bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Shorter Treatment Regimens for Hepatitis C on Population Health and Under Fixed Budgets
Authors: Morgan Jake R , Kim Arthur Y , Naggie Susanna , Linas Benjamin P
Published: December 2017

Background

Direct acting antiviral hepatitis C virus (HCV) therapies are highly effective but costly. Wider adoption of an 8-week ledipasvir/sofosbuvir treatment regimen could result in significant savings, but may be less efficacious compared with a 12-week regimen. We evaluated outcomes under a constrained budget and cost-effectiveness of 8 vs 12 weeks of therapy in treatment-naïve, noncirrhotic, genotype 1 HCV-infected black and nonblack individuals and considered scenarios of IL28B and NS5A resistance testing to determine treatment duration in sensitivity analyses.

Methods

We developed a decision tree to use in conjunction with Monte Carlo simulation to investigate the cost-effectiveness of recommended treatment durations and the population health effect of these strategies given a constrained budget. Outcomes included the total number of individuals treated and attaining sustained virologic response (SVR) given a constrained budget and incremental cost-effectiveness ratios.

Results

We found that treating eligible (treatment-naïve, noncirrhotic, HCV-RNA <6 million copies) individuals with 8 weeks rather than 12 weeks of therapy was cost-effective and allowed for 50% more individuals to attain SVR given a constrained budget among both black and nonblack individuals, and our results suggested that NS5A resistance testing is cost-effective.

Conclusions

Eight-week therapy provides good value, and wider adoption of shorter treatment could allow more individuals to attain SVR on the population level given a constrained budget. This analysis provides an evidence base to justify movement of the 8-week regimen to the preferred regimen list for appropriate patients in the HCV treatment guidelines and suggests expanding that recommendation to black patients in settings where cost and relapse trade-offs are considered.
Long-Term Neurological and Radiological Results of Consecutive 63 Unruptured Anterior Communicating Artery Aneurysms Clipped via Lateral Supraorbital Keyhole Minicraniotomy
Authors: Mori Kentaro , Wada Kojiro , Otani Naoki , Tomiyama Arata , Toyooka Terushige , Tomura Satoshi , Takeuchi Satoru , Yamamoto Takuji , Nakao Yasuaki , Arai Hajime
Published: December 2017

BACKGROUND

Treatments for unruptured anterior communicating artery (AcomA) aneurysm have relatively high morbidity.

OBJECTIVE

To assess the lateral supraorbital keyhole approach for safe and complete clipping of unruptured AcomA aneurysm and evaluate the long-term clinical and radiological outcomes, including cognitive and depressive status.

METHODS

A total of 63 patients (aged 41-79 yr, mean 64 yr) with relatively small AcomA aneurysms clipped via the lateral supraorbital approach were retrospectively analyzed among the 105 AcomA aneurysms treated by clipping from 2005 to 2014. Neurological and cognitive functions were examined by several scales, including the modified Rankin Scale (mRS) and Mini-Mental Status Examination. The depressive state was assessed using the Beck Depression Inventory and Hamilton Depression Scale. The state of clipping was assessed 1 yr and then every few years after the operation by 3-dimensional computed tomography angiography.

RESULTS

Complete neck clipping was confirmed in 62 aneurysms (98.4%). Perioperative complications occurred in 5 patients (5/63; mild frontalis muscle weakness in 3, anosmia in 1, and meningitis in 1). The mean clinical follow-up period was 5.2 ± 2.1 yr. No patient showed an mRS score more than 2 and all were completely independent in daily life. The depression scores were significantly improved after surgery. The overall mortality was 0% and overall morbidity (mRS score > 2 or Mini-Mental Status Examination score < 24) was 1.6%. All completely clipped aneurysms did not show any recurrence during the mean follow-up period of 4.9 ± 2.1 yr.

CONCLUSION

Lateral supraorbital keyhole approach to clip relatively small unruptured AcomA aneurysm promises less invasive and durable treatment.
Management of Complex Epithelial Ingrowth After Laser In Situ Keratomileusis Using Fibrin Tissue Glue
Authors: Chen Lisa Y. , Kung Jennifer S. , Manche Edward E.
Published: December 2017

Objectives:

To evaluate the efficacy and safety of adjunctive fibrin tissue glue in the treatment of complex epithelial ingrowth after laser in situ keratomileusis (LASIK).

Methods:

A retrospective review was performed of 12 eyes in 12 patients treated for clinically significant epithelial ingrowth after LASIK with mechanical debridement of the ingrowth and placement of fibrin tissue glue. Primary outcome measurements including recurrence of ingrowth, visual acuity, and manifest refraction were evaluated at each postoperative examination. Changes in higher-order aberrometry were also evaluated.

Results:

After epithelial ingrowth removal with adjunctive fibrin tissue glue, 11 eyes (91.7%) had no recurrence of ingrowth at the final follow-up examination. Uncorrected distance visual acuity changed from 20/20 or better in 3 eyes (25%) and 20/40 or better in 6 eyes (50%) preoperatively to 20/20 or better in 5 eyes (41.7%) and 20/40 or better in 10 eyes (83.3%) postoperatively. Nine eyes (75%) gained one or more lines of best-corrected distance visual acuity (CDVA). No eyes lost any lines of CDVA. There was no significant change in mean spherical equivalent (P=0.22) or mean cylinder (P=0.26) before and after surgery. Higher-order aberrations also remained stable with no significant change in root-mean-square error, coma, trefoil, and spherical aberration. There were no complications associated with the treatment.

