bluuebunny/crossref_metadata_2025 huggingface dataset:
Injectable mechanical pillows for attenuation of load-induced post-traumatic osteoarthritis
Authors: Holyoak Derek T , Wheeler Tibra A , van der Meulen Marjolein C H , Singh Ankur
Published: April 2019

Osteoarthritis (OA) of the knee joint is a degenerative disease initiated by mechanical stress that affects millions of individuals. The disease manifests as joint damage and synovial inflammation. Post-traumatic osteoarthritis (PTOA) is a specific form of OA caused by mechanical trauma to the joint. The progression of PTOA is prevented by immediate post-injury therapeutic intervention. Intra-articular injection of anti-inflammatory therapeutics (e.g. corticosteroids) is a common treatment option for OA before end-stage surgical intervention. However, the efficacy of intra-articular injection is limited due to poor drug retention time in the joint space and the variable efficacy of corticosteroids. Here, we endeavored to characterize a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system as a ‘mechanical pillow’ to cushion the load-bearing joint, withstand repetitive loading and improve the efficacy of intra-articular injections of nanoparticles containing dexamethasone, an anti-inflammatory agent. PEG-4MAL hydrogels maintained their mechanical properties after physiologically relevant cyclic compression and released therapeutic payload in an on-demand manner under in vitro inflammatory conditions. Importantly, the on-demand hydrogels did not release nanoparticles under repetitive mechanical loading as experienced by daily walking. Although dexamethasone had minimal protective effects on OA-like pathology in our studies, the PEG-4MAL hydrogel functioned as a mechanical pillow to protect the knee joint from cartilage degradation and inhibit osteophyte formation in an in vivo load-induced OA mouse model.
Accelerated mineralization on nanofibers via non-thermal atmospheric plasma assisted glutamic acid templated peptide conjugation
Authors: Onak Günnur , Karaman Ozan
Published: April 2019

Surface modification by non-thermal atmospheric plasma (NTAP) treatment can produce significantly higher carboxylic groups on the nanofibers (NF) surface, which potentially can increase biomineralization of NF via promoting glutamic acid (GLU) templated peptide conjugation. Herein, electrospun poly(lactide-co-glycolide) (PLGA) scaffolds were treated with NTAP and conjugated with GLU peptide followed by incubation in simulated body fluids for mineralization. The effect of NTAP treatment and GLU peptide conjugation on mineralization, surface wettability and roughness were investigated. The results showed that NTAP treatment significantly increased GLU peptide conjugation which consequently enhanced mineralization and mechanical properties of NTAP treated and peptide conjugated NF (GLU-pNF) compared to neat PLGA NF, NTAP treated NF (pNF) and GLU peptide conjugated NF (GLU-NF). The effect of surface modification on human bone marrow derived mesenchymal stem cells adhesion, proliferation and morphology was evaluated by cell proliferation assay and fluorescent microscopy. Results demonstrated that cellular adhesion and proliferation were significantly higher on GLU-pNF compared to NF, pNF and GLU-NF. In summary, NTAP treatment could be a promising modification technique to induce biomimetic peptide conjugation and biomineralization for bone tissue engineering applications.
The Fragile Brain: Stress Vulnerability, Negative Affect and GABAergic Neurocircuits in Psychosis
Authors: Taylor Stephan F , Grove Tyler B , Ellingrod Vicki L , Tso Ivy F
Published: April 2019

Persons with schizophrenia exhibit sensitivity to stress and negative affect (NA), both strongly correlated with poor functional outcome. This theoretical review suggests that NA reflects a “fragile brain,” ie, vulnerable to stress, including events not experienced as stressful by healthy individuals. Based on postmortem evidence of altered gamma-aminobutyric acid (GABA) function in parvalbumin positive interneurons (PVI), animal models of PVI abnormalities and neuroimaging data with GABAergic challenge, it is suggested that GABAergic disruptions weaken cortical regions, which leads to stress vulnerability and excessive NA. Neurocircuits that respond to stressful and salient environmental stimuli, such as the hypothalamic-pituitary-adrenal axis and the amygdala, are highly dysregulated in schizophrenia, exhibiting hypo- and hyper-activity. PVI abnormalities in lateral prefrontal cortex and hippocampus have been hypothesized to affect cognitive function and positive symptoms, respectively; in the medial frontal cortex (dorsal anterior cingulate cortex and dorsal medial prefrontal cortex), these abnormalities may lead to vulnerability to stress, NA and dysregulation of stress responsive systems. Given that postmortem PVI disruptions have been identified in other conditions, such as bipolar disorder and autism, stress vulnerability may reflect a transdiagnostic dimension of psychopathology.
Reaching out to smokers: Technology, timing, and tailoring
Authors: DiClemente Carlo C
Published: April 2019

Designing interventions for technology requires paying attention to timing of messages and to tailoring of content of message to address smoker concerns and barriers. Using a consumer-focused design can assist in creating messaging that is acceptable and effective.
Spatiotemporal palaeodiversity patterns of modern crocodiles (Crocodyliformes: Eusuchia)
Authors: De Celis Ane , Narváez Iván , Ortega Francisco
Published: April 2019

