bluuebunny/crossref_metadata_2025 huggingface dataset:
Examination Innovation: Transforming the National Board of Examiners in Optometry's Clinical Skills Examination
Authors: Hobbs Brianne Nicole , Bryant Jill
Published: December 2019

SIGNIFICANCE

The National Board of Examiners in Optometry recognizes the need for innovation and is creating a multidimensional clinical examination to parallel advancements within optometry. As optometry evolves, so must the assessments which form the path to optometric licensure. The current performance-based Part III, Clinical Skills Examination, is undergoing a transformation to best assess the diversity of knowledge, skills, and abilities needed to practice contemporary optometry. The objectives for the new clinical examination include increasing clinical authenticity, prioritizing the most essential and relevant skills, and emphasizing patient-centered care. This initiative is evidence based and consistent with best practices within the larger assessment community.
Community Health Centers: A Model for Integrating Eye Care Services with the Practice of Primary Care Medicine
Authors: McNamara Nancy A. , Polse Kenneth A.
Published: December 2019

SIGNIFICANCE

Optometry is desperately needed to combat the increasing rate of avoidable visual impairment that goes undiagnosed largely owing to the lack of integration of eye care services with primary care medicine. Government leaders are actively discussing substantive changes to health care legislation that will impact optometrists and their patients. The importance of a regular eye examination for disease prevention has long been undervalued in the setting of primary care. Consequently, many serious and potentially treatable ocular and systemic diseases go undiagnosed. Despite clear indicators that vision impairment increases the risk of morbidity and mortality from chronic systemic disease and decreases quality of life, vision health remains among the greatest unmet health care needs in the United States. To improve vision care services for all Americans, we must focus our attention on two central themes. First, we must educate the public, health care professionals, and policymakers on the importance of routine eye care as a preventive measure in the setting of primary care. Next, we need to recognize that optometrists, through their geographic distribution and advanced training, are in a strategic position to deliver integrated, comprehensive, cost-effective eye care services for individuals most in need. In this perspective, we discuss a model for integrating optometric services with the practice of primary care medicine to facilitate early detection of both eye and systemic disease while reducing serious and preventable health-related consequences.
Current evidence for therapy of ceftriaxone-resistant Gram-negative bacteremia
Authors: Paterson David L. , Henderson Andrew , Harris Patrick N.A.
Published: December 2019

Purpose of review

This article aims to give a state-of-the-art assessment of treatment options for bloodstream infection because of ceftriaxone-resistant Gram-negative bacilli, especially those caused by extended-spectrum beta-lactamase (ESBL) or AmpC-producing Enterobacteriaceae. In particular, this review assesses whether current data support ‘carbapenem-sparing options’ for treatment of these serious infections.

Recent findings

The MERINO trial refuted earlier observational studies some of which showed equivalence in outcomes between beta-lactam/beta-lactamase inhibitor combinations and carbapenems for treatment of bloodstream infection because of ceftriaxone-resistant Escherichia coli or Klebsiella spp. Although numerous factors influence mortality following bloodstream infection, the variability in piperacillin/tazobactam MICs observed in the MERINO trial make this a less secure option than meropenem. However, the search for carbapenem-sparing options continues with four randomized controlled trials (RCTs) in progress and a number of other options in clinical development.

Hard outcomes from RCTs are still needed before intravenous carbapenems can be displaced as the treatment of choice for ceftriaxone-resistant Gram-negative bacilli.
Determining the Spike–Wave Index Using Automated Detection Software
Authors: Reus Elisabeth E. M. , Visser Gerhard H. , Cox Fieke M. E.
Published: December 2019

Purpose:

The spike–wave index (SWI) is a key feature in the diagnosis of electrical status epilepticus during slow-wave sleep. Estimating the SWI manually is time-consuming and is subject to interrater and intrarater variability. Use of automated detection software would save time. Thereby, this software will consistently detect a certain EEG phenomenon as epileptiform and is not influenced by human factors. To determine noninferiority in calculating the SWI, we compared the performance of a commercially available spike detection algorithm (P13 software, Persyst Development Corporation, San Diego, CA) with human expert consensus.

Methods:

The authors identified all prolonged EEG recordings for the diagnosis or follow-up of electrical status epilepticus during slow-wave sleep carried out from January to December 2018 at an epilepsy tertiary referral center. The SWI during the first 10 minutes of sleep was estimated by consensus of two human experts. This was compared with the SWI calculated by the automated spike detection algorithm using the three available sensitivity settings: “low,” “medium,” and “high.” In the software, these sensitivity settings are denoted as perception values.

Results:

Forty-eight EEG recordings from 44 individuals were analyzed. The SWIs estimated by human experts did not differ from the SWIs calculated by the automated spike detection algorithm in the “low” perception mode (P = 0.67). The SWIs calculated in the “medium” and “high” perception settings were, however, significantly higher than the human expert estimated SWIs (both P < 0.001).