Conclusions:

Adjunctive fibrin tissue glue seems to be a safe and effective treatment for epithelial ingrowth after LASIK. This therapy may be particularly useful in managing challenging cases of complex or recalcitrant ingrowth.
Orthokeratology and Contact Lens Quality of Life Questionnaire (OCL-QoL)
Authors: McAlinden Colm , Lipson Michael
Published: December 2017

Objectives:

To develop a quality of life (QoL) instrument for patients fitted with Orthokeratology (OrthoK) and other modalities of contact lenses.

Methods:

A 45-item pilot questionnaire was developed from an extensive literature review, focus groups, and interviews. Subsequently, 234 participants fitted with contact lenses (OrthoK, soft lenses, and gas permeable lenses) or spectacles completed the pilot questionnaire. Rasch analysis was used to assess the psychometric properties in terms of person separation, item fit statistics, category threshold ordering, differential item functioning (DIF), and targeting. A subset of participants completed the final questionnaire twice (1 week apart) and the repeatability assessed (within-subject standard deviation). The Spearman rank–order correlation coefficient between the questionnaire score and binocular visual acuity was calculated to assess construct validity.

Results:

Inspection of category probability curves suggested that one category was underused and the response options were collapsed. Furthermore, Rasch analyses indicated 22 items misfitted the model and were removed. The final questionnaire contained 23 items with a person separation of 2.18, item fit statistics within the range 0.83 to 1.15, targeting 1.05 logits, and no significant DIF (<0.8 logits). The repeatability (S

r
) was 4.21 and there was no correlation between questionnaire scores and binocular visual acuity (r

s
=0.03, P=0.65).

Conclusions:

The Orthokeratology and Contact Lens Quality of Life Questionnaire demonstrated excellent psychometric properties and is capable of measuring vision-related QoL in patients fitted with various forms of contact lenses including OrthoK lenses. The tool is scored on a 0 to 100 interval level scale with higher scores indicating better QoL.
What Is the Sensitive Period to Initiate Auditory Stimulation for the Second Ear in Sequential Cochlear Implantation?
Authors: Park Hong Ju , Lee Jee Yeon , Yang Chan Joo , Park Jun Woo , Kang Byung Chul , Kang Woo Seok , Ahn Joong Ho , Chung Jong Woo
Published: December 2017

Objectives:

Bilateral cochlear implants (CI) are the standard treatment for bilaterally deaf children, but it is unclear how much the second CI can be delayed in sequential bilateral CI. We investigated the performances of sequential CI to answer this question.

Study Design:

Retrospective case series review.

Setting:

Tertiary referral center.

Methods:

We studied a cohort of congenitally deaf children (n = 73) who underwent sequential CI without any inner ear anomaly or combined disabilities. Hearing threshold levels and speech perception were evaluated by aided pure tone audiometry and Asan-Samsung Korean word recognition test. The scores were analyzed by the ages at surgery and compared among the different age groups.

Results:

When the second CI was performed before 3.5 years (the optimal period for the first CI), the second CI scores (96.9%) were comparable to the first CI scores. Although the first CI scores were more than or equal to 80% when the first CI was implanted before the age of 7 years, the second CI scores were more than or equal to 80% when the second CI was implanted before the age of 12 to 13 years. The hearing threshold levels were not different regardless of the ages and between the first and second CIs.

Conclusion:

Our cohort demonstrated that the second CI showed comparable results to the first CI when implanted before 3.5 years, suggesting that optimal periods for the first CI and the second CI are same. However, the sensitive period (12–13 yr) for the second CI with good scores (≥80%) was much longer than that (7 yr) of the first CI, suggesting that the first CI prolongs the sensitive period for the second CI. The second CI should be implanted early, but considered even at a later age.
Associations Between Medicare Part D and Out-of-Pocket Spending, HIV Viral Load, Adherence, and ADAP Use in Dual Eligibles With HIV
Authors: Belenky Nadya , Pence Brian W. , Cole Stephen R. , Dusetzina Stacie B. , Edmonds Andrew , Oberlander Jonathan , Plankey Michael W. , Adedimeji Adebola , Wilson Tracey E. , Cohen Jennifer , Cohen Mardge H. , Milam Joel E. , Golub Elizabeth T. , Adimora Adaora A.
Published: December 2017

Background:

The implementation of Medicare part D on January 1, 2006 required all adults who were dually enrolled in Medicaid and Medicare (dual eligibles) to transition prescription drug coverage from Medicaid to Medicare part D. Changes in payment systems and utilization management along with the loss of Medicaid protections had the potential to disrupt medication access, with uncertain consequences for dual eligibles with human immunodeficiency virus (HIV) who rely on consistent prescription coverage to suppress their HIV viral load (VL).

Objective:

To estimate the effect of Medicare part D on self-reported out-of-pocket prescription drug spending, AIDS Drug Assistance Program (ADAP) use, antiretroviral adherence, and HIV VL suppression among dual eligibles with HIV.

Methods:

Using 2003–2008 data from the Women’s Interagency HIV Study, we created a propensity score–matched cohort and used a difference-in-differences approach to compare dual eligibles’ outcomes pre-Medicare and post-Medicare part D to those enrolled in Medicaid alone.