Eusuchia is a crocodyliform clade with a rich and diverse fossil record dating back to the Mesozoic. There are several recent studies that analyse crocodyliform palaeodiversity over time, but none of them focuses exclusively on eusuchians. Thus, we estimated subsampled eusuchian palaeodiversity species dynamics over time not only at a global scale, but also by continents and main crocodylian lineages (Alligatoroidea, Crocodyloidea and Gavialoidea). These estimates reveal complex spatiotemporal palaeodiversity patterns, in which two maxima can be detected: the first during the Palaeocene and the second, which is also the biggest, in the middle-late Miocene. The Palaeocene shift is related to a North American alligatoroid diversification, whereas the middle–late Miocene maximum is related to a diversification of the three main Crocodylia lineages in Gondwanan land masses, but especially in South America. Additionally, a model-based study using generalized least squares was carried out to analyse the relationships between different abiotic and sampling proxies and eusuchian palaeodiversity. The results show that palaeotemperature is the most important factor amongst the analysed proxies, in accordance with previous studies. However, the results suggest that, along with palaeotemperature, other abiotic and/or biotic factors might also be driving eusuchian palaeodiversity dynamics.
Internal friction can be measured with the Jarzynski equality
Authors: Kailasham R. , Chakrabarti Rajarshi , Prakash J. Ravi
Published: April 2019

A simple protocol for the extraction of the internal friction coefficient of polymers is presented. The proposed scheme necessitates repeatedly stretching the polymer molecule, and measuring the average work dissipated in the process by applying the Jarzynski equality. The internal friction coefficient is then estimated from the average dissipated work in the hypothetical limit of zero solvent viscosity. The validity of the protocol is established through Brownian dynamics simulations of a single-mode spring-dashpot model for a polymer. Well-established single-molecule manipulation techniques, such as optical tweezer-based pulling, can be used to implement the suggested protocol experimentally.
Caldicellulosiruptor besciiregulates pilus expression in response to the polysaccharide, xylan
Authors: Khan Asma M.A.M. , Hauk Valerie J. , Ibrahim Mena , Raffel Thomas R. , Blumer-Schuette Sara E.
Published: April 2019

Biological hydrolysis of cellulose above 70°C involves microorganisms that secrete free enzymes, and deploy separate protein systems to adhere to their substrate. Strongly cellulolyticCaldicellulosiruptor besciiis one such extreme thermophile, which deploys modular, multi-functional carbohydrate acting enzymes to deconstruct plant biomass. Additionally,C. besciialso encodes for non-catalytic carbohydrate binding proteins, which likely evolved as a mechanism to compete against other heterotrophs in carbon limited biotopes that these bacteria inhabit. Analysis of theCaldicellulosiruptorpangenome identified a type IV pilus (T4P) locus encoded upstream of the tāpirins, that is encoded for by allCaldicellulosiruptorspecies. In this study, we sought to determine if theC. besciiT4P plays a role in attachment to plant polysaccharides. The majorC. besciipilin (CbPilA) was identified by the presence of pilin-like protein domains, paired with transcriptomics and proteomics data. Using immuno-dot blots, we determined that the plant polysaccharide, xylan, induced production of CbPilA 10 to 14-fold higher than glucomannan or xylose. Furthermore, we are able to demonstrate that recombinant CbPilA directly interacts with xylan, and cellulose at elevated temperatures. Localization of CbPilA at the cell surface was confirmed by immunofluorescence microscopy. Lastly, a direct role for CbPilA in cell adhesion was demonstrated using recombinant CbPilA or anti-CbPilA antibodies to reduceC. besciicell adhesion to xylan and crystalline cellulose up to 4.5 and 2-fold, respectively. Based on these observations, we propose that CbPilA and by extension, the T4P, plays a role inCaldicellulosiruptorcell attachment to plant biomass.

IMPORTANCE

Most microorganisms are capable of attaching to surfaces in part to persist in their environment. Here, we describe that the thermophilic, plant degrading bacterium,Caldicellulosiruptor bescii, uses type IV pili to attach to carbohydrates found in plant biomass. This ability is likely key to survival in environments where carbon sources are limiting, allowingC. besciito compete against other plant degrading microorganisms. Interestingly, the carbohydrate that induced the highest expression of pilin protein was xylan, a hemicellulose that is not the majority polysaccharide in plant biomass. Not only do we demonstrate a direct interaction of the pilin with the polysaccharides, but also that cell attachment to polysaccharides can be disrupted by the addition of recombinant pilin and notably by antibody neutralization of the native pilin. This mechanism mirrors those recently described in pathogenic Gram-positive bacteria, and further supports the ancient origins of type IV pilus systems.
Enriched environmental conditions modify the gut microbiome composition and fecal markers of inflammation in Parkinson’s disease
Authors: Singh Yogesh , Hadidi Mohamed El , Matthes Jakob , Wassouf Zinah , Schulze-Hentrich Julia M. , Kohlhofer Ursula , de Fend Leticia Quintanilla-Martinez , Huson Daniel , Riess Olaf , Casadei Nicolas
Published: April 2019

Background

Recent findings suggest an implication of the gut microbiome in Parkinson’s disease patients. Parkinson’s disease onset and progression has also been linked with various environmental factors such as physical activity, exposure to pesticides, head injury, nicotine, and dietary factors.