Conclusions:

Automated spike detection (P13) is a useful tool in determining SWI, especially when using the “low” sensitivity setting. Using such automated detection tools may save time, especially when reviewing larger epochs.
Effects of regional differences and demography in modelling foot-and-mouth disease in cattle at the national scale
Authors: Tsao Kimberly , Sellman Stefan , Beck-Johnson Lindsay M. , Murrieta Deedra J. , Hallman Clayton , Lindström Tom , Miller Ryan S. , Portacci Katie , Tildesley Michael J. , Webb Colleen T.
Published: December 2019

Foot-and-mouth disease (FMD) is a fast-spreading viral infection that can produce large and costly outbreaks in livestock populations. Transmission occurs at multiple spatial scales, as can the actions used to control outbreaks. The US cattle industry is spatially expansive, with heterogeneous distributions of animals and infrastructure. We have developed a model that incorporates the effects of scale for both disease transmission and control actions, applied here in simulating FMD outbreaks in US cattle. We simulated infection initiating in each of the 3049 counties in the contiguous US, 100 times per county. When initial infection was located in specific regions, large outbreaks were more likely to occur, driven by infrastructure and other demographic attributes such as premises clustering and number of cattle on premises. Sensitivity analyses suggest these attributes had more impact on outbreak metrics than the ranges of estimated disease parameter values. Additionally, although shipping accounted for a small percentage of overall transmission, areas receiving the most animal shipments tended to have other attributes that increase the probability of large outbreaks. The importance of including spatial and demographic heterogeneity in modelling outbreak trajectories and control actions is illustrated by specific regions consistently producing larger outbreaks than others.
Mathematical methods for visualization and anomaly detection in telemetry datasets
Authors: Aminian Manuchehr , Andrews-Polymenis Helene , Gupta Jyotsana , Kirby Michael , Kvinge Henry , Ma Xiaofeng , Rosse Patrick , Scoggin Kristin , Threadgill David
Published: December 2019

Recent developments in both biological data acquisition and analysis provide new opportunities for data-driven modelling of the health state of an organism. In this paper, we explore the evolution of temperature patterns generated by telemetry data collected from healthy and infected mice. We investigate several techniques to visualize and identify anomalies in temperature time series as temperature relates to the onset of infectious disease. Visualization tools such as Laplacian Eigenmaps and Multidimensional Scaling allow one to gain an understanding of a dataset as a whole. Anomaly detection tools for nonlinear time series modelling, such as Radial Basis Functions and Multivariate State Estimation Technique, allow one to build models representing a healthy state in individuals. We illustrate these methods on an experimental dataset of 306 Collaborative Cross mice challenged with
Salmonella typhimurium
and show how interruption in circadian patterns and severity of infection can be revealed directly from these time series within 3 days of the infection event.
Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma
Authors: Koivisto Christopher S. , Parrish Melodie , Bonala Santosh B. , Ngoi Soo , Torres Adrian , Gallagher James , Sanchez-Hodge Rebekah , Zeinner Victor , Nahhas Georges J. , Liu Bei , Cohn David E. , Backes Floor J. , Goodfellow Paul J. , Chamberlin Helen M. , Leone Gustavo
Published: December 2019

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC,Sprr2f-Cre;Ptenfl/fl. In this model, ablation ofPtenin the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquiredTrp53mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.
Identification of 20 novel loci associated to ischemic stroke. Epigenome-Wide Association Study
Authors: Soriano-Tárraga Carolina , Lazcano Uxue , Giralt-Steinhauer Eva , Avellaneda-Gómez Carla , Ois Ángel , Rodríguez-Campello Ana , Cuadrado-Godia Elisa , Gomez-Gonzalez Alejandra , Fernández-Sanlés Alba , Elosua Roberto , Fernández-Cadenas Israel , Cullell Natalia , Montaner Joan , Moran Sebastian , Esteller Manel , Jiménez-Conde Jordi , Roquer Jaume
Published: December 2019

Rationale

DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1–2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism.

Objective

To detect epigenetic variants associated to stroke occurrence and stroke subtypes.

Methods and Results

A two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N=226 and N=166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locusZFHX3, which includes known genetic variants associated with stroke. The pathways associated to these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. Stratification analysis by stroke subtypes revealed distinct methylation patterns.

Conclusions

We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.
Influence of age and gender on taste function of healthy subjects
Authors: Wang Jing-Jie , Liang Kai-Li , Lin Wen-Jiun , Chen Chih-Yi , Jiang Rong-San
Published: December 2019

Objectives

To determine the influences of age and gender on the taste functions of healthy Taiwanese.

Methods

We evaluated taste functions of healthy Taiwanese using the whole mouth suprathreshold taste test, along with the taste quad test. In the whole-mouth test, we applied in a counterbalanced order sweet, sour, salty, and bitter solutions, each at 5 different suprathreshold concentrations to subjects, who were instructed to sip and swish in mouth twice. Each subject had to indicate the taste quality, and to rate the intensity and unpleasantness/pleasantness of each taste of the solutions. In the quad test, the 4 quadrants of the tongue surface were tested by dripping one concentration of sweet, sour, salty, or bitter solutions for 6 times. Subjects then indicated the taste quality, and rated the intensity of the solution.