Results:

Transition to Medicare part D was associated with a sharp increase in the proportion of dual eligibles with self-reported out-of-pocket prescription drug costs, followed by an increase in ADAP use. Despite the increase in out-of-pocket costs, both adherence and HIV VL suppression remained stable.

Conclusions:

Medicare part D was associated with increased out-of-pocket spending, although the increased spending did not seem to compromise antiretroviral therapy adherence or HIV VL suppression. It is possible that increased ADAP use mitigated the increase in out-of-pocket spending, suggesting successful coordination between Medicare part D and ADAP as well as the vital role of ADAP during insurance transitions.
Intraoral Pleomorphic Adenoma in Young Patients
Authors: Alves Violante Lina Assunção , Pérez-de-Oliveira Maria Eduarda , de Castro Jurema Freire Lisboa , Vieira Camila Lins , Leão Jair Carneiro , Perez Danyel Elias da Cruz
Published: December 2017

Background:

Intraoral pleomorphic adenoma (PA) is rare in young individuals, with only single clinical reports or small patient series reported previously.

Aim:

The aim of this study was to describe the clinicopathological features of PA in 4 patients under 18 years of age, and to discuss the differential diagnosis of pediatric patients presenting with intraoral submucosal nodules.

Methods:

Between 2000 and 2015, all patients of intraoral PA in patients aged ≤18 years diagnosed in the Oral Pathology Laboratory of the Universidade Federal de Pernambuco, Brazil, were retrieved for the study. Clinical data were recorded from the clinical charts. Histopathological slides stained with hematoxylin and eosin were reviewed to confirm the diagnosis.

Results:

There were 4 cases of PA in patients aged ≤18 years. All patients in this patient series were males, with a mean age of 16.7 years. Three cases occurred in the palate, and in 1 case, the upper lip was affected. All PAs appeared as a painless, smooth surface, well-circumscribed, and submucosal nodule. All patients were surgically excised and subsequent histopathological analysis revealed well-circumscribed tumors composed of cells that were arranged in ducts within a fibromyxoid stroma. No signs of recurrence were observed in 3 patients after a mean follow-up of 30 months. One patient is lost to follow-up.

Conclusion:

Although PAs are unusual in young patients, they should be considered in the differential diagnosis of oral submucosal nodules.
Climatic influence on the anthrax niche in warming northern latitudes
Authors: Walsh Michael G. , de Smalen Allard W. , Mor Siobhan M.
Published: December 2017

Climate change is impacting ecosystem structure and function, with potentially drastic downstream effects on human and animal health. Emerging zoonotic diseases are expected to be particularly vulnerable to climate and biodiversity disturbance. Anthrax is an archetypal zoonosis that manifests its most significant burden on vulnerable pastoralist communities. The current study sought to investigate the influence of temperature increases on the landscape suitability of anthrax in the temperate, boreal, and arctic North, where observed climate impact has been rapid. This study also explored the influence of climate relative to more traditional factors, such as livestock distribution, ungulate biodiversity, and soil-water balance, in demarcating high risk landscapes. Machine learning was used to model landscape suitability as the ecological niche of anthrax in northern latitudes. The model identified climate, livestock density and wild ungulate species richness as the most influential landscape features in predicting suitability. These findings highlight the significance of warming temperatures for anthrax ecology in northern latitudes, and suggest potential mitigating effects of interventions targeting megafauna biodiversity conservation in grassland ecosystems, and animal health promotion among small to midsize livestock herds.

Significance Statement

We present evidence that a warming climate may be associated with the current distribution of anthrax risk in the temperate, boreal, and arctic North. Moreover, projected warming over the coming decades was associated with substantive expansion of this risk. In addition, livestock distribution, ungulate biodiversity, and soil-water balance were also influential to anthrax risk. While these results are sobering for the future health of livestock and pastoralist communities in the northern latitudes, the coincident modulating effect of ungulate biodiversity may suggest targeted ecosystem conservation as a possible buffer against a growing anthrax niche.
Sharpening of hierarchical visual feature representations of blurred images
Authors: Abdelhack Mohamed , Kamitani Yukiyasu
Published: December 2017

The robustness of the visual system lies in its ability to perceive degraded images. This is achieved through interacting bottom-up, recurrent, and top-down pathways that process the visual input in concordance with stored prior information. The interaction mechanism by which they integrate visual input and prior information is still enigmatic. We present a new approach using deep neural network (DNN) representation to reveal the effects of such integration on degraded visual inputs. We transformed measured human brain activity resulting from viewing blurred images to the hierarchical representation space derived from a feedforward DNN. Transformed representations were found to veer towards the original non-blurred image and away from the blurred stimulus image. This indicated deblurring or sharpening in the neural representation, and possibly in our perception. We anticipate these results will help unravel the interplay mechanism between bottom-up, recurrent, and top-down pathways, leading to more comprehensive models of vision.