Objectives

In this study, we used a transgenic mouse model overexpressing the complete human SNCA genes modeling familial and sporadic forms of Parkinson’s disease to study whether environmental conditions such as standard versus enriched environment changes the gut microbiome and influences disease progression.

Methods

We performed 16S rRNA DNA sequencing on fecal samples for microbiome analysis and studied fecal inflammatory calprotectin from the colon of control and transgenic mice kept under standard environment and enriched environment conditions.

Results

The overall composition of the gut microbiota was not changed in transgenic mice compared with wild-type in enriched environment, however, individual gut bacteria at genus level such as Lactobacillus sp. were significantly changed in transgenic mice. Furthermore, enriched environment significantly reduced colon fecal inflammatory calprotectin protein in wild-type and transgenic enriched environment conditions compared to standard environment.

Conclusion

Our data suggest that enriched social environment has a positive effect on the induction of SNCA mediated inflammation in the intestine by changing anti-inflammatory gut bacteria.
Evaluation of Bacteria Detected in Both Urine and Open Wounds in Nursing Facility Residents
Authors: Libertucci Josie , Bassis Christine M. , Cassone Marco , Gibson Kristen , Lansing Bonnie , Mody Lona , Young Vincent B. , Meddings Jennifer
Published: April 2019

Nursing home residents are at a greater risk of developing pressure injuries that develop into an open wound. Open wounds can be colonized with bacteria from multiple sources. Emerging evidence suggests the specific composition of the open wound microbial community can result in delayed wound healing and increased infection risk. Understanding the factors that influence microbial colonization of open wounds, can lead to the prevention of infections. The relationship between bacteria found in urine and that of open wounds, is currently unknown. Recent studies have shown that nursing home residents can harbor a urinary microbiota independent of symptoms and frequently experience urinary incontinence. To determine if the colonization of open wounds mirrors urinary colonization, we conducted a pilot study with nursing home residents, comparing bacteria present in open pressure injuries below the umbilicus and urine. To identify microbial species that were present in both urine and open wound at one timepoint, standard bacteriologic culture techniques followed by MALDI-TOF was used as well as16S rRNA-encoding gene amplicon sequencing. In this study we found that some bacteria detected in urine were also detected in open wounds in one individual at one timepoint, using both culture dependent and independent techniques. Bacterial species that were more often detected at both sites included Enterococcus faecalis, Proteus mirabilis, Escherichia coli, and Providencia stuartii. This pilot study provides evidence that urinary colonization can mirror open wound colonization. Further studies are needed to investigate if parallel colonization of these anatomical sites affect infection outcomes.
Amygdala Reward Neurons Form and Store Fear Extinction Memory
Authors: Zhang Xiangyu , Kim Joshua , Tonegawa Susumu
Published: April 2019

The ability to extinguish conditioned fear memory is critical for adaptive control of fear response, and its impairment is a hallmark of emotional disorders like post-traumatic stress disorder (PTSD). Fear extinction is thought to take place when animals form a new memory that suppresses the original fear memory. However, little is known about the nature and the site of formation and storage of the new extinction memory. Here, we demonstrate that a fear extinction memory engram is formed and stored in a genetically distinct basolateral amygdala (BLA) neuronal population that drive reward behaviors and antagonize the BLA’s original fear neurons. The activation of the fear extinction engram neurons and natural reward-responsive neurons overlap extensively in the BLA. Furthermore, these two neuron subsets are mutually interchangeable in driving reward behaviors and fear extinction behaviors. Thus, fear extinction memory is a newly formed reward memory.
SnapATAC: A Comprehensive Analysis Package for Single Cell ATAC-seq
Authors: Fang Rongxin , Preissl Sebastian , Li Yang , Hou Xiaomeng , Lucero Jacinta , Wang Xinxin , Motamedi Amir , Shiau Andrew K. , Zhou Xinzhu , Xie Fangming , Mukamel Eran A. , Zhang Kai , Zhang Yanxiao , Behrens M. Margarita , Ecker Joseph R. , Ren Bing
Published: April 2019

Identification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by heterogeneity of the samples. Single cell analysis of transposase-accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volumes of data could pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC can efficiently dissect cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, a sampling technique that generates the low rank embedding for large-scale dataset, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC was applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis revealed ∼370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate transcriptional regulators in each of the cell types.
Organising the cell cycle in the absence of transcriptional control: Dynamic phosphorylation co-ordinates theTrypanosoma bruceicell cycle post-transcriptionally
Authors: Benz Corinna , Urbaniak Michael D.
Published: April 2019

The cell division cycle of the unicellular eukaryoteTrypanosome bruceiis tightly regulated despite the paucity of transcriptional control that results from the arrangement of genes in polycistronic units and lack of dynamically regulated transcription factors. To identify the contribution of dynamic phosphorylation toT. bruceicell cycle control we have combined cell cycle synchronisation by centrifugal elutriation with quantitative phosphoproteomic analysis. Cell cycle regulated changes in phosphorylation site abundance (917 sites, average 5-fold change) were more widespread and of a larger magnitude than changes in protein abundance (443 proteins, average 2-fold change) and were mostly independent of each other. Hierarchical clustering of co-regulated phosphorylation sites according to their cell cycle profile revealed that a bulk increase in phosphorylation occurs across the cell cycle, with a significant enrichment of known cell cycle regulators and RNA binding proteins (RBPs) within the largest clusters. Cell cycle regulated changes in essential cell cycle kinases are temporally co-ordinated with differential phosphorylation of components of the kinetochore and eukaryotic initiation factors, along with many RBPs not previously linked to the cell cycle such as eight PSP1-C terminal domain containing proteins. The temporal profiles demonstrate the importance of dynamic phosphorylation in co-ordinating progression through the cell cycle, and provide evidence that RBPs play a central role in post-transcriptional regulation of theT. bruceicell cycle.