Results

Subjects were divided into groups based on their gender and age: 20-39 years, 40-59 years, or ≥ 60 years. We found that in the whole mouth taste test, the total correct identification score dropped with age. But identifying sweet and salty qualities was not affected by age. No differences were found between male and female, except women scored better than men for sweet quality in the age group of 40-59 years. The total correct identification score of the taste quad test also decreased with an increased age of the taste quad test, without gender differences.

Conclusion

Both age and gender affected the taste functions in healthy Taiwanese to some extent, and differences were dependent on age, tongue region, and taste quality.
Landscape structured by physical settings and benthic polychaete and avifauna habitat uses in a mangrove-vegetated estuary
Authors: Shih Shang-Shu , Ding Tzung-Su , Chen Chang-Po , Huang Shou-Chung , Hsieh Hwey-Lian
Published: December 2019

Mangrove expansion monopolizes estuarine landscapes by diminishing habitat diversity and hence biodiversity. Physical landcover types, including mangrove vegetation, influence polychaete and avifauna habitat uses. The connections between the physical to biota-associated landscapes warrant investigation. We determine how to best describe the landscape in a mangrove-vegetated wetland according to the physical, polychaete and bird domains and identify what physical attributes would affect the biota-associated landscapes. Differences among the physical and biota-associated landscapes were evaluated using multivariate ordination analyses. Six physical landcover types were aligned along elevation, inundation and sedimentary gradients. The polychaete-associated landscape was structured by three landcover types, mainly mangroves and tidal flats with intermediate and high inundation. Deposit-feeding spionid and nereid, carnivorous goniadid and suspension-feeding sabellid polychaetes depended on the different landcover types. Shorebirds occurred distinctively in tidal flats with large, open surface areas. Egrets characterized tidal flats and mangroves, and foliage and ground gleaners characterized mangroves. Open tidal flats are crucial to polychaetes, which are the main prey of shorebirds and are also important to egret foraging. Our results suggest that effective management strategies for conserving these migratory birds require the maintenance of open tidal flats in the landscape.
Live cell imaging and analysis reveal cell phenotypic transition dynamics inherently missing in snapshot data
Authors: Wang Weikang , Douglas Diana , Zhang Jingyu , Chen Yi-Jiun , Cheng Ya-Yun , Kumari Sangeeta , Enuameh Metewo Selase , Dai Yan , Wallace Callen T. , Watkins Simon C. , Shu Weiguo , Xing Jianhua
Published: December 2019

Recent advances in single-cell techniques catalyze an emerging field of studying how cells convert from one phenotype to another, in a step-by-step process. Two grand technical challenges, however, impede further development of the field. Fixed cell-based approaches can provide genome-wide snapshots of cell status but have fundamental limits on revealing temporal information, and fluorescence-based live cell imaging approaches provide temporal information but are technically challenging for multiplex long-term imaging. We first developed a live-cell imaging platform that tracks cellular status change through combining endogenous fluorescent labeling that minimizes perturbation to cell physiology, and/or live cell imaging of high-dimensional cell morphological and texture features. With our platform and an A549 VIM-RFP EMT reporter line, live cell trajectories reveal parallel paths of epithelial-to-mesenchymal transition missing from snapshot data due to cell-cell heterogeneity. Our results emphasize the necessity of extracting dynamical information of phenotypic transitions from multiplex live cell imaging.
Integration of immunome with disease-gene network reveals common cellular mechanisms between IMIDs and drug repurposing strategies
Authors: Devaprasad Abhinandan , Radstake Timothy RDJ , Pandit Aridaman
Published: December 2019

Objective

Development and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease associated genes (DAGs) and their expressing immune cells. Due to the complex molecular mechanism, identifying the top disease associated cells (DACs) in IMIDs has been challenging. Here, we aim to identify the top DACs and DAGs to help understand the cellular mechanism involved in IMIDs and further explore therapeutic strategies.

Method

Using transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network, and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets.

Result

We found CD4+Treg, CD4+Th1, and NK cells as top DACs in the inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes and BDCA1+CD14+cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as potential drug repurposing candidate for Crohn’s disease, and other IMIDs.