Significance statement

One powerful characteristic of the visual system is its ability to complement visual information for incomplete visual images. It operates by projecting information from higher visual and semantic areas of the brain into the lower and mid-level representations of the visual stimulus. We investigate the mechanism by which the human brain represents blurred visual stimuli. By decoding fMRI activity into a feedforward-only deep neural network reference space, we found that neural representations of blurred images are biased towards their corresponding deblurred images. This indicates a sharpening mechanism occurring in the visual cortex.
Zebrafish differentially process colour across visual space to match natural scenes
Authors: Zimmermann Maxime JY , Nevala Noora E , Yoshimatsu Takeshi , Osorio Daniel , Nilsson Dan-Eric , Berens Philipp , Baden Tom
Published: December 2017

Animal eyes evolve to process behaviourally important visual information, but how retinas deal with statistical asymmetries in visual space remains poorly understood. Using hyperspectral imaging in the field,in-vivo2-photon imaging of retinal neurons and anatomy, here we show that larval zebrafish use a highly anisotropic retina to asymmetrically survey their natural visual world. First, different neurons dominate different parts of the eye, and are linked to a systematic shift in inner retinal function: Above the animal, there is little colour in nature and retinal circuits are largely achromatic. Conversely, the lower visual field and horizon are colour-rich, and are predominately surveyed by chromatic and colour-opponent circuits that are spectrally matched to the dominant chromatic axes in nature. Second, above the frontal horizon, a high-gain ultraviolet-system piggy-backs onto retinal circuits, likely to support prey-capture. Our results demonstrate high functional diversity among single genetically and morphologically defined types of neurons.
What does not kill a tumour may make it stronger:in silicoInsights into Chemotherapeutic Drug Resistance
Authors: Hamis Sara , Nithiarasu Perumal , Powathil Gibin G
Published: December 2017

Tumour recurrence post chemotherapy is an established clinical problem and many cancer types are often observed to be increasingly drug resistant subsequent to chemotherapy treatments. Drug resistance in cancer is a multipart phenomenon which can be derived from several origins and in many cases it has been observed that cancer cells have the ability to possess, acquire and communicate drug resistant traits.

Here, anin silicoframework is developed in order to study drug resistance and drug response in cancer cell populations exhibiting various drug resistant features. The framework is based on an on-lattice hybrid multiscale mathematical model and is equipped to simulate multiple mechanisms on different scales that contribute towards chemotherapeutic drug resistance in cancer. This study demonstrates how drug resistant tumour features may depend on the interplay amongst intracellular, extracelluar and intercellular factors. On a cellular level, drug resistant cell phenotypes are here derived from inheritance or mutations that are spontaneous, drug-induced or communicated via exosomes. Furthermore intratumoural heterogeneity and spatio-temporal drug dynamics heavily influences drug delivery and the development of drug resistant cancer cell subpopulations. Chemotherapy treatment strategies are here optimised for variousin silicotumour scenarios and treatment objectives. We demonstrate that optimal chemotherapy treatment strategies drastically depend on which drug resistant mechanisms are activated, and that furthermore suboptimal chemotherapy administration may promote drug resistance.
Mutation accumulation in selfing populations under fluctuating selection
Authors: Ho Eddie K.H. , Agrawal Aneil F.
Published: December 2017

Selfing species are prone to extinction, possibly because highly selfing populations can suffer from a continuous accumulation of deleterious mutations, a process analogous to Muller’s ratchet in asexual populations. However, current theory provides little insight into which types of genes are most likely to accumulate deleterious alleles and what environmental circumstances may accelerate genomic degradation. Here we investigate temporal changes in the environment that cause fluctuations in the strength of purifying selection. We simulate selfing populations with genomes containing a mixture of loci experiencing constant selection and loci experiencing selection that fluctuates in strength (but not direction). Even when both types of loci experience the same average strength of selection, loci under fluctuating selection contribute disproportionately more to deleterious mutation accumulation. Moreover, the presence of loci experiencing fluctuating selection in the genome increases the deleterious fixation rate at loci under constant selection; under most realistic scenarios this effect of linked selection can be attributed to a reduction inNe. Fluctuating selection is particularly injurious when selective environments are strongly autocorrelated over time and when selection is concentrated into rare bouts of strong selection. These results imply that loci under fluctuating selection are likely important drivers of extinction in selfing species.
AVery Oil Yellow1modifier of theOil Yellow1-N1989allele uncovers a cryptic phenotypic impact of cis-regulatory variation in maize
Authors: Khangura Rajdeep S. , Marla Sandeep , Venkata Bala P. , Heller Nicholas J. , Johal Gurmukh S. , Dilkes Brian P.
Published: December 2017

Forward genetics determines the function of genes underlying trait variation by identifying the change in DNA responsible for changes in phenotype. Detecting phenotypically-relevant variation outside protein coding sequences and distinguishing this from neutral variants is not trivial; partly because the mechanisms by which DNA polymorphisms in the intergenic regions affect gene regulation are poorly understood. Here we utilized a dominant genetic marker with a convenient phenotype to investigate the effect of cis and trans-acting regulatory variation. We performed a forward genetic screen for natural variation that suppress or enhance the semi-dominant mutant alleleOy1-N1989,encoding the magnesium chelatase subunit I of maize. This mutant permits rapid phenotyping of leaf color as a reporter for chlorophyll accumulation, and mapping of natural variation in maize affecting chlorophyll metabolism. We identified a single modifier locus segregating between B73 and Mo17 that was linked to the reporter gene itself, which we callvery oil yellow1. Based on the variation in OY1 transcript abundance and genome-wide association data,vey1is predicted to consist of multiple cis-acting regulatory sequence polymorphisms encoded at the wild-typeoy1alleles. Thevey1allele appears to be a common polymorphism in the maize germplasm that alters the expression level of a key gene in chlorophyll biosynthesis. Thesevey1alleles have no discernable impact on leaf chlorophyll in the absence of theOy1-N1989reporter. Thus, use of a mutant as a simple and efficient reporter for magnesium chelatase activity resulted in the detection of expression-level polymorphisms not readily visible in the laboratory.
Cell Lysate Microarray for Mapping the Network of Genetic Regulators for Histone Marks
Authors: Cheng Li , Liu Cheng-xi , Jiang Shuang-ying , Hou Sha , Huang Jin-guo , Chen Zi-qing , Sun Yang-yang , Qi Huan , Jiang He-wei , Wang Jing-fang , Zhou Yi-ming , Czajkowsky Daniel M , Dai Jun-biao , Tao Sheng-ce
Published: December 2017