Data are available via ProteomeXchange with identifier PXD013488.
pathwayPCA: an R package for integrative pathway analysis with modern PCA methodology and gene selection
Authors: Odom Gabriel J. , Ban Yuguang , Liu Lizhong , Sun Xiaodian , Pico Alexander R. , Zhang Bing , Wang Lily , Chen Xi
Published: April 2019

With the advance in high-throughput technology for molecular assays, multi-omics datasets have become increasingly available. However, most currently available pathway analysis software provide little or no functionalities for analyzing multiple types of -omics data simultaneously. In addition, most tools do not provide sample-specific estimates of pathway activities, which are important for precision medicine. To address these challenges, we present pathwayPCA, a unique R package for integrative pathway analysis that utilizes modern statistical methodology including supervised PCA and adaptive elastic-net PCA for principal component analysis. pathwayPCA can analyze continuous, binary, and survival outcomes in studies with multiple covariate and/or interaction effects. We provide three case studies to illustrate pathway analysis with gene selection, integrative analysis of multi-omics datasets to identify driver genes, estimating and visualizing sample-specific pathway activities in ovarian cancer, and identifying sex-specific pathway effects in kidney cancer. pathwayPCA is an open source R package, freely available to the research community. We expect pathwayPCA to be a useful tool for empowering the wide scientific community on the analyses and interpretation of the wealth of multiomics data recently made available by TCGA, CPTAC and other large consortiums.
Homozygous noncanonical splice variant in LSM1 in two siblings with multiple congenital anomalies and global developmental delay
Authors: Okur Volkan , LeDuc Charles A. , Guzman Edwin , Valivullah Zaheer M. , Anyane-Yeboa Kwame , Chung Wendy K.
Published: April 2019

Two siblings, one male and one female, ages 6 and 13 yr old, have similar clinical features of global developmental delay, multiple congenital anomalies affecting the cardiac, genitourinary, and skeletal systems, and abnormal eye movements. Whole-genome sequencing revealed a homozygous splice variant (NM_014462.3:c.231+4A>C) in LSM1 that segregated with the phenotype in the family. LSM1 has a role in pre-mRNA splicing and degradation. Expression studies revealed absence of expression of the canonical isoform in the affected individuals. The Lsm1 knockout mice have a partially overlapping phenotype that affects the brain, heart, and eye. To our knowledge, LSM1 has not been associated with any human disorder; however, the tissue expression pattern, gene constraint, and the similarity of the phenotype in our patients and the knockout mice models suggest it has a role in the development of multiple organ systems in humans.
Lidocaine‐Propitocain Cream, a Eutectic Mixture of Local Anesthetics, Effectively Relieves Pain Associated With Vascular Access Intervention Therapy in Patients Undergoing Hemodialysis: A Placebo‐Controlled, Double‐Blind, Crossover Study
Authors: Aihara Seishi , Yamada Shunsuke , Shichijo Satoru , Fukumitsu Kento , Kondo Mika , Hirashima Yutaro , Oka Hideaki , Kamimura Taro , Harada Atsumi , Nakano Toshiaki , Tsuruya Kazuhiko , Kitazono Takanari
Published: April 2019

Vascular access intervention therapy (VAIVT) is necessary to maintain vascular access in patients undergoing hemodialysis. VAIVT‐associated vasodilatation is painful. However, few reports have focused on effective pain relief at the time of VAIVT. The present study was performed to determine whether lidocaine‐propitocain cream, a eutectic mixture of local anesthetics (EMLA), effectively reduces VAIVT‐associated pain in patients undergoing hemodialysis. This placebo‐controlled, double‐blind, crossover study was conducted in a single center. Among 210 patients who underwent a total of 437 VAIVT procedures from August 2017 to June 2018, 30 patients were randomly allocated to either the EMLA–placebo arm or placebo–EMLA arm at the time of VAIVT. EMLA application significantly reduced the visual analog scale score compared with placebo (47.0 ± 21.1 vs. 68.6 ± 20.7 mm, respectively; P < 0.05). EMLA is a safe and effective treatment for relief of VAIVT‐associated pain in patients undergoing hemodialysis.
Producing race disparities: A study of drug arrests across place and race*
Authors: Gaston Shytierra
Published: April 2019