Conclusion

Our method identified top DACs, DAGs, common pathways, and proposed potential drug repurposing targets between IMIDs. To extend our method to other diseases, we built the DIME tool. Thus paving way for future (pre-)clinical research.
A precisely adjustable, variation-suppressed eukaryotic transcriptional controller to enable genetic discovery
Authors: Azizoğlu Asli , Brent Roger , Rudolf Fabian
Published: December 2019

Methods to express genes conditionally into phenotype remain central to biological experimentation and biotechnology. Current methods enable either on/off or imprecisely controlled graded gene expression. We developed a “well-tempered” controller, WTC846, for precisely adjustable, graded and growth condition independent conditional expression of genes inSaccharomyces cerevisiae. In WTC846strains, the controlled genes are expressed from a strong, native promoter engineered to be repressed by the prokaryotic TetR protein and induced by tetracycline and analogues. A second instance of this promoter drives TetR itself. This autorepression loop exhibits low cell-to-cell variation in gene expression and allows precise adjustment of the steady state abundance of any protein with inducer. A second, constitutively expressed zeroing repressor abolishes basal expression in the absence of inducer. WTC846-controlled, stable (Cdc42, Tpi1) and unstable (Ipl1) proteins recapitulated known knockout and overexpression phenotypes.WTC846::CDC20strains enabled inducer regulated cell cycle synchronization. WTC846alleles ofCDC28,TOR1,PBR1andPMA1exhibited expected gene dosage-dependent growth rates and morphological phenotypes, andWTC846::WHI5strains exhibited inducer controlled differences in cell volume. WTC846controlled genes comprise a new kind of “expression clamped” allele, for which variation in expression is minimized and gene dosage can be set by the experimenter across the range of cellular protein abundances. In yeast, we expect WTC846alleles to find use in assessment of phenotypes now incompletely penetrant due to variable dosage of the causative protein, and in genome-wide epistasis screens. Implementation in higher cells should enable experiments now impossible due to cell-to-cell variation and imprecise control.
A fast and simple method for detecting identity by descent segments in large-scale data
Authors: Zhou Ying , Browning Sharon R. , Browning Brian L.
Published: December 2019

Segments of identity by descent (IBD) are used in many genetic analyses. We present a method for detecting identical-by-descent haplotype segments that is optimized for large-scale genotype data. Our method, called hap-IBD, combines a compressed representation of genotype data, the positional Burrows-Wheeler transform, and multi-threaded execution to produce very fast analysis times. An attractive feature of hap-IBD is its simplicity: the input parameters clearly and precisely define the IBD segments that are reported, so that program correctness can be confirmed by users.

We evaluate hap-IBD and four state-of-the-art IBD segment detection methods (GERMLINE, iLASH, RaPID, and TRUFFLE) using UK Biobank chromosome 20 data and simulated sequence data. We show that hap-IBD detects IBD segments faster and more accurately than competing methods, and that hap-IBD is the only method that can rapidly and accurately detect short 2-4 cM IBD segments in the full UK Biobank data. Analysis of 485,346 UK Biobank samples using hap-IBD with 12 computational threads detects 231.5 billion autosomal IBD segments with length ≥2 cM in 24.4 hours.
ASTRAL-Pro: quartet-based species tree inference despite paralogy
Authors: Zhang Chao , Scornavacca Celine , Molloy Erin K. , Mirarab Siavash
Published: December 2019

Species tree inference via summary methods that combine gene trees has become an increasingly common analysis in recent phylogenomic studies. This broad adoption has been partly due to the greater availability of genome-wide data and ample recognition that gene trees and species trees can differ due to biological processes such as gene duplication and gene loss. This increase has also been encouraged by the recent development of accurate and scalable summary methods, such as ASTRAL. However, most of these methods, including ASTRAL, can only handle single-copy gene trees and do not attempt to model gene duplication and gene loss. In this paper, we introduce a measure of quartet similarity between single-copy and multi-copy trees (accounting for orthology and paralogy relationships) that can be optimized via a scalable dynamic programming similar to the one used by ASTRAL. We then present a new quartet-based species tree inference method: ASTRAL-Pro (ASTRAL for PaRalogs and Orthologs). By studying its performance on an extensive collection of simulated datasets and on a real plant dataset, we show that ASTRAL-Pro is more accurate than alternative methods when gene trees differ from the species tree due to the simultaneous presence of gene duplication, gene loss, incomplete lineage sorting, and estimation errors.
Phase of Firing Coding of Learning Variables across Prefrontal Cortex, Anterior Cingulate Cortex and Striatum during Feature Learning
Authors: Voloh Benjamin , Oemisch Mariann , Womelsdorf Thilo
Published: December 2019

The prefrontal cortex and striatum form a recurrent network whose spiking activity encodes multiple types of learning-relevant information. This spike-encoded information is evident in average firing rates, but finer temporal coding might allow multiplexing and enhanced readout across the connected the network. We tested this hypothesis in the fronto-striatal network of nonhuman primates during reversal learning of feature values. We found that neurons encoding current choice outcomes, outcome prediction errors, and outcome history in their firing rates also carried significant information in their phase-of-firing at a 10-25 Hz beta frequency at which they synchronized across lateral prefrontal cortex, anterior cingulate cortex and striatum. The phase-of-firing code exceeded information that could be obtained from firing rates alone, was strong for inter-areal connections, and multiplexed information at three different phases of the beta cycle that were offset from the preferred spiking phase of neurons. Taken together, these findings document the multiplexing of three different types of information in the phase-of-firing at an interareally shared beta oscillation frequency during goal-directed behavior.

Highlights

Lateral prefrontal cortex, anterior cingulate cortex and striatum show phase-of-firing encoding for outcome, outcome history and reward prediction errors.

Neurons with phase-of-firing code synchronize long-range at 10-25 Hz.

Spike phases encoding reward prediction errors deviate from preferred synchronization phases.

Anterior cingulate cortex neurons show strongest long-range effects.
PREDATION CAPACITY OF SOIL-DWELLING PREDATORY MITES ON TWO GROUND BEETLE IMMATURE STAGES: A BIOLOGICAL CONTROL PERSPECTIVE FOR TWO MAJOR MAIZE PESTS
Authors: Pasquier Antoine , Andrieux Thibault , Martinez-Rodriguez Paloma , Vercken Elodie , Ferrero Maxime
Published: December 2019

Soil-dwelling predatory mites already proved their efficiency as biocontrol agents against many pests (Carrillo et al. 2015). Western Corn Rootworm (WCR), (Diabrotica virgifera virgifera)and Wireworm (WW) (Agriotes sordidus) are important pests of various crops (Furlan et al. 2002; Krysan et al., 1986; Ritter and Richter 2013; Wesseler and Fall 2010) whose eggs and first instar larvae also inhabit the first centimeters of soil (Furlan 2004; Vidal et al., 2005). In order to evaluate the potential of predatory mites as biological control agents against WCR and WW, we investigated the predation capacity ofStratiolaelaps scimitus,Gaeolaelaps aculeiferandMacrocheles robustuluson immature stages of these two prey species. First, we observed if one or more species could feed upon eggs and first instar larvae as Prischmann et al. (2011) suggested for WCR. We then explored their predation abilities through time using a survival analysis to identify the best biocontrol agent among the species tested.

Surprisingly, none of the predator species tested identified WCR or WW eggs as preys. However, at least 50% of WCR and WW first instar larvae have been attacked byG. aculeiferandM. robustulus.Stratiolaelaps scimitusshowing a slightly lower efficiency (30% of preys attacked). The survival analysis confirmed this trend with slower predation dynamics forS. scimitus.

These results show a potential of soil-dwelling predatory mites as biocontrol agents against WCR and WW. Furthermore, targeting the neonate stage instead of the egg stage in pest management strategies seems necessary for maximizing efficiency.
AFM images of open and collapsed states of yeast condensin suggest a scrunching model for DNA loop extrusion
Authors: Ryu Je-Kyung , Katan Allard J. , van der Sluis Eli O. , Wisse Thomas , de Groot Ralph , Haering Christian , Dekker Cees
Published: December 2019

Structural Maintenance of Chromosome (SMC) protein complexes are the key organizers of the spatiotemporal structure of chromosomes. The condensin SMC complex, which compacts DNA during mitosis, was recently shown to be a molecular motor that extrudes large loops of DNA. The mechanism of this unique motor, which takes large steps along DNA at low ATP consumption, remains elusive however. Here, we use Atomic Force Microscopy (AFM) to visualize the structure of yeast condensin and condensin-DNA complexes. Condensin is found to exhibit mainly open ‘O’ shapes and collapsed ‘B’ shapes, and it cycles dynamically between these two states over time. Condensin binds double-stranded DNA via a HEAT subunit and, surprisingly, also via the hinge domain. On extruded DNA loops, we observe a single condensin complex at the loop stem, where the neck size of the DNA loop correlates with the width of the condensin complex. Our results suggest that condensin extrudes DNA by a fast cyclic switching of its conformation between O and B shapes, consistent with a scrunching model.
Millet-based supplement restored microbiota diversity of acute undernourished pigs
Authors: Li Xuejing , Hui Yan , Ren JunLi , Song Yanni , Liu Songling , Che Lianqiang , Peng Xi , Dai Xiaoshuang
Published: December 2019

The strong connection between undernutrition and gut microbiota (GM) has enabled microbiota-targeting to become an evolving strategy, which witnessed urgent need for fortified formula of supplementary food in undernutrition therapy. Using undernourished pigs as models, we investigated how corn- and millet-based nutritional supplement acted differently in modulating microbiota. Undernourished pigs at age of 9 weeks were fed with pure maize diet (Maize), corn-based (CSB+) and millet-based (MSB+) supplementary food for 3 weeks. Compared with Maize group, both CSB+ and MSB+ improved serum total protein and globulin level, but no physiological improvement was observed by short-term food intervention. MSB+ shown superior influence on GM immaturity which were more normally-grown like at both structural and functional level. Higher level of Bacteriodetes, Firmicutes and lower level of Preteobacteria were detected in MSB+ fed piglets in contrast with CSB+.Lachnospira.sppwas significantly raised after nutritional intervention, indicating high correlation with the undernutrition-associated phenotype. Thus, especially from the GM aspect, millet could be one promising source to help undernourished children reconstruct balanced microbiota in short therapeutic term.
Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders
Authors: Nachun D , Ramos EM , Karydas A , Dokuru D , Gao F , Yang Z , Van Berlo V , Sears R , Kramer J , Boxer AL , Rosen H , Miller BL , Coppola G.
Published: December 2019