Protein, as the major executer for cell progresses and functions, its abundance and the level of post-translational modifications, are tightly monitored by regulators. Genetic perturbation could help us to understand the relationships between genes and protein functions. Herein, we developed a cell lysate microarray on kilo-conditions (CLICK) from 4,837 yeast knockout (YKO) strains and 322 temperature-sensitive mutant strains to explore the impact of the genome-wide interruption on certain protein. Taking histone marks as examples, a general workflow was established for the global identification of upstream regulators. Through a single CLICK array test, we obtained a series of regulators for H3K4me3 which covers most of the known regulators in Saccharomyces cerevisiae. We also noted that several group of proteins that are linked to negatively regulation of H3K4me3. Further, we discovered that Cab4p and Cab5p, two key enzymes of CoA biosynthesis, play central roles in histone acylation. Because of its general applicability, CLICK array could be easily adopted to rapid and global identification of upstream protein/enzyme(s) that regulate/modify the level of a protein or the posttranslational modification of a non-histone protein.
Increasing sensitivity and accuracy of brain-wide quantitative studies in light-sheet microscopy
Authors: Müllenbroich Caroline M. , Silvestri Ludovico , Turrini Lapo , Alterini Tommaso , Di Giovanna Antonino P. , Costantini Irene , Gheisari Ali , Vanzi Francesco , Sacconi Leonardo , Pavone Francesco S.
Published: December 2017

Light-sheet microscopy (LSM) has proven a useful tool in neuroscience to image whole brains with high frame rates at cellular resolution. LSM is employed either in combination with tissue clearing to reconstruct the cyto-architecture over the entire mouse brain or with intrinsically transparent samples like zebrafish larvae for functional imaging. Inherently to LSM, however, residual opaque objects cause stripe artifacts, which obscure features of interest and, during functional imaging, modulate fluorescence variations related to neuronal activity. Here, we report how Bessel beams reduce streaking artifacts and produce high-fidelity structural data. Furthermore, using Bessel beams, we demonstrate a fivefold increase in sensitivity to calcium transients and a 20 fold increase in accuracy in the detection of activity correlations in functional imaging. Our results demonstrate the contamination of data by systematic and random errors through Gaussian illumination and furthermore quantify the increase in fidelity of such data when using Bessel beams.
The Role of Left Dorsolateral Prefrontal Cortex in Language Processing
Authors: Klaus Jana , Schutter Dennis J. L. G.
Published: December 2017

In addition to the role of left frontotemporal areas in language processing, there is increasing evidence that language comprehension and production require control and working memory resources involving the left dorsolateral prefrontal cortex (DLPFC). The aim of this study was to investigate the role of the left DLPFC in both language comprehension and production. In a double-blind, sham-controlled crossover experiment, thirty-two participants received cathodal or sham transcranial direct current stimulation (tDCS) to the left DLPFC while performing a language comprehension and a language production task. Results showed that cathodal tDCS increases reaction times in the language comprehension task, but decreases naming latencies in the language production task. However, additional analyses revealed that the polarity of tDCS effects was highly correlated across tasks, implying differential individual susceptibility to the effect of tDCS within participants. Overall, our findings demonstrate that left DLPFC is part of the complex cortical network associated with language processing.
Planning and navigation as active inference
Authors: Kaplan Raphael , Friston Karl J
Published: December 2017

This paper introduces an active inference formulation of planning and navigation. It illustrates how the exploitation–exploration dilemma is dissolved by acting to minimise uncertainty (i.e., expected surprise or free energy). We use simulations of a maze problem to illustrate how agents can solve quite complicated problems using context sensitive prior preferences to form subgoals. Our focus is on how epistemic behaviour – driven by novelty and the imperative to reduce uncertainty about the world – contextualises pragmatic or goal-directed behaviour. Using simulations, we illustrate the underlying process theory with synthetic behavioural and electrophysiological responses during exploration of a maze and subsequent navigation to a target location. An interesting phenomenon that emerged from the simulations was a putative distinction between ‘place cells’ – that fire when a subgoal is reached – and ‘path cells’ – that fire until a subgoal is reached.
Correlated disasters and need-based transfers: The limits of risk pooling systems in simulated ecologies
Authors: Campenni Marco , Cronk Lee , Aktipis Athena
Published: December 2017