In studies of race disparities in policing, scholars generally employ quantitative methodologies with the goal of determining whether race disparities exist or, in fewer instances, of ruling out correlates. Yet, lacking from theoretical and empirical efforts is an elucidation of how and why on‐the‐ground policing produces race disparities that are justified in legal, race‐neutral terms. To address this knowledge gap, I analyze officers’ self‐reported accounts of their enforcement activities, justifications, and decision‐making in a representative sample of 300 official reports of drug arrests made in St. Louis from 2009 to 2013. These accounts are analyzed across neighborhood racial contexts and arrestee race, revealing important differences that help illuminate the race disparity problem. Unlike drug arrests in White neighborhoods or of White citizens that primarily stem from reactive policing, drug arrests in Black and racially mixed neighborhoods and of Black citizens result from officers’ greater use of discretionary stops based on neighborhood conditions, suspicion of ambiguous demeanor, or minor infractions. During such stops, officers’ discovery of drug possession often results from discretionary Terry frisks or searches incident to arrests for outstanding bench warrants. These findings fill important theoretical and empirical gaps and have implications for reforms toward racially just policing.
Food Assistance Programmes and Food Insecurity in the United States
Authors: Gundersen Craig
Published: April 2019

A central goal of the US Department of Agriculture is to reduce food insecurity among the US population. This is pursued both by agricultural policies that focus on food supply and, arguably of greater importance, through food and nutrition programmes. The Supplemental Nutrition Assistance Program (SNAP), formerly known as the Food Stamp Program, is the largest in terms of the number of participants and annual expenditure. SNAP is particularly well‐suited to alleviating food insecurity insofar as it is designed to target those most in need, is flexible enough to address geographical variations in food insecurity, has the ability to expand in times of increased need, such as economic downturns, and gives recipients the dignity and autonomy to make their own food choices. Due to its size – about US$ 70 billion in expenditures per year – the programme has generated proposals to impose direct and indirect restrictions on recipients in order to reduce expenditure. These proposals include removing the ability of states to set higher income thresholds for eligibility, imposing work requirements, and curtailing the food choices of recipients. In contrast, other proposals would build on the perceived successes of SNAP both to expand the number of recipients and to increase benefit levels.
High Homogenization Speeds for Preparing Unstable Myofibrillar Protein–Olive Oil Emulsions
Authors: Li Ruren , He Qing , Rong Liangyan , Lin Yanting , Jia Na , Shao Junhua , Liu Dengyong
Published: April 2019

Natural protein‐based oil‐in‐water emulsions have recently attracted a lot of attention because of their potential as a synthetic emulsifier replacer. It is, however, unclear how the emulsification process and protein concentration may affect the stability of such emulsions. Therefore, this study investigated the effects of homogenization speeds (4,000, 8,000, 12,000, and 16,000 rpm/min) and myofibrillar protein (MP) concentrations (10, 20, 30, 40, and 50 mg/mL) on the stability of MP–olive oil emulsion. The emulsifying creaming index, emulsifying activity index (EAI), droplet size, microstructure, free sulfhydryl content, and zeta potential of the emulsion were measured. The results showed that with the condition of sufficient emulsifier (at least 20 mg/mL), the EAI increased, and the droplet size and zeta potential of emulsions decreased with the increase of homogenization speed. Emulsions were stable at 4,000 and 8,000 rpm/min (20, 30, 40, and 50 mg/mL) within 48 hr, and they were unstable at 12,000 and 16,000 rpm/min (20, 30, 40, and 50 mg/mL) within 48 hr. This result is mainly attributed to the fact that sulfhydryl–disulfide interchange leads the excessive aggregate of MP at the oil–water interface.

Practical Application

Myofibrillar protein–olive oil emulsions (oil‐in‐water) may be used to deliver nutrients into food products. In this study, myofibrillar protein–olive oil emulsions stabilized with the optimizing emulsification conditions. This study may have important implications to produce food‐grade myofibrillar protein–olive oil emulsions to deliver nutrients.
Akkermansia muciniphila is a promising probiotic
Authors: Zhang Ting , Li Qianqian , Cheng Lei , Buch Heena , Zhang Faming
Published: April 2019

Akkermansia muciniphila (A. muciniphila), an intestinal symbiont colonizing in the mucosal layer, is considered to be a promising candidate as probiotics. A. muciniphila is known to have an important value in improving the host metabolic functions and immune responses. Moreover, A. muciniphila may have a value in modifying cancer treatment. However, most of the current researches focus on the correlation between A. muciniphila and diseases, and little is known about the causal relationship between them. Few intervention studies on A. muciniphila are limited to animal experiments, and limited studies have explored its safety and efficacy in humans. Therefore, a critical analysis of the current knowledge in A. muciniphila will play an important foundation for it to be defined as a new beneficial microbe. This article will review the bacteriological characteristics and safety of A. muciniphila, as well as its causal relationship with metabolic disorders, immune diseases and cancer therapy.
Random PCR‐based genotyping by sequencing technology GRAS‐Di (genotyping by random amplicon sequencing, direct) reveals genetic structure of mangrove fishes
Authors: Hosoya Sho , Hirase Shotaro , Kikuchi Kiyoshi , Nanjo Kusuto , Nakamura Yohei , Kohno Hiroyoshi , Sano Mitsuhiko
Published: April 2019