The role of peripheral inflammation in dementia is an important but complex topic. We present here the largest cohort of peripheral blood gene expression data ever assembled from patients with dementia and matching controls. Importantly, this cohort includes individuals from a diverse set of dementia disorders, including Alzheimer’s Disease (AD), mild cognitive impairment (MCI), and multiple disorders within the frontotemporal dementia (FTD) spectrum. We found strong transcriptional evidence of an innate immune inflammatory response, mediated by monocytes and neutrophils, in AD, MCI, and two FTD subtypes, PSP and nfvPPA. This transcriptional inflammatory response is enriched for genetic risk for AD, in part because it is also enriched for microglial genes, which have previously been implicated in AD risk. Finally, we show that this transcriptional response is strongly enriched for binding of the transcription factors PU.1 and RELA, which have previously been linked to AD risk and progression.
Early life adversity and borderline intellectual functioning negatively impact limbic system connectivity in childhood: a connectomics-based study
Authors: Blasi Valeria , Pirastru Alice , Cabinio Monia , Di Tella Sonia , Laganà Maria Marcella , Giangiacomo Alice , Baglio Gisella , Zanette Michela , Canevini Maria Paola , Walder Mauro , Clerici Mario , Baglio Francesca
Published: December 2019

Epigenetic factors related to early life adversity (ELA) in childhood are major risk factors for borderline intellectual functioning (BIF). BIF affects both adaptive and intellectual abilities, commonly leading to school failure and to an increased risk to develop mental and social problems in the adulthood. This study aimed to investigate the neurobiological underpinnings of ELA associated with BIF in terms of global topological organization and structural connectivity and their relation with intellectual functioning.

BIF (N=32) and age-matched typical development (TD, N=14) children were evaluated for intelligence quotient (IQ), behavioral competencies, and ELA. Children underwent an anatomical and diffusion-weighted MR imaging (DWI) protocol. Global brain topological organization was assessed measuring segregation and integration indexes. Moreover, structural matrices, measuring normalized number of fibers (NFn), were compared between the 2 groups using network-based statistics. Finally, a linear regression model was used to explore the relationship between network parameters and clinical measures.

Results showed increased behavioral difficulties and ELA, together with decreased network integration in BIF children. Moreover, significantly lower NFn was observed in the BIF group (p=.039) in a sub-network comprising anterior and posterior cingulate, the pericallosal sulcus, the orbital frontal areas, amygdala, basal ganglia, the accumbens nucleus, and the hippocampus. Linear regression showed that NFn significantly predicted IQ (p<.0001).

This study demonstrated that ELA in children with BIF is associated with a decreased information integration at the global level, and with an altered structural connectivity within the limbic system strictly related to the intellectual functioning.
Impaired cholesterol metabolism in the mice model of cystic fibrosis. A vicious circle?
Authors: Amato Felice , Castaldo Alice , Castaldo Giuseppe , Cernera Gustavo , Corso Gaetano , Ferrari Eleonora , Gelzo Monica , Monzani Romina , Villella Valeria Rachela , Raia Valeria
Published: December 2019

Patients with cystic fibrosis (CF) have low cholesterol absorption and, despite enhanced endogenous biosynthesis, low serum cholesterol. Herein, we investigated cholesterol metabolism in a murine CF model in comparison towild type(WT) testing serum and liver surrogate biomarkers together with the hepatic expression of genes involved in cholesterol metabolism. CF mice display lower sterols absorption and increased endogenous biosynthesis. Subsequently, we evaluated the effects of a cholesterol-supplemented diet on cholesterol metabolism in CF and WT mice. The supplementation in WT mice determines biochemical changes similar to humans. Instead, CF mice with supplementation did not show significant changes, except for serum phytosterols (−50%), liver cholesterol (+35%) and TNFα mRNA expression, that resulted 5-fold higher than in CF without supplementation. However, liver cholesterol in CF mice with supplementation resulted significantly lower compared to WT supplemented mice. This study shows that in CF mice there is a vicious circle in which the altered bile salts synthesis/secretion contribute to reduce cholesterol digestion/absorption. The consequence is the enhanced liver cholesterol biosynthesis that accumulates in the cell triggering inflammation.
Glucose starvation to rapid death of Nrf1, but not Nrf2, deficient hepatoma cells from its fatal defects in the redox metabolism reprogramming
Authors: Zhu Yu-ping , Zheng Ze , Xiang Yuancai , Zhang Yiguo
Published: December 2019

