bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive peritoneal implant metastases of malignant struma ovarii treated by thyroidectomy and 131I therapy
Authors: Wu Mengxue , Hu Fengqiong , Huang Xing , Tan Zuwen , Lei Chengming , Duan Dong
Published: December 2018

Rationale:

Malignant struma ovarii is extremely rare in the clinic. The diagnosis and modalities of treatment are still controversial. Here we describe a case of extensive peritoneal implant metastasis originating from malignant struma ovarii discovered 14 years after ovariectomy and chemotherapy.

Patient concerns:

A 48-year-old female was admitted to our clinic due to hematochezia with a past history of left malignant struma ovarii. Enhanced computed tomography (CT) examination suggested multiple metastasis nodules in the abdomen and pelvic cavity.

Diagnoses:

Laparoscopy biopsy results of intraperitoneal nodules showed a metastasis of papillary thyroid carcinoma. While pathological examination after total thyroidectomy showed no definite malignant tumor component in the thyroid tissue. Finally, combined with the patient's past history of malignant struma ovarii, peritoneal implantation metastasis derived from the malignant struma ovarii was diagnosed.

Interventions:

The patient was treated by total thyroidectomy and iodine 131 (131I) therapy. Post-therapy iodine scan and the single-photon emission computed tomography/computed tomography (SPECT/CT) fusion image showed iodine uptake in the distal descending colon, sigmoid colon, rectal lesions, and a larger lesion in the liver.

Outcome:

After treatment, although the thyroid globulin remained at a high level 3 months after treatment, the patient's hematochezia was relieved.

Lessons:

Therefore, thyroidectomy followed by adjuvant 131I treatment should be recommended in patients with malignant struma ovarii as metastatic risk is difficult to predict based on histopathologic examination.
Computed tomography-guided cryoablation for adrenal metastases: local control and survival
Authors: Zhang Wei , Sun Li-Jun , Xu Jian , Fu Yu-Fei , Zhuang Zhi-Xiang
Published: December 2018

To evaluate the feasibility, local control, and survival after computed tomography (CT)-guided cryoablation for adrenal metastases.

This study included 31 consecutive patients with adrenal metastases who were treated by CT-guided cryoablation in our center from July 2011 to October 2017. The technical success rate, local progression rate, local progression-free survival (LPFS), systemic progression-free survival (SPFS), and overall survival were assessed. The predictors of survival were determined using univariate and multivariate Cox regression analyses.

The primary and secondary technical success rates were 90.3% and 100%, respectively. None of the patients experienced a hypertensive crisis. The local progression rate during follow-up was 19.4%. Systemic progression was found in 9 patients. The cumulative 1-, 3-, and 5-year LPFS rates were 80.6%, 37.8%, and 18.4%, respectively. The cumulative 1-, 3-, and 5-year SPFS rates were 77.4%, 31.9%, and 14.6%, respectively. The cumulative 1-, 3-, and 5-year overall survival rates were 83.9%, 45.0%, and 30.0%, respectively. The existence of an extra-adrenal tumor was a significant independent predictor of worse overall survival (P = .012). The mean overall survival durations were significantly different between patients with and without an extra-adrenal tumor (16.6 ± 2.4 vs 50.9 ± 4.5 months, P <.001).

Our findings support that CT-guided cryoablation is a safe and effective method for controlling adrenal metastases and imply that this approach may improve the survival of patients with adrenal metastases.
Latent Transition Analysis of the Symptom Experience of Cancer Patients Undergoing Chemotherapy
Authors: Jeon Sangchoon , Sikorskii Alla , Given Barbara A. , Given Charles W. , Redeker Nancy S.
Published: December 2018

Background

Symptom clusters reflect the person's experience of multiple cooccurring symptoms. Although a variety of statistical methods are available to address the clustering of symptoms, latent transition analysis (LTA) characterizes patient membership in classes defined by the symptom experience and captures changes in class membership over time.

Objectives

The purposes of this article are to demonstrate the application of LTA to cancer symptom data and to discuss the advantages and disadvantages of LTA relative to other methods of managing and interpreting data on multiple symptoms.

Methods

Data from a total of 495 adult cancer patients who participated in randomized clinical trials of two symptom management interventions were analyzed. Eight cancer- and treatment-related symptoms reflected the symptom experience. Latent transition analysis was employed to identify symptom classes and evaluate changes in symptom class membership from baseline to the end of the interventions.

Results

Three classes, “A (mild symptoms),” “B (physical symptoms),” and “C (physical and emotional symptoms),” were identified. Class A patients had less comorbidity, better physical and emotional role effect, and better physical function than the other classes did. The number of symptoms, general health perceptions, and social functioning were significantly different across the three classes and were poorest in Class C. Emotional role functioning was poorest in Class C. Older adults were more likely to be in Class B than younger adults were. Younger adults were more likely to be in Class C (p < .01). Among patients in Class C at baseline, 41.8% and 29.0%, respectively, transitioned to Classes A and B at the end of the interventions.

Discussion

These results demonstrate that symptom class membership characterizes differences in the patient symptom experience, function, and quality of life. Changes in class membership represent longitudinal changes in the course of symptom management. Latent class analysis overcomes the problem of multiple statistical testing that separately addresses each symptom.
Multi-drug-resistant Enterococcus faecium bacteraemia in a liver transplant recipient
Authors: Summers Nathan A. , Gharbin John , Friedman-Moraco Rachel , Lyon G. Marshall , Lutgring Joseph
Published: December 2018

Introduction.
Enterococcus faecium is a commensal organism commonly colonizing the human gastrointestinal tract. Although it is generally a non-virulent organism, E. faecium can cause significant morbidity and mortality due to its inherent and acquired resistances to commonly used antimicrobials. Patients who are immunosuppressed are particularly vulnerable.

Case presentation. A 65–75-year-old patient with a history of an orthotopic liver transplant for hepatitis C infection and diabetes was re-admitted to the hospital with abdominal pain and fever. The patient had several recent admissions related to the presentation reported here, which included treatment with a prolonged course of broad-spectrum antibiotics. The patient was found to have a recurrent liver abscess and blood cultures grew vancomycin-resistant E. faecium, non-susceptible to all tested agents: ampicillin, penicillin, vancomycin, daptomycin and linezolid. The patient was started initially on chloramphenicol intravenously while awaiting additional susceptibility testing, which ultimately revealed chloramphenicol non-susceptibility. Tigecycline was started but the patient ultimately decided to pursue hospice care.

Conclusion. Multi-drug-resistant organisms are increasingly being recognized and are associated with poorer outcomes, particularly in immunosuppressed patients. We describe a particularly resistant organism and discuss potential therapeutic options.
TREM2 R47H exacerbates immune response in Alzheimer’s disease brain
Authors: Korvatska Olena , Kiianitsa Kostantin , Ratushny Alexander , Matsushita Mark , Beeman Neal , Chien Wei-Ming , Satoh J-I , Dorschner Michael O. , Keene C. Dirk , Bammler Theo K. , Bird Thomas D. , Raskind Wendy H.
Published: December 2018

The R47H variant in the microglial TREM2 receptor is a strong risk factor for Alzheimer’s disease (AD). To characterize processes affected by R47H we performed integrative network analysis of genes expressed in brains of AD patients with R47H, sporadic AD without the variant and patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), a systemic disease with early onset dementia caused by loss-of function mutations in TREM2 or its adaptor TYROBP. While sporadic AD had few perturbed microglial and immune genes, TREM2 R47H AD demonstrated upregulation of interferon type I response and pro-inflammatory cytokines accompanied by induction of NKG2D stress ligands. In contrast, PLOSL had distinct sets of highly perturbed immune and microglial genes that included inflammatory mediators, immune signaling, cell adhesion and phagocytosis. TREM2 knock-out in THP1, a human myeloid cell line that constitutively expresses the TREM2-TYROBP receptor, inhibited response to the viral RNA mimetic poly(I:C), and overexpression of ectopic TREM2 restored the response. Compared to wild type protein, R47H TREM2 had higher stimulatory effect on the interferon type I response signature. Our findings point to a role of the TREM2 receptor in the control of the interferon type I response in myeloid cells and provide insight regarding the contribution of R47H TREM2 to AD pathology.
Girls’ attentive traits associate with cerebellar to dorsal attention and default mode network connectivity
Authors: Rohr Christiane S. , Dimond Dennis , Schuetze Manuela , Cho Ivy Y. K. , Lichtenstein-Vidne Limor , Okon-Singer Hadas , Dewey Deborah , Bray Signe
Published: December 2018

Attention traits are a cornerstone to the healthy development of children’s performance in the classroom, their interactions with peers, and in predicting future success and problems. The cerebellum is increasingly appreciated as a region involved in complex cognition and behavior, and moreover makes important connections to key brain networks known to support attention: the dorsal attention and default mode networks (DAN; DMN). The cerebellum has also been implicated in childhood disorders affecting attention, namely autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), suggesting that attention networks extending to the cerebellum may be important to consider in relation to attentive traits. Yet, direct investigations into the association between cerebellar FC and attentive traits are lacking. Therefore, in this study we examined attentive traits, assessed using parent reports of ADHD and ASD symptoms, in a community sample of 52 girls aged 4-7 years, i.e. around the time of school entry, and their association with cerebellar connections with the DAN and DMN. We found that cortico-cerebellar functional connectivity (FC) jointly and differentially correlated with attentive traits, through a combination of weaker and stronger FC across anterior and posterior DAN and DMN nodes. These findings suggest that cortico-cerebellar integration may play an important role in the manifestation of attentive traits.
Immunomodulatory activity of Ganoderma lucidum immunomodulatory protein via PI3K/Akt and MAPK signaling pathways in macrophage RAW264.7 cells
Authors: Zhou Xuanwei , Li Qizhang , Chang Yuzhou , Li Liu-Ding-Ji , Du Xiaoyu , Bai Xiaohui , He Zhu-Mei , Chen Lei
Published: December 2018

Ganoderma lucidum, a traditional edible and medicinal fungus, holds an important status in health care systems in China and other Asian countries. Fungal immunomodulatory protein (FIP), one of the active ingredients isolated from G. lucidum, is a class of naturally occurring proteins and possesses potential biological functions. This study was conducted to explore the molecular mechanism of its immunomodulatory potency in immune responses of macrophages. In vitro assays of biological activity indicated that rFIP-glu significantly activated macrophage RAW264.7 cells, and possessed the ability of pro- and anti-inflammation the cells. RNA sequencing analysis showed that macrophage activation involved Toll-like receptors and mitogen-activated protein kinases pathways. Furthermore, qRT-PCR indicated that phosphoinositide 3 kinase inhibitor LY294002 blocked the mRNA levels of MCP-1, MEK1/2 inhibitor U0126 reduced the mRNA levels of TNF-α and MCP-1, and JNK inhibitor SP600125 prevented the up-regulation of iNOS mRNA in the rFIP-glu-induced cells. FIP-glu mediated these inflammatory effects not through a general pathway, instead through a different pathway for different inflammatory mediator. These data indicate the possibility that rFIP-glu has an important immune-regulation function and thus has potential therapeutic uses.
AMPK promotes induction of a tumor suppressor FLCN through activation of TFEB independently of mTOR
Authors: Collodet Caterina , Foretz Marc , Deak Maria , Bultot Laurent , Metairon Sylviane , Viollet Benoit , Lefebvre Gregory , Raymond Frederic , Parisi Alice , Civiletto Gabriele , Gut Philipp , Descombes Patrick , Sakamoto Kei
Published: December 2018

AMP-activated protein kinase (AMPK) is a central energy sensor and master regulator of energy homeostasis. AMPK not only elicits acute metabolic responses, but also promotes metabolic reprogramming and adaptions in the long-term through regulation of specific transcription factors/co-activators. We performed a whole-genome transcriptome profiling in wild-type and AMPK-deficient mouse embryonic fibroblasts (MEF) and primary hepatocytes that had been treated with two distinct classes of small-molecule AMPK activators, namely 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or 991. This led to the identification of distinct compound-dependent gene expression signatures and to the discovery of several AMPK-regulated genes, including Flcn encoding a tumor suppressor and nutrient sensor folliculin (FLCN). Gene set enrichment and pathway analyses identified the lysosomal pathway and the associated transcription factor EB (TFEB) as key transcriptional mediator responsible for AMPK-dependent gene expression changes. AMPK-induced Flcn expression was abolished in TFEB/TFE3 double knockout MEF and the promoter activity of Flcn was profoundly reduced when its putative TFEB-binding site was mutated. Mechanistically, we have found that AMPK promotes the dephosphorylation and nuclear localization of TFEB independently of mTOR activity. Collectively, we identified the AMPK-TFEB-FLCN axis as a potential key regulator for cellular and metabolic homeostasis. Moreover, data from zebrafish with physiologically and pharmacologically activated AMPK supports the existence of the AMPK-TFEB-FLCN cascade in vivo.
Intravital optoacoustic ultrasound bio-microscopy reveals radiation-inhibited skull angiogenesis
Authors: Estrada Héctor , Rebling Johannes , Sievert Wolfgang , Hladik Daniela , Hofmann Urs , Gottschalk Sven , Tapio Soile , Multhoff Gabriele , Razansky Daniel
Published: December 2018

Angiogenesis is critical in bone development and growth. Dense, large-scale, and multi-layered vascular networks formed by thin-walled sinusoidal vessels perfuse the plate bones and play an important role in bone repair. Yet, the intricate functional morphology of skull microvasculature remains poorly understood as it is difficult to visualize using existing intravital microscopy techniques. Here we introduced an intravital fully-transcranial imaging approach based on hybrid optoacoustic and ultrasound bio-microscopy, allowing for large-scale observations and quantitative analysis of the vascular morphology, angiogenesis, vessel remodeling, and subsurface roughness in murine skulls. Our approach also enabled high-throughput physiological studies to understand radiation-inhibited angiogenesis in the skull bone. We observed previously undocumented sinusoidal vascular networks spanning the entire skullcap, thus opening new vistas for studying the complex interactions between calvarian, pial, and cortical vascular systems.
OncodriveCLUSTL: a sequence-based clustering method to identify cancer drivers
Authors: Arnedo-Pac Claudia , Mularoni Loris , Muiños Ferran , Gonzalez-Perez Abel , Lopez-Bigas Nuria
Published: December 2018

The identification of the genomic alterations driving tumorigenesis is one of the main goals in oncogenomics research. Given the evolutionary principles of cancer development, computational methods that detect signals of positive selection in the pattern of tumor mutations have been effectively applied in the search for cancer genes. One of these signals is the abnormal clustering of mutations, which has been shown to be complementary to other signals in the detection of driver genes. We have developed OncodriveCLUSTL, a new sequence-based clustering algorithm to detect significant clustering signals across genomic regions. OncodriveCLUSTL is based on a local background model derived from the simulation of mutations accounting for the composition of tri- or penta-nucleotide context substitutions observed in the cohort under study. Our method is able to identify known clusters and bona-fide cancer drivers across cohorts of tumor whole-exomes, outperforming the existing OncodriveCLUST algorithm and complementing other methods based on different signals of positive selection. We show that OncodriveCLUSTL may be applied to the analysis of non-coding genomic elements and non-human mutations data.

Availability and implementation

OncodriveCLUSTL is available as an installable Python 3.5 package. The source code and running examples are freely available at https://bitbucket.org/bbglab/oncodriveclustl under GNU Affero General Public License.

Contact

nuria.lopez@irbbarcelona.org
Using high-resolution annotation of insect mitochondrial DNA to decipher tandem repeats in the control region
Authors: Haishuo Ji , Xiaofeng Xu , Xiufeng Jin , Zhi Cheng , Hong jin , Guangyuan Liu , Qiang Zhao , Ze Chen , Wenjun Bu , Shan Gao
Published: December 2018

In this study, we used a small RNA sequencing (sRNA-seq) based method to annotate the mitochondrial genome of the insect Erthesina fullo Thunberg at 1 bp resolution. Most of the new annotations were consistent with the previous annotations which were obtained using PacBio full-length transcripts. Two important findings are that animals transcribe both entire strands of mitochondrial genomes and the tandem repeat in the control region of the E. fullo mitochondrial genome contains the repeated Transcