bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards region-specific propagation of protein functions
Authors: Emily Koo Da Chen , Bonneau Richard 
Published: March 2018

AbstractMotivationDue to the nature of experimental annotation, most protein function prediction methods operate at the protein-level, where functions are assigned to full-length proteins based on overall similarities. However, most proteins function by interacting with other proteins or molecules, and many functional associations should be limited to specific regions rather than the entire protein length. Most domain-centric function prediction methods depend on accurate domain family assignments to infer relationships between domains and functions, with regions that are unassigned to a known domain-family left out of functional evaluation. Given the abundance of residue-level annotations currently available, we present a function prediction methodology that automatically infers function labels of specific protein regions using protein-level annotations and multiple types of region-specific features.ResultsWe apply this method to local features obtained from InterPro, UniProtKB and amino acid sequences and show that this method improves both the accuracy and region-specificity of protein function transfer and prediction by testing on both human and yeast proteomes. We compare region-level predictive performance of our method against that of a whole-protein baseline method using a held-out dataset of proteins with structurally-verified binding sites and also compare protein-level temporal holdout predictive performances to expand the variety and specificity of GO terms we could evaluate. Our results can also serve as a starting point to categorize GO terms into site-specific and whole-protein terms and select prediction methods for different classes of GO terms.AvailabilityThe code is freely available at: https://github.com/ek1203/region_spec_func_pred
Immediate early gene activation throughout the brain is associated with dynamic changes in social context
Authors: Williamson Cait M. , Klein Inbal S. , Lee Won , Curley James P. 
Published: March 2018

ABSTRACTSocial competence is dependent on successful processing of social context information. The social opportunity paradigm is a methodology in which dynamic shifts in social context are induced through removal of the alpha male in a dominance hierarchy, leading to rapid ascent in the hierarchy of the beta male and of other subordinate males in the social group. In the current study, we use the social opportunity paradigm to determine what brain regions respond to this dynamic change in social context, allowing an individual to recognize the absence of the alpha male and subsequently perform status-appropriate social behaviors. Replicating our previous work, we show that following removal of the alpha male, beta males rapidly ascend the social hierarchy and attain dominant status by increasing aggression towards more subordinate individuals. Analysis of patterns of Fos immunoreactivity throughout the brain indicates that in individuals undergoing social ascent, there is increased activity in regions of the social behavior network, as well as the infralimbic and prelimbic regions of the prefrontal cortex and areas of the hippocampus. Our findings demonstrate that male mice are able to respond to changes in social context and provide insight into the how the brain processes these complex behavioral changes.
Network-based prediction of protein interactions
Authors: Kovács István A. , Luck Katja , Spirohn Kerstin , Wang Yang , Pollis Carl , Schlabach Sadie , Bian Wenting , Kim Dae-Kyum , Kishore Nishka , Hao Tong , Calderwood Michael A. , Vidal Marc , Barabási Albert-László 
Published: March 2018

As biological function emerges through interactions between a cell’s molecular constituents, understanding cellular mechanisms requires us to catalogue all physical interactions between proteins [1–4]. Despite spectacular advances in high-throughput mapping, the number of missing human protein-protein interactions (PPIs) continues to exceed the experimentally documented interactions [5, 6]. Computational tools that exploit structural, sequence or network topology information are increasingly used to fill in the gap, using the patterns of the already known interactome to predict undetected, yet biologically relevant interactions [7–9]. Such network-based link prediction tools rely on the Triadic Closure Principle (TCP) [10–12], stating that two proteins likely interact if they share multiple interaction partners. TCP is rooted in social network analysis, namely the observation that the more common friends two individuals have, the more likely that they know each other [13, 14]. Here, we offer direct empirical evidence across multiple datasets and organisms that, despite its dominant use in biological link prediction, TCP is not valid for most protein pairs. We show that this failure is fundamental - TCP violates both structural constraints and evolutionary processes. This understanding allows us to propose a link prediction principle, consistent with both structural and evo-lutionary arguments, that predicts yet uncovered protein interactions based on paths of length three (L3). A systematic computational cross-validation shows that the L3 principle significantly outperforms existing link prediction methods. To experimentally test the L3 predictions, we perform both large-scale high-throughput and pairwise tests, finding that the predicted links test positively at the same rate as previously known interactions, suggesting that most (if not all) predicted interactions are real. Combining L3 predictions with experimen-tal tests provided new interaction partners of FAM161A, a protein linked to retinitis pigmentosa, offering novel insights into the molecular mechanisms that lead to the disease. Because L3 is rooted in a fundamental biological principle, we expect it to have a broad applicability, enabling us to better understand the emergence of biological function under both healthy and pathological conditions.SummaryWe unveil a fundamental organizing principle of biological networks and demonstrate its predictive power for uncovering novel protein interactions.
A three-dimensional culture model of innervated human skeletal muscle enables studies of the adult neuromuscular junction and disease modeling
Authors: Bakooshli Mohsen Afshar , Lippmann Ethan S , Mulcahy Ben , Iyer Nisha R , Nguyen Christine T , Tung Kayee , Stewart Bryan A , van den Dorpel Hubrecht , Fuehrmann Tobias , Shoichet Molly S , Bigot Anne , Pegoraro Elena , Ahn Henry , Ginsberg Howard , Zhen Mei , Ashton Randolph S , Gilbert Penney M 
Published: March 2018

SummaryTwo-dimensional (2D) human skeletal muscle fiber cultures are ill equipped to support the contractile properties of maturing muscle fibers. This limits their application to the study of adult human neuromuscular junction (NMJ) development, a process requiring maturation of muscle fibers in the presence of motor neuron endplates. Here we describe a three-dimensional (3D) co-culture method whereby human muscle progenitors mixed with human pluripotent stem cell-derived motor neurons self-organize to form functional NMJ connections within two weeks. Functional connectivity between motor neuron endplates and muscle fibers is confirmed with calcium transient imaging and electrophysiological recordings. Notably, we only observed epsilon acetylcholine receptor subunit protein upregulation and activity in 3D co-culture. This demonstrates that the 3D co-culture system supports a developmental shift from the embryonic to adult form of the receptor that does not occur in 2D co-culture. Further, 3D co-culture treatments with myasthenia gravis patient sera shows the ease of studying human disease with the system. This work delivers a simple, reproducible, and adaptable method to model and evaluate adult human NMJ de novo development and disease in culture.
OsIQD14 regulates rice grain shape through modulating the microtubule cytoskeleton
Authors: Yang Baojun , Wendrich Jos R. , Rybel Bert De , Weijers Dolf , Xue HongWei 
Published: March 2018

AbstractCortical microtubule (MT) arrays play a critical role in plant cell shape determination by defining the direction of cell expansion1-3. The control of plant organ shape and architecture is a major target of cereal crop improvement. Given the pleiotropic effects of MT modification, however, it is challenging to exploiting MT array organization for crop improvement. Moreover, as plants continuously adapt cell growth and expansion to ever-changing environmental conditions, multiple environmental (e.g. light4) and developmental (e.g. hormones5,6) inputs need to be translated into changes of the MT cytoskeleton. Here, we identify and functionally characterize an auxin-inducible and MT-localized protein OsIQ67-DOMAIN14 (OsIQD14), which is highly expressed in rice seed hull cells. While deficiency of OsIQD14 results in short and wide seeds and increases overall yield, overexpression leads to narrow and long seeds, caused by changes in the direction of MT arrangement. We further show that OsIQD14-mediated MT reordering is regulated through interacting with SPIRAL2, a MT-binding protein involved in KATANIN1-mediated MT rearrangement7,8, and with calmodulin proteins. As such, OsIQD14 acts as an integrator of auxin and calcium inputs into MT rearrangements, and allows effective local cell shape manipulation to improve a key rice yield trait.
IQD proteins integrate auxin and calcium signaling to regulate microtubule dynamics duringArabidopsisdevelopment
Authors: Wendrich Jos R. , Yang Bao-Jun , Mijnhout Pieter , Xue Hong-Wei , Rybel Bert De , Weijers Dolf 
Published: March 2018

AbstractGeometry and growth and division direction of individual cells are major contributors to plant organ shape and these processes are dependent on dynamics of microtubules (MT). Different MT structures, like the cortical microtubules, preprophase band and mitotic spindle, are characterized by diverse architectural dynamics (Hashimoto, 2015). While several MT binding proteins have been identified that have various effects on MT stability and architecture, they do not discriminate between the different MT structures. It is therefore likely that specific MT binding proteins exist that differentiate between MT structures in order to allow for the differences in architectural dynamics. Although evidence for the effect of specific cues, such as light and auxin, on MT dynamics has been shown in recent years (Lindeboomet al., 2013; Chenet al., 2014), it remains unknown how such cues are integrated and lead to specific effects. Here we provide evidence for how auxin and calcium signaling can be integrated to modulate MT dynamics, by means of IQD proteins. We show that theArabidopsisIQD15-18 subclade of this family is regulated by auxin signaling, can bind calmodulins in a calcium-dependent manner and are evolutionarily conserved. Furthermore, AtIQD15-18 directly bind SPIRAL2 proteinin vitroandin vivoand modulate its function, likely in a calmodulin-dependent way, thereby providing a missing link between two important regulatory pathways of MT dynamics.One sentence summaryIQD proteins integrate auxin and calcium signaling, two major signaling pathways, to control the cytoskeleton dynamics and cell shape ofArabidopsis.
Understanding the factors that shape patterns of nucleotide diversity in the house mouse genome
Authors: Booker Tom R. , Keightley Peter D. 
Published: March 2018

AbstractA major goal of population genetics has been to determine the extent to which selection at linked sites influences patterns of neutral nucleotide diversity in the genome. Multiple lines of evidence suggest that diversity is influenced by both positive and negative selection. For example, in many species there are troughs in diversity surrounding functional genomic elements, consistent with the action of either background selection (BGS) or selective sweeps. In this study, we investigated the causes of the diversity troughs that are observed in the wild house mouse genome. Using the unfolded site frequency spectrum (uSFS), we estimated the strength and frequencies of deleterious and advantageous mutations occurring in different functional elements in the genome. We then used these estimates to parameterize forward-in-time simulations of chromosomes, using realistic distributions of functional elements and recombination rate variation in order to determine if selection at linked sites can explain the observed patterns of nucleotide diversity. The simulations suggest that BGS alone cannot explain the dips in diversity around either exons or conserved non-coding elements (CNEs). A combination of BGS and selective sweeps, however, can explain the troughs in diversity around CNEs. This is not the case for protein-coding exons, where observed dips in diversity cannot be explained by parameter estimates obtained from the uSFS. We discuss the extent to which our results provide evidence of sweeps playing a role in shaping patterns of nucleotide diversity and the limitations of using the uSFS for obtaining inferences of the frequency and effects of advantageous mutations.Author SummaryWe present a study examining the causes of variation in nucleotide diversity across the mouse genome. The status of mice as a model organism in the life sciences makes them an excellent model system for studying molecular evolution in mammals. In our study, we analyse how natural selection acting on new mutations can affect levels of nucleotide diversity through the processes of background selection and selective sweeps. To perform our analyses, we first estimated the rate and strengths of selected mutations from a sample of wild mice and then use our estimates in realistic population genetic simulations. Analysing simulations, we find that both harmful and beneficial mutations are required to explain patterns of nucleotide diversity in regions of the genome close to gene regulatory elements. For protein-coding genes, however, our approach is not able to fully explain observed patterns and we think that this is because there are strongly advantageous mutations that occur in protein-coding genes that we were not able to detect.
Case of punctate palmoplantar keratoderma type I treated with combination of low‐dose oral acitretin and topical salicylic acid and steroid
Authors: Jo Jeong Won , Jeong Do Seon , Kim Chi Yeon 
Published: March 2018