While various technologies for high‐throughput genotyping have been developed for ecological studies, simple methods tolerant to low‐quality DNA samples are still limited. In this study, we tested the availability of a random PCR‐based genotyping‐by‐sequencing technology, genotyping by random amplicon sequencing, direct (GRAS‐Di). We focused on population genetic analysis of estuarine mangrove fishes, including two resident species, the Amboina cardinalfish (Fibramia amboinensis, Bleeker, 1853) and the Duncker's river garfish (Zenarchopterus dunckeri, Mohr, 1926), and a marine migrant, the blacktail snapper (Lutjanus fulvus, Forster, 1801). Collections were from the Ryukyu Islands, southern Japan. PCR amplicons derived from ~130 individuals were pooled and sequenced in a single lane on a HiSeq2500 platform, and an average of three million reads was obtained per individual. Consensus contigs were assembled for each species and used for genotyping of single nucleotide polymorphisms by mapping trimmed reads onto the contigs. After quality filtering steps, 4,000–9,000 putative single nucleotide polymorphisms were detected for each species. Although DNA fragmentation can diminish genotyping performance when analysed on next‐generation sequencing technology, the effect was small. Genetic differentiation and a clear pattern of isolation‐by‐distance was observed in F. amboinensis and Z. dunckeri by means of principal component analysis, FST and the admixture analysis. By contrast, L. fulvus comprised a genetically homogeneous population with directional recent gene flow. These genetic differentiation patterns reflect patterns of estuary use through life history. These results showed the power of GRAS‐Di for fine‐grained genetic analysis using field samples, including mangrove fishes.
Reliable species distributions are obtainable with sparse, patchy and biased data by leveraging over species and data types
Authors: Peel Samantha L. , Hill Nicole A. , Foster Scott D. , Wotherspoon Simon J. , Ghiglione Claudio , Schiaparelli Stefano
Published: April 2019

New methods for species distribution models (SDMs) utilise presence–absence (PA) data to correct the sampling bias of presence‐only (PO) data in a spatial point process setting. These have been shown to improve species estimates when both datasets are large and dense. However, is a PA dataset that is smaller and patchier than hitherto examined able to do the same? Furthermore, when both datasets are relatively small, is there enough information contained within them to produce a useful estimate of species’ distributions? These attributes are common in many applications.

A stochastic simulation was conducted to assess the ability of a pooled data SDM to estimate the distribution of species from increasingly sparser and patchier datasets. The simulated datasets were varied by changing the number of presence–absence sample locations, the degree of patchiness of these locations, the number of PO observations, and the level of sampling bias within the PO observations. The performance of the pooled data SDM was compared to a PA SDM and a PO SDM to assess the strengths and limitations of each SDM.

The pooled data SDM successfully removed the sampling bias from the PO observations even when the presence–absence data were sparse and patchy, and the PO observations formed the majority of the data. The pooled data SDM was, in general, more accurate and more precise than either the PA SDM or the PO SDM. All SDMs were more precise for the species responses than they were for the covariate coefficients.

The emerging SDM methodology that pools PO and PA data will facilitate more certainty around species’ distribution estimates, which in turn will allow more relevant and concise management and policy decisions to be enacted. This work shows that it is possible to achieve this result even in relatively data‐poor regions.
Changes in hemostasis parameters in nonfatal methicillin‐sensitive Staphylococcus aureus bacteremia complicated by endocarditis or thromboembolic events: a prospective gender‐age adjusted cohort study
Authors: Forsblom Erik , Lepäntalo Aino , Wartiovaara‐Kautto Ulla , Ruotsalainen Eeva , Järvinen Asko
Published: April 2019

The aim of this study was to examine the changes in hemostasis parameters in endocarditis and thromboembolic events in nonfatal methicillin‐sensitive Staphylococcus aureus bacteremia (MS‐SAB) – a topic not evaluated previously. In total, 155 patients were recruited and were categorized according to the presence of endocarditis or thromboembolic events with gender‐age adjusted controls. Patients who deceased within 90 days or patients not chosen as controls were excluded. SAB management was supervised by an infectious disease specialist. Patients with endocarditis (N = 21), compared to controls (N = 21), presented lower antithrombin III at day 4 (p < 0.05), elevated antithrombin III at day 90 (p < 0.01), prolonged activated partial thromboplastin time at days 4 and 10 (p < 0.05), and enhanced thrombin–antithrombin complex at day 4 (p < 0.01). Thromboembolic events (N = 8), compared to controls (N = 34), significantly increased thrombin–antithrombin complex at day 4 (p < 0.05). In receiver operating characteristic analysis, the changes in these hemostasis parameters at day 4 predicted endocarditis and thromboembolic events (p < 0.05). No differences in hemoglobin, thrombocyte, prothrombin fragment, thrombin time, factor VIII, D‐dimer or fibrinogen levels were observed between cases and controls. The results suggest that nonfatal MS‐SAB patients present marginal hemostasis parameter changes that, however, may have predictability for endocarditis or thromboembolic events. Larger studies are needed to further assess the connection of hemostasis to complications in SAB.
Brain metabolic alterations in patients with long‐term calcineurin inhibitor therapy after liver transplantation
Authors: Schmitz Birte , Pflugrad Henning , Tryc Anita B. , Lanfermann Heinrich , Jäckel Elmar , Schrem Harald , Beneke Jan , Barg‐Hock Hannelore , Klempnauer Jürgen , Weissenborn Karin , Ding Xiao‐Qi
Published: April 2019

Background

Calcineurin inhibitor (CNI) neurotoxicity after liver transplantation might be due to impairment of the cerebral metabolism.