Throughout their evolutionary history, humans have faced risks including drought, disease, natural disasters and other unexpected negative events. To deal with these risks, humans use a variety of risk management strategies, some of which involve relying on others in times of need in order to pool risk. However, the effectiveness of risk pooling strategies can be limited when there is high synchronicity of need. Here we investigate the limits of two resource transfer systems for pooling risk (need-based transfers, NBT, and debt-based transfers, DBT) in simulated ecologies with different degrees of correlated disasters using an agent-based model of the need-based transfer system of the Maasai. Overall, we find that survival is higher when shocks are less correlated among partners, when groups are larger, and when network structure is characterized by preferential attachment networks, which have a more modular structure than regular or small world networks. We also find that NBT strategies consistently outperform DBT strategies across a wide variety of parameter values and that the advantage of NBT over DBT is greatest when shocks are less correlated and group size is small. Our results also suggest that systems of sharing that are based on recipient need are less vulnerable than systems that are based on debt and credit, especially in small world and regular networks.
Dual tRNA mimicry in the Cricket Paralysis Virus IRES uncovers an unexpected similarity with the Hepatitis C Virus IRES
Authors: Pisareva Vera P. , Pisarev Andrey. V. , Fernández Israel S.
Published: December 2017

Co-opting the cellular machinery for protein production is a compulsory requirement for viruses. The Cricket Paralysis virus employs an Internal Ribosomal Entry Site (IRES) to express its structural genes in the late stage of infection. Ribosome hijacking is achieved by a sophisticated use of molecular mimicry to tRNA and mRNA, employed to manipulate intrinsically dynamic components of the ribosome. Binding and translocation through the ribosome is required for this IRES to initiate translation. We report two structures, solved by single particle electron cryomicroscopy (cryoEM), of a double translocated CrPV IRES with aminoacyl-tRNA in the peptidyl site (P site) of the ribosome. CrPV IRES adopts a previously unseen conformation, mimicking the acceptor stem of a canonical E site tRNA. The structures suggest a mechanism for the positioning of the first aminoacyl-tRNA shared with the distantly related Hepatitis C Virus IRES.
NuMA is a negative regulator of 53BP1 in DNA double-strand break repair
Authors: Salvador-Moreno Naike , Liu Jing , Haas Karen M. , Parker Laurie L. , Chakraborty Chaitali , Kron Stephen J. , Hodges Kurt , Miller Lance D. , Robinson Paul J. , Leliévre Sophie A. , Vidi Pierre-Alexandre
Published: December 2017

Accumulation of 53BP1 at DNA breaks determines DNA repair pathway choice and promotes checkpoint activation. Here, we show regulation of 53BP1 beyond repair foci. 53BP1 movements are constrained in the nucleoplasm and increase in response to DNA damage. 53BP1 interacts with the structural protein NuMA, which controls 53BP1 diffusion. This interaction, and colocalization between the two proteins in vitro and in breast tissues, is reduced after DNA damage. In cell lines and breast carcinoma, NuMA prevents 53BP1 accumulation at DNA breaks and high NuMA expression predicts better patient outcomes. Manipulating NuMA expression alters PARP inhibitor sensitivity of BRCA1-null cells, end-joining activity, and immunoglobulin class switching that rely on 53BP1. We propose a new mechanism that involves the sequestration of 53BP1 by NuMA in the absence of DNA damage. Such mechanism may have evolved to disable repair functions and may be a decisive factor for tumor responses to genotoxic treatments.
Formation of correlated chromatin domains at nanoscale dynamic resolution during transcription
Authors: Shaban Haitham A. , Barth Roman , Bystricky Kerstin
Published: December 2017

Intrinsic dynamics of chromatin contribute to gene regulation. How chromatin mobility responds to genomic processes and whether this response relies on coordinated movement is still unclear. Here, we introduce an approach called Dense Flow reConstruction and Correlation (DFCC) to quantify correlation of chromatin motion with sub-pixel sensitivity at the level of the whole nucleus. DFCC is based on reconstructing dense global flow fields of fluorescent images acquired in real-time. By simulating variations in microscopic and dynamic parameters, we demonstrate that our approach is robust and more accurate than other methods to estimate flow fields and spatial correlations of dense structures such as chromatin. We applied our approach to analyze stochastic movements of DNA and histones based on direction and magnitude at different time lags in human cells. We observe long-range correlations extending over several μm between coherently moving regions over the entire nucleus. Spatial correlation of global chromatin dynamics was reduced by inhibiting elongation by RNA polymerase II and abolished in quiescent cells. Furthermore, quantification of spatial smoothness over time intervals up to 30 seconds points to clear-cut boundaries between distinct regions, while smooth transitions in small (<1 μm) neighborhoods dominate for short time intervals. Clear transitions between regions of coherent motion indicate directed squeezing or stretching of chromatin boundaries suggestive of changes in local concentrations of actors regulating gene expression. The DFCC approach hence allows characterizing stochastically forming domains of specific nuclear activity.