Metabolic reprogramming exists in a variety of cancer cells, with the most relevance to glucose as a source of energy and carbon for survival and proliferation. Of note, Nrf1 was shown to be essential for regulating glycolysis pathway, but it is unknown whether it plays a role in cancer metabolic reprogramming, particularly in response to glucose starvation. Herein, we discover thatNrf1α−/−-derived hepatoma cells are sensitive to rapid death induced by glucose deprivation, such cell death appears to be rescued byNrf2interference, butNrf1/2+/+orNrf2−/−-derived cells are roughly unaffected by glucose starvation. Further evidence revealed thatNrf1α−/−cell death is resulted from severe oxidative stress arising from abberrant redox metabolism. Strikingly, altered gluconeogenesis pathway was aggravated by glucose starvation ofNrf1α−/−cells, as also accompanied by weakened pentose phosphate pathway, dysfunction of serine-to-glutathione synthesis, and accumulation of reactive oxygen species (ROS) and damages, such that the intracellular GSH and NADPH were exhausted. These demonstrate that glucose starvation leads to acute death ofNrf1α−/−, rather thanNrf2−/−, cells resulting from its fatal defects in the redox metabolism reprogramming. This is owing to distinct requirements of Nrf1 and Nrf2 for regulating key genes involved in the redox metabolic reprogramming. Altogether, this work substantiates the preventive and therapeutic strategies againstNrf1α-deficient cancer by limiting its glucose and energy demands.
Inositol pyrophosphates promote the interaction of SPX domains with the coiled-coil motif of PHR transcription factors to regulate plant phosphate homeostasis
Authors: Ried Martina K. , Wild Rebekka , Zhu Jinsheng , Broger Larissa , Harmel Robert K. , Hothorn Ludwig A. , Fiedler Dorothea , Hothorn Michael
Published: December 2019

Phosphorus is an essential nutrient taken up by organisms in the form of inorganic phosphate (Pi). Eukaryotes have evolved sophisticated Pi sensing and signalling cascades, enabling them to maintain cellular Pi concentrations. Pi homeostasis is regulated by inositol pyrophosphate signalling molecules (PP-InsPs), which are sensed by SPX-domain containing proteins. In plants, PP-InsP bound SPX receptors inactivate Myb coiled-coil (MYB-CC) Pi starvation response transcription factors (PHRs) by an unknown mechanism. Here we report that a InsP8– SPX complex targets the plant-unique CC domain of PHRs. Crystal structures of the CC domain reveal an unusual four-stranded anti-parallel arrangement. Interface mutations in the CC domain yield monomeric PHR1, which is no longer able to bind DNA with high affinity. Mutation of conserved basic residues located at the surface of the CC domain disrupt interaction with the SPX receptorin vitroandin planta, resulting in constitutive Pi starvation responses. Together, our findings suggest that InsP8regulates plant Pi homeostasis by controlling the oligomeric state and hence the promoter binding capability of PHRs via their SPX receptors. (173 words)
The compact genome ofGiardia murisreveals important steps in the evolution of intestinal protozoan parasites
Authors: Xu Feifei , Jiménez-González Alejandro , Einarsson Elin , Ástvaldsson Ásgeir , Peirasmaki Dimitra , Eckmann Lars , Andersson Jan O. , Svärd Staffan G. , Jerlström-Hultqvist Jon
Published: December 2019

Diplomonad parasites of the genusGiardiahave adapted to colonizing different hosts, most notably the intestinal tract of mammals. The human-pathogenicGiardiaspecies,Giardia intestinalis, has been extensively studied at the genome and gene expression level, but no such information is available for otherGiardiaspecies. Comparative data would be particularly valuable forGiardia muris, which colonizes mice and is commonly used as a prototypicin vivomodel for investigating host responses to intestinal parasitic infection. Here we report the draft-genome ofG. muris. We discovered a highly streamlined genome, amongst the most densely encoded ever described for a nuclear eukaryotic genome.G. murisandG. intestinalisshare many known or predicted virulence factors, including cysteine proteases and a large repertoire of cysteine-rich surface proteins involved in antigenic variation. Different toG. intestinalis, G. murismaintains tandem arrays of pseudogenized surface antigens at the telomeres, whereas intact surface antigens are present centrally in the chromosomes. The two classes of surface antigens engage in genetic exchange. Reconstruction of metabolic pathways from theG. murisgenome suggest significant metabolic differences toG. intestinalis. Additionally,G. murisencodes proteins that might be used to modulate the prokaryotic microbiota. The responsible genes have been introduced in theGiardiagenus via lateral gene transfer from prokaryotic sources. Our findings point to important evolutionary steps in theGiardiagenus as it adapted to different hosts and it provides a powerful foundation for mechanistic exploration of host-pathogen interaction in theG. muris– mouse pathosystem.