Aims

To investigate CNI‐related alterations of brain metabolite distributions and associations between cognitive function and brain metabolism in patients with long‐term CNI treatment after liver transplantation.

Methods

Eighty‐two patients (19 CNI free, 34 CNI low‐dose and 29 standard‐dose CNI immunosuppression) 10 years after liver transplantation and 32 adjusted healthy controls underwent nonlocalised brain phosphorus magnetic resonance spectroscopy (MRS) and single voxel proton MRS in the parietal white matter to estimate brain metabolite contents. The MRS results were correlated with psychometric data assessing cognitive function.

Results

Phosphorus metabolite concentrations with the exception of phosphocreatine (PCr) were reduced in patients compared to controls. Particularly, patients with low‐dose CNI therapy showed a significant decrease in adenosine triphosphate (0.209 ± 0.012 vs 0.222 ± 0.010; P < 0.001) and a significant increase in PCr (0.344 ± 0.026 vs 0.321 ± 0.017; P < 0.001) compared to controls. Myo‐Inositol in the CNI free group (2.719 ± 0.549 institutional unit [iu]) was significantly lower compared to controls (3.181 ± 0.425 iu; P = 0.02), patients on low‐dose (3.130 ± 0.513 iu; P < 0.05) and standard‐dose CNI therapy (3.207 ± 0.632 iu; P < 0.02). Glutamate and glutamine levels correlated negatively with cognitive function (Repeatable Battery for the Assessment of Neuropsychological Status Total Scale: R = −0.362, P = 0.029).

Conclusion

Long‐term CNI therapy after liver transplantation might be associated with alterations of brain metabolites.
Granger Mediation Analysis of Multiple Time Series With an Application to Functional Magnetic Resonance Imaging
Authors: Zhao Yi , Luo Xi
Published: April 2019

This paper presents Granger mediation analysis, a new framework for causal mediation analysis of multiple time series. This framework is motivated by a functional magnetic resonance imaging (fMRI) experiment where we are interested in estimating the mediation effects between a randomized stimulus time series and brain activity time series from two brain regions. The independent observation assumption is thus unrealistic for this type of time-series data. To address this challenge, our framework integrates two types of models: causal mediation analysis across the mediation variables, and vector autoregressive (VAR) models across the temporal observations. We use “Granger” to refer to VAR correlations modeled in this paper. We further extend this framework to handle multilevel data, in order to model individual variability and correlated errors between the mediator and the outcome variables. Using Rubin's potential outcome framework, we show that the causal mediation effects are identifiable under our time-series model. We further develop computationally efficient algorithms to maximize our likelihood-based estimation criteria. Simulation studies show that our method reduces the estimation bias and improves statistical power, compared with existing approaches. On a real fMRI data set, our approach quantifies the causal effects through a brain pathway, while capturing the dynamic dependence between two brain regions.
Analysis of Covariance in Randomized Trials: More Precision and Valid Confidence Intervals, Without Model Assumptions
Authors: Wang Bingkai , Ogburn Elizabeth L. , Rosenblum Michael
Published: April 2019

“Covariate adjustment” in the randomized trial context refers to an estimator of the average treatment effect that adjusts for chance imbalances between study arms in baseline variables (called “covariates”). The baseline variables could include, for example, age, sex, disease severity, and biomarkers. According to two surveys of clinical trial reports, there is confusion about the statistical properties of covariate adjustment. We focus on the analysis of covariance (ANCOVA) estimator, which involves fitting a linear model for the outcome given the treatment arm and baseline variables, and trials that use simple randomization with equal probability of assignment to treatment and control. We prove the following new (to the best of our knowledge) robustness property of ANCOVA to arbitrary model misspecification: Not only is the ANCOVA point estimate consistent (as proved by Yang and Tsiatis, 2001) but so is its standard error. This implies that confidence intervals and hypothesis tests conducted as if the linear model were correct are still asymptotically valid even when the linear model is arbitrarily misspecified, for example, when the baseline variables are nonlinearly related to the outcome or there is treatment effect heterogeneity. We also give a simple, robust formula for the variance reduction (equivalently, sample size reduction) from using ANCOVA. By reanalyzing completed randomized trials for mild cognitive impairment, schizophrenia, and depression, we demonstrate how ANCOVA can achieve variance reductions of 4 to 32%.
Multiclass Linear Discriminant Analysis With Ultrahigh-Dimensional Features
Authors: Li Yanming , Hong Hyokyoung G. , Li Yi
Published: April 2019

Within the framework of Fisher's discriminant analysis, we propose a multiclass classification method which embeds variable screening for ultrahigh-dimensional predictors. Leveraging interfeature correlations, we show that the proposed linear classifier recovers informative features with probability tending to one and can asymptotically achieve a zero misclassification rate. We evaluate the finite sample performance of the method via extensive simulations and use this method to classify posttransplantation rejection types based on patients' gene expressions.
Impact of mentoring on socio‐emotional and mental health outcomes of youth with learning disabilities and attention‐deficit hyperactivity disorder
Authors: Haft Stephanie L. , Chen Tiffany , LeBlanc Chloe , Tencza Francesca , Hoeft Fumiko
Published: April 2019

Background

Learning disabilities (LD) and attention‐deficit hyperactivity disorder (ADHD) are often accompanied by significant socio‐emotional impairments and mental health challenges. However, there is a lack of controlled, quantitative research on potential interventions to address this issue. The current study evaluated the impact of a near‐peer mentoring program for youth with LD/ADHD designed to promote socio‐emotional well‐being.