AbstractPalmoplantar keratodermas (PPK) are heterogeneous disorders characterized by abnormal keratinization. Especially, punctate PPK (PPPK), one of the subtypes of hereditary PPK, is a rare punctate keratoderma characterized by tiny “raindrop” keratoses having a tendency to coalesce on the edge of soles, which are exposed to sustained pressure. If typical punctate lesions are confined to the palms and soles and the patient has a family history and late onset, it can be considered as PPPK type I (PPKP1), also called Buschke–Fisher–Brauer disease. The exact etiology of PPPK has not been fully understood. Furthermore, no standardized treatment for PPPK has been established and treatment options are limited. Above all, traditional systemic retinoids have been used in several cases, but dose‐related adverse effects are common. Therefore, combination of low‐dose systemic retinoids and adjuvant topical therapy can be an alternative treatment option for PPPK. Herein, we report a case of PPKP1 treated with combination of low‐dose oral acitretin (10 mg/day) and topical salicylic acid and steroid. Despite low capacity, low‐dose acitretin showed excellent regression of the lesions by combined use of topical ointments. The supplementary topical therapy may be useful in reducing the dose of systemic retinoids and preventing potential toxicity.
Splice site mutation in COL7A1 resulting in aberrant in‐frame transcripts identified in a case of recessive dystrophic epidermolysis bullosa, pretibial
Authors: Masunaga Takuji , Kubo Akiharu , Ishiko Akira 
Published: March 2018

AbstractDystrophic epidermolysis bullosa (DEB), pretibial, a rare subtype of epidermolysis bullosa (EB), is characterized by recurrent blisters and erosions predominantly on the pretibial region. We report the case of a 60‐year‐old Japanese woman with persistent blistering eruptions and scar formation on the pretibial region and elbows. Mutational analysis revealed a previously reported c.5797C>T mutation in exon 70 (p.R1933X) and a novel c.6348+1G>A mutation in intron 76 of COL7A1. Reverse transcription polymerase chain reaction revealed that the c.6348+1G>A mutation resulted in the skipping of exon 76 (69 bp) and the retention of intron 76 (75 bp), and both transcripts were in‐frame. From these results, we diagnosed the patient as having recessive DEB, pretibial. A review of previously reported mutations in DEB, pretibial, revealed that one‐third of DEB, pretibial, cases showed a recessive inheritance pattern, and no case had a combination of premature termination codon (PTC)/PTC mutations. The DEB, pretibial, case described herein is the first reported case of a compound heterozygote with PTC/in‐frame mutations. Although no special characteristic features of the mutations were identified, a high diversity of COL7A1 mutations was shown even in DEB, pretibial.
Changes in salivary chromogranin A levels in adults with atopic dermatitis are correlated with changes in their condition
Authors: Cai Liang , Kaneko Sakae , Morita Eishin 
Published: March 2018

AbstractStress‐induced scratching is an issue in patients with adult atopic dermatitis (AD). Symptoms of stress‐induced AD are common in clinical practise. Salivary chromogranin A (CgA) level has research value as a possible index related to a patient's psychological stress. Using saliva, which is easily collectable, we compared two assessments of the severities of AD and stress with the levels of stress proteins in the saliva of 30 patients with AD in the Department of Dermatology of Shimane University between April 2015 and May 2017. The severities of AD and stress were assessed using the Scoring Atopic Dermatitis (SCORAD) score and State–Trait Anxiety Inventory score, respectively. Additionally, the assessments included those of personality using the Tokyo University Egogram (TEG)‐II score and quality of life using the Dermatology Life Quality Index score. Simultaneously, we measured their salivary CgA levels. The change in salivary CgA per protein in patients with AD was correlated with their changes in SCORAD score (correlation coefficient, r = 0.596, P = 0.001) and objective SCORAD (r = 0.608, P < 0.001). The changes in CgA per protein correlated with those in TEG‐II A (r = 0.370, P = 0.022), while the changes in SCORAD score correlated with those in DLQI (r = 0.309, P = 0.048). Our results suggest that changes in a patient's condition are reflective of the changes in the patient's stress. The changes in salivary CgA level in patients with AD correlated with the changes in their condition.
Association between serum autotaxin or phosphatidylserine‐specific phospholipase A1 levels and melanoma
Authors: Kurano Makoto , Miyagaki Tomomitsu , Miyagawa Takuya , Igarashi Koji , Shimamoto Satoshi , Ikeda Hitoshi , Aoki Junken , Sato Shinichi , Yatomi Yutaka 
Published: March 2018

AbstractAutotaxin (ATX), a producing enzyme for lysophosphatidic acids, was first identified from the medium of a melanoma cell line and has been considered to be one of the candidate targets to treat melanoma; however, the association between serum ATX and melanoma in human subjects has not been elucidated. Along with ATX, phosphatidylserine‐specific phospholipase A1 (PS‐PLA1) is a producing enzyme for lysophosphatidylserine, a similar glycero‐lysophospholipid mediator to lysophosphatidic acids. In the present study, we aimed to investigate the association between serum ATX or PS‐PLA1 levels and melanoma. We measured the serum levels of ATX, ATX isoforms and PS‐PLA1 in subjects with melanoma (n = 57) and healthy subjects (n = 58). We further investigated the existence of trends according to the clinical stages of melanoma. We observed that serum total ATX and classical ATX levels were significant higher and serum novel ATX levels tended to be higher in male subjects with melanoma, while no significant difference was observed between the two groups in female subjects. The trend test revealed that the serum total ATX and ATX isoforms were significantly associated with the clinical stages of female subjects with melanoma. Regarding PS‐PLA1, serum PS‐PLA1 levels were significantly higher in the melanoma subjects and associated with the clinical stages. The present study is the first study which revealed the association between ATX or PS‐PLA1 and melanoma, suggesting the possible involvement of ATX/lysophosphatidic acids or PS‐PLA1/lysophosphatidylserine axis in the pathogenesis of melanoma.
Cultural adaptation and psychometric testing of The Scenario Test UK for people with aphasia
Authors: Hilari Katerina , Galante Lara , Huck Anneline , Pritchard Madeleine , Allen Lucy , Dipper Lucy 
Published: March 2018

AbstractBackgroundThis study explores the psychometric properties of The Scenario Test UK, a culturally adapted version of the Dutch original (The Scenario Test) developed by van der Meulen et al. in 2010, which evaluates functional, daily‐life communication in aphasia. The Scenario Test assesses communication in an interactive context with a supportive communication partner.AimsTo evaluate the reliability (internal consistency, interrater and test–retest reliability) and construct validity (convergent, discriminant and known‐groups validity) of The Scenario Test UK.Methods & ProceduresThe Scenario Test UK and other language, cognition and praxis assessments were administered to persons with aphasia after stroke (3+ months post‐stroke) and to non‐aphasic controls. Participants were recruited primarily through community stroke groups. Measures were completed in an interview format. Standard psychometric criteria were used to evaluate reliability and construct validity.Outcomes & ResultsA total of 74 participants with aphasia and 20 participants without aphasia took part in The Scenario Test UK. The test showed high levels of reliability. Internal consistency (Cronbach's α = 0.92), interrater reliability (ICC = 0.95) and test–retest reliability (ICC = 0.96) were excellent. Interrater agreement in scores on the individual items ranged from good to excellent (κ = 0.41–1.00) for all but two items (item 4c κ = 0.38, item 6c κ = 0.36). The test demonstrated good levels of convergent (ρ = 0.37–0.75) and discriminant validity (ρ = –0.04 to 0.23). There was strong evidence for known groups validity (U = 132.50, p < .001), with those with aphasia scoring significantly lower [median (interquartile range—IQR) = 47 (39.8–51.0)] than those without aphasia [53 (52–54)].Conclusions & ImplicationsThe data support the reliability and validity of the Scenario Test UK as an assessment of functional, daily‐life communication for persons with aphasia. Further testing is needed in independent samples on the measure's psychometric properties, including its sensitivity to change. Pending this testing, The test can be used as an assessment tool to evaluate communication skills with people with aphasia, to guide goal setting for therapy and to measure outcomes in response to therapy.