Significance Statement

Control of gene expression relies on modifications of chromatin structure and activity of the transcription machinery. However, how chromatin responds dynamically to this genomic process and whether this response is coordinated in space is still unclear. We introduce a novel approach called Dense Flow reConstruction and Correlation (DFCC) to characterize spatially correlated dynamics of chromatin in living cells at nanoscale resolution. DFCC allows us to detect chromatin domains in living cells with long range correlations over the entire nucleus. Furthermore, transitions between domains can be quantified by the newly introduced smoothness parameter of local chromatin motion. The DFCC approach permits characterizing stochastically forming domains of other DNA dependent activity in any cell type in real time imaging.
The Relation Between α-Helical Conformation and Amyloidogenicity
Authors: Haimov B. , Srebnik S.
Published: December 2017

Amyloid fibrils are stable aggregates of misfolded proteins and polypeptides that are insoluble and resistant to protease activity. Abnormal formation of amyloid fibrils in vivo may lead to neurodegenerative disorders and other systemic amyloidosis such as Alzheimer’s, Parkinson’s, and atherosclerosis. Because of their clinical importance amyloids are found under intense scientific research. Amyloidogenic sequences of short polypeptide segments within proteins are responsible for the transformation of correctly folded proteins into parts of larger amyloid fibrils. The α-helical secondary structure is believed to host many amyloidogenic sequences and be a key player in different stages of the amyloidogenesis process. Most of the studies on amyloids focus on the role of amyloidogenic sequences. The focus of this study is the relation between amyloidogenicity and the structure of the amyloidogenic α-helical sequence. We have previously shown that the α-helical conformation may be expressed by two parameters (θ and ρ) that form orthogonal coordinates based on the Ramachandran dihedrals (φ and ψ) and provide an illuminating interpretation of the α-helical conformation. By performing statistical analysis on α-helical conformations found in the protein data bank, an apparent relation between α-helical conformation, as expressed by θ and ρ, and amyloidogenicity is revealed. Remarkably, random amino acid sequences, whose helical structure was obtained from the most probably dihedral angles as obtained from PDB data, revealed the same dependency of amyloidogenicity, suggesting the importance of α-helical structure as opposed to sequence.
Differential expression analysis of log-ratio transformed counts: benchmarking methods for RNA-Seq data
Authors: Quinn Thomas P. , Crowley Tamsyn M. , Richardson Mark F.
Published: December 2017

Background

Count data generated by next-generation sequencing assays do not measure absolute transcript abundances. Instead, the data are constrained to an arbitrary “library size” by the sequencing depth of the assay, and typically must be normalized prior to statistical analysis. The constrained nature of these data means one could alternatively use a log-ratio transformation in lieu of normalization, as often done when testing for differential abundance (DA) of operational taxonomic units (OTUs) in 16S rRNA data. Therefore, we benchmark how well the ALDEx2 package, a transformation-based DA tool, detects differential expression in high-throughput RNA-sequencing data (RNA-Seq), compared to conventional RNA-Seq differential expression methods.

Results

To evaluate the performance of log-ratio transformation-based tools, we apply the ALDEx2 package to two simulated, and one real, RNA-Seq data sets. The latter was previously used to benchmark dozens of conventional RNA-Seq differential expression methods, enabling us to directly compare transformation-based approaches. We show that ALDEx2, widely used in meta-genomics research, identifies differentially expressed genes (and transcripts) from RNA-Seq data with high precision and, given sufficient sample sizes, high recall too (regardless of the alignment and quantification procedure used). Although we show that the choice in log-ratio transformation can affect performance, ALDEx2 has high precision (i.e., few false positives) across all transformations. Finally, we present a novel, iterative log-ratio transformation (now implemented in ALDEx2) that further improves performance in simulations.

Conclusions

Our results suggest that log-ratio transformation-based methods can work to measure differential expression from RNA-Seq data, provided that certain assumptions are met. Moreover, these methods have high precision (i.e., few false positives) in simulations and perform as good as, or better than, than conventional methods on real data. With previously demonstrated applicability to 16S rRNA data, ALDEx2 can work as a single tool for data from multiple sequencing modalities.
Genome-wide DNA methylation profiling using the methylation-dependent restriction enzyme LpnPI
Authors: Boers Ruben , Boers Joachim , de Hoon Bas , Kockx Christel , Ozgur Zeliha , Molijn Anco , van IJcken Wilfred , Laven Joop , Gribnau Joost
Published: December 2017

DNA methylation is a well-known epigenetic modification that plays a crucial role in gene regulation, but genome-wide analysis of DNA methylation remains technically challenging and costly. DNA methylation-dependent restriction enzymes can be used to restrict CpG methylation analysis to methylated regions of the genome only, which significantly reduces the required sequencing depth and simplifies subsequent bioinformatics analysis. Unfortunately, this approach has been hampered by complete digestion of DNA in CpG methylation-dense regions, resulting in fragments that are too small for accurate mapping. Here, we show that the activity of DNA methylation-dependent enzyme, LpnPI, is blocked by a fragment size smaller than 32 bp. This unique property prevents complete digestion of methylation-dense DNA and allows accurate genome-wide analysis of CpG methylation at single-nucleotide resolution. Methylated DNA sequencing (MeD-seq) of LpnPI digested fragments revealed highly reproducible genome-wide CpG methylation profiles for >50% of all potentially methylated CpGs, at a sequencing depth less than one-tenth required for whole-genome bisulfite sequencing (WGBS). MeD-seq identified a high number of patient and tissue-specific differential methylated regions (DMRs) and revealed that patient-specific DMRs observed in both blood and buccal samples predict DNA methylation in other tissues and organs. We also observed highly variable DNA methylation at gene promoters on the inactive X Chromosome, indicating tissue-specific and interpatient-specific escape of X Chromosome inactivation. These findings highlight the potential of MeD-seq for high-throughput epigenetic profiling.
Crystal structure of 8-(4-methylphenyl)-2′-deoxyadenosine hemihydrate
Authors: Ardhapure Ajaykumar V. , Sanghvi Yogesh S. , Borozdina Yulia , Kapdi Anant Ramakant , Schulzke Carola
Published: December 2017

In the asymmetric unit, equalling the unit cell (triclinic,P1,Z= 1), two molecules of the title compound, 8-(4-methylphenyl)-D-2′-deoxyadenosine, C17H19N5O3, are present, with distinct conformations of the two sugar moieties, together with one solvent water molecule. All three ribose O atoms are involved in hydrogen bonding and the crystal packing is largely determined by hydrogen-bonding or hydrogen–heteroatom interactions (O—H...O, O—H...N, N—H...O, C—H...O and C—H...N) with one independent molecule directly linked to four neighbouring molecules and the other molecule directly linked to six neighbouring molecules. The two independent molecules of the asymmetric unit display three weak intramolecular C—H-to-heteroatom contacts, two of which are very similar despite the different conformations of the deoxyribosyl moieties. The aromatic ring systems of both molecules are in proximity to each other and somehow aligned, though not coplanar. The absolute structures of the two molecules were assumed with reference to the reactant 8-bromo-D-2′-deoxyadenosine as they could not be determined crystallographically.
Crystal structure of 3-benzyl-2-[(E)-2-(furan-2-yl)ethenyl]-2,3-dihydroquinazolin-4(1H)-one and 3-benzyl-2-[(E)-2-(thiophen-2-yl)ethenyl]-2,3-dihydroquinazolin-4(1H)-one from synchrotron X-ray diffraction
Authors: Toze Flavien A. A. , Zaytsev Vladimir P. , Chervyakova Lala V. , Kvyatkovskaya Elisaveta A. , Dorovatovskii Pavel V. , Khrustalev Victor N.
Published: December 2017

The chiral title compounds, C21H18N2O2, (I), and C21H18N2OS, (II) – products of the three-component reaction between benzylamine, isatoic anhydride and furyl- or thienyl-acrolein – are isostructural and form isomorphous racemic crystals. The tetrahydropyrimidine ring in (I) and (II) adopts a sofa conformation. The amino N atom has a trigonal–pyramidal geometry [sum of the bond angles is 347.0° for both (I) and (II)], whereas the amido N atom is flat [sum of the bond angles is 359.3° for both (I) and (II)]. The furyl- and thienylethenyl substituents in (I) and (II) are planar and the conformation about the bridging C=C bond isE. These bulky fragments occupy the axial position at the quaternary C atom of the tetrahydropyrimidine ring, apparently, due to steric reasons. In the crystals, molecules of (I) and (II) form hydrogen-bonded helicoidal chains propagating along [010] by strong intermolecular N—H...O hydrogen bonds.
(E)-2-{[(4-Anilinophenyl)imino]methyl}-4-bromo-5-fluorophenol
Authors: Kalecik Sedanur , Yavuz Metin , Kavraz Fatih , Eserci Hande , Ağar Erbil
Published: December 2017

In the title compound, C19H14BrFN2O, the dihedral angles between the central benzene ring and the pendant trisubstituted ring and phenyl group are 25.7 (2) and 51.7 (2)°, respectively. The molecular conformation is influenced by an intramolecular O—H...N hydrogen bond. In the crystal, N—H...O hydrogen bonds link molecules intoC(11) chains propagating in [100] and weak aromatic π–π stacking is also observed [centroid–centroid separation = 3.682 (3) Å]
(E)-3-[4-(Benzo[d]oxazol-2-yl)styryl]-1-methylpyridin-1-ium trifluoroacetate
Authors: Xia Ying , Wang Haiyan , Yu Jianhua , Wu Zhichao
Published: December 2017

In the title molecular salt, C21H17N2O+·CF3CO2−, the dihedral angles between the benzene ring and pendant pyridyl and benzoxazole substituents of the cation are 15.35 (10) and 2.55 (9)°, respectively. In the crystal, the components are linked by weak C—H...O hydrogen bonds, C—F...π interactions and aromatic π–π stacking interactions. The F atoms of the anion are disordered over two set of sites in a 0.536 (6):0.464 (6) ratio.
The perception of risk in the flood-prone area: a case study from the Czech municipality
Authors: Bera Mohan Kumar , Daněk Petr
Published: December 2017

Purpose

The purpose of this paper is to explore the risk perceptions and activities of people to reduce impacts of disaster.

Design/methodology/approach

Case study research has been conducted in village Podhradí nad Dyjí in the Dyje river basin in Czech Republic. Villagers from different age groups, experts, NGO members have been interviewed to understand people’s perceptions of flood risks and their actions.

Findings

The research has found that changing flood insurance policy influenced people’s risk perception. There is also increasing self-dependency among people to reduce impacts of disaster. They come together to support each other and develop collectivities in managing disaster. People’s actions and willingness to participate in disaster management activities change with distance from the river bank.

Research limitations/implications

The village identified for the case study research has been affected by floods after implementation of the Crisis Management Act No. 240/2000 Coll. The findings of the study are influenced by geographical location of the municipality and cannot be generalised in the Czech Republic.

Practical implications

The research has listed physical as well as socio-economic and cultural indicators of risk perception in the Czech Republic. These indicators and outcomes should help to assess and identify the gaps in reducing impacts of floods.

Originality/value

The study has revealed the interconnection between physical, socio-economic, and cultural factors of risk perception after implementing the Crisis Management Act No. 240/2000 Coll. and changing strategies in disaster management in the Czech Republic.