Methods

Youth with LD/ADHD who participated in the mentoring program (Mentored; n = 99) were compared to both nonmentored youth with LD/ADHD (Control‐NM; n = 51) and typically developing youth without LD/ADHD (Control‐TD; n = 81) prementoring in the fall and postmentoring in the spring. Participants were assessed using self‐report measures of anxiety, depression, interpersonal relations, and self‐esteem.

Results

Youth with LD/ADHD showed significantly higher scores of depression and significantly lower scores of interpersonal relations compared to the Control‐TD group at fall baseline. The depression and self‐esteem scores of the Mentored group significantly decreased and increased, respectively, after mentoring. These changes were associated with mentee‐perceived mentorship quality. The Control‐NM group showed significant decreases in both self‐esteem and interpersonal relations, as well as increases in depression over time, while the Control‐TD group remained stable across all measures.

Conclusions

Results suggest that mentoring shows promise as a potential intervention for youth with LD/ADHD who experience co‐occurring socio‐emotional and mental health difficulties. The study is the first, to our knowledge, to quantify the effect of a near‐peer mentoring program on youth with LD/ADHD in a design with two control groups. Implications for research and practice involving LD, ADHD, and mental health disorders are discussed.

Key Practitioner Message

LD and ADHD are associated with increased anxiety, depression, and impaired self‐esteem and interpersonal relationships.

There is a lack of research on interventions that could address the mental health problems and socio‐emotional difficulties that co‐occur with learning disabilities and ADHD.

Near‐peer mentoring is a promising intervention that can improve socio‐emotional well‐being and mental health in youth with learning disabilities and ADHD, and highlights the importance of strong interpersonal relationships as a protective factor.
Epigenome‐wide association studies in asthma: A systematic review
Authors: Edris Ahmed , den Dekker Herman T. , Melén Erik , Lahousse Lies
Published: April 2019

Objective

Asthma is a common chronic respiratory airway disease influenced by environmental factors and possibly their interaction with the human genome causing epigenetic changes. Epigenome‐wide association studies (EWAS) have mainly investigated DNA methylation and its association with disease or traits, exposure factors or gene expression. This systematic review aimed to identify all EWAS assessing differentially methylated sites associated with asthma in humans.

Design

Structured systematic literature search following PRISMA guidelines, Newcastle‐Ottawa Scale (NOS) for cohort studies was used for bias assessment.

Data Sources

We searched PubMed and Embase databases from 2005 to 2019.

Eligibility Criteria

Epigenome‐wide association studies testing association between differential methylation and asthma in humans.

Results

Overall, we identified 16 EWAS studies complying with our search criteria. Twelve studies were conducted on children, and 10 were conducted on sample sizes <150 subjects. Four hundred and nineteen CpGs were reported in children studies after correction for multiple testing. In the adult studies, thousands of differentially methylated sites were identified. Differential methylation in inflammatory‐related genes correlated with higher levels of gene expressions of inflammatory modulators in asthma. Differentially methylated genes associated with asthma included SMAD3, SERPINC1, PROK1, IL13, RUNX3 and TIGIT. Forty‐one CpGs were replicated at least once in blood samples, and 28 CpGs were replicated in nasal samples.

Conclusion

Although many differentially methylated CpGs in genes known to be involved in asthma have been identified in EWAS to date, we conclude that further studies of larger sample sizes and analyses of differential methylation between different phenotypes are needed in order to comprehensively evaluate the role of epigenetic factors in the pathophysiology and heterogeneity of asthma, and the potential clinical utility to predict or classify patients with asthma.
Embryonic extracellular vesicles as informers to the immune cells at the maternal–fetal interface
Authors: Giacomini E , Alleva E , Fornelli G , Quartucci A , Privitera L , Vanni V S , Viganò P
Published: April 2019

Extracellular vesicle (EV) exchange is emerging as a novel method of communication at the maternal–fetal interface. The presence of the EVs has been demonstrated in the preimplantation embryo culture medium from different species, such as bovines, porcines and humans. Preimplantation embryo-derived EVs have been shown to carry molecules potentially able to modulate the local endometrial immune system. The non-classical major histocompatibility complex (MHC) class I molecule human leucocyte antigen (HLA)-G, the immunomodulatory molecule progesterone-induced blocking factor and some regulatory miRNAs species are contained in embryo-derived EV cargo. The implanted syncytiotrophoblasts are also well known to secrete EVs, with microvesicles exerting a mainly proinflammatory effect while exosomes in general mediate local immunotolerance. This review focuses on the current knowledge on the potential role of EVs released by the embryo in the first weeks of pregnancy on the maternal immune cells. Collectively, the data warrant further exploration of the dialogue between the mother and the embryo via EVs.