Author summary

TheGiardiagenus comprises eukaryotic single-celled parasites that infect many animals. TheGiardia intestinalisspecies complex, which can colonize and cause diarrheal disease in humans and different animal hosts has been extensively explored at the genomic and cell biologic levels. OtherGiardiaspecies, such as the mouse parasiteGiardia muris, have remained uncharacterized at the genomic level, hampering our understanding ofin vivohost-pathogen interactions and the impact of host dependence on the evolution of theGiardiagenus. We discovered that theG. murisgenome encodes many of the same virulence factors asG. intestinalis. TheG. murisgenome has undergone genome contraction, potentially in response to a more defined infective niche in the murine host. We describe differences in metabolic and microbiome modulatory gene repertoire, mediated mainly by lateral gene transfer, that could be important for understanding infective success across theGiardiagenus. Our findings provide new insights for the use ofG. murisas a powerful model for exploring host-pathogen interactions in giardiasis.
Compound heterozygous novel frameshift variants in the PROM1 gene result in Leber congenital amaurosis
Authors: Ragi Sara D. , Lima de Carvalho Jose Ronaldo , Tanaka Akemi J. , Park Karen Sophia , Mahajan Vinit B. , Maumenee Irene H. , Tsang Stephen H.
Published: December 2019

The PROM1 (prominin 1) gene encodes an 865-amino acid glycoprotein that is expressed in retinoblastoma cell lines and in the adult retina. The protein is localized to photoreceptor outer segment disc membranes, where it plays a structural role, and in the retinal pigment epithelium (RPE), where it acts as a cytosolic protein that mediates autophagy. Mutations in PROM1 are typically associated with cone-rod dystrophy 12 (OMIM#3612657), autosomal dominant retinal macular dystrophy 2 (OMIM#608051), autosomal recessive retinitis pigmentosa 41 (OMIM#612095), and Stargardt disease 4 (OMIM#603786). Here we describe the first case of PROM1-associated Leber congenital amaurosis (LCA) in a 12-yr-old Asian male, caused by two not previously described deleterious frameshift variants in the compound heterozygous state. Clinical features include the presence of bull's eye maculopathy, pendular horizontal nystagmus, and photodysphoria consistent with the clinical diagnosis of LCA. The patient was evaluated using ophthalmic imaging, electroretinography, and whole-exome sequencing. Electroretinography revealed extinguished retinal activity.
Civic localism, anti-mainland localism, and independence
Authors: So Alvin Y. , Ip Ping Lam
Published: December 2019

Purpose

The purpose of this paper is to trace the changing pattern of identity politics in Hong Kong Special Administrative Region (HKSAR). It shows that in response to the massive urban renewal projects in the 2000s, “civic localism” in the form of cultural preservation movement emerged to protect local community culture against the government-business hegemony. However, due to the deepening of social integration between Hong Kong and the mainland, a new “anti-mainland localism” emerged in the 2010s against the influx of mainlanders. In 2015–2016, as a result of Beijing’s active interference in Hong Kong affairs, localism is further transformed to Hong Kong “independence.”

Design/methodology/approach

This paper uses a historical methodology to trace the changing pattern of identity politics in Hong Kong after it becomes a special administrative region of China in 1997.

Findings

It shows how the interaction among the following three factors has shaped the pattern of localism in Hong Kong: macro historical-structural context, social movement dynamics and the response of Hong Kong and mainland government.

Practical implications

This paper argues that Beijing’s hardline policy toward Hong Kong localism may work in the short run to all push the pro-independence activities underground. However, unless the structural contradiction of the HKSAR is resolved, it seems likely that anti-mainland localism and Hong Kong independence sentiment and movement will come back with a vengeance at a later stage.

Originality/value

The literature tends to discuss Hong Kong localism in very general terms and fails to reveal its changing nature. This paper contributes by distinguishing three different forms of localism: civic localism in the mid-2000s, anti-mainland in the late 2000s and early 2010s, and independence after 2016. It shows how the macro historical-structural transformation, social movement dynamics and the responses of the Hong Kong SAR government and Beijing government have led to the changes of civic localism to anti-mainland localism, and finally to independence.
New structural economics: the third generation of development economics
Authors: Lin Justin Yifu
Published: December 2019

Purpose

Development economics is a new sub-discipline in modern economics. The first generation of development economics is structuralism. The second generation of development economics is neoliberalism. Most developing countries followed the above two generations of development economics and failed to achieve industrialization and modernization. The purpose of this paper is to introduce the third generation of development economics, called new structural economics, which advises governments in developing countries to play a facilitating role in the development of industries in a market economy according to the country’s comparative advantages. The paper also discusses how the government may use industrial policies to play this facilitating role and some new theoretical insights from new structural economics.

Design/methodology/approach

The paper draws on the experiences of success and failure in developing countries to generate new understanding about the nature and causes of economic development in developing countries.

Findings

The structuralism failed because it ignored the endogeneity of economic structure in a country. The neoliberalism failed because it neglected the endogeneity of distortions in the transition economies.

Originality/value

The paper proposes new policy and theoretical framework for developing countries.