from the right border ofSk-2causes it to be inactivated by a genome defense process called meiotic silencing by unpaired DNA (MSUD), adding to accumulating evidence that MSUD exists, at least in part, to protect genomes from meiotic drive.
Antimicrobial resistance prevalence, rates of hospitalization with septicemia and rates of mortality with sepsis in adults in different US states
Authors: Goldstein Edward , MacFadden Derek R. , Karaca Zeynal , Steiner Claudia A. , Viboud Cecile , Lipsitch Marc
Published: August 2018

Objectives

Rates of hospitalization with sepsis/septicemia and associated mortality in the US have risen significantly during the last two decades. Antibiotic resistance may contribute to the rates of sepsis-related outcomes through lack of clearance of bacterial infections following antibiotic treatment during different stages of infection. However, there is limited information about the relation between prevalence of resistance to various antibiotics in different bacteria and rates of sepsis-related outcomes.

Methods

For different age groups of adults (18-49y,50-64y,65-74y,75-84y,85+y) and combinations of antibiotics/bacteria, we evaluated associations between state-specific prevalence (percentage) of resistant samples for a given combination of antibiotics/bacteria among catheter-associated urinary tract infections in the CDC Antibiotic Resistance Patient Safety Atlas data between 2011-2014 and rates of hospitalization with septicemia (ICD-9 codes 038.xx present on the discharge diagnosis) reported to the Healthcare Cost and Utilization Project (HCUP), as well as rates of mortality with sepsis (ICD-10 codes A40-41.xx present on death certificate).

Results

Among the different combinations of antibiotics/bacteria, prevalence of resistance to fluoroquinolones inE. colihad the strongest association with septicemia hospitalization rates for individuals aged over 50y, and with sepsis mortality rates for individuals aged 18-84y. A number of positive correlations between prevalence of resistance for different combinations of antibiotics/bacteria and septicemia hospitalization/sepsis mortality rates in adults were also found.

Conclusions

Our findings, as well as our related work on the relation between antibiotic use and sepsis rates support the association between resistance to/use of certain antibiotics and rates of sepsis-related outcomes, suggesting the potential utility of antibiotic replacement.
Measuring interdependencies of preferred supplier enablers
Authors: C.V. Sunil Kumar , Routroy Srikanta
Published: August 2018

Purpose

The purpose of this paper is to analyze preferred supplier enablers (PSEs) and measure the interdependencies among themselves for enhancing preferred supplier relationship.

Design/methodology/approach

In the current study, an approach has been developed in which the significance of various PSEs was determined by applying Fuzzy Analytic Hierarchy Process (FAHP) and the prominent PSEs were screened out through Pareto analysis. Also, the interdependence among the prominent PSEs was measured by applying the Fuzzy Decision Making Trial and Evaluation Laboratory method in order to select the right PSEs in ascribing the Preferred Supplier Status. Finally, the weakest relationships among the PSEs were confirmed by applying the student’st-test and then an impact relationship map of PSEs was developed.

Findings

The strength of relationships among the PSEs, grouping of PSEs into causes and effects on a causal diagram and a concise impact relationship map of PSEs were determined. Further, the PSEs that a manufacturer must primarily focus and monitor were also obtained.

Research limitations/implications

The study was conducted in an Indian electronic manufacturing environment. Therefore, the results obtained would be more relevant to the high end technology product manufacturers operating in the developing countries.

Practical implications

From the current study, a manufacturer can alleviate, favorably associate and integrate with the good suppliers and then eventually establish a strong supply base.

Originality/value

Manufacturers are looking for the closer and favored relationships by bringing in the concept of preferred supplier while dealing with their key suppliers. Thus, the results obtained from the current study would be of great assistance to a manufacturer in gaining an extra cutting-edge and, in turn, tackling the increased competitive pressures and reduced availability of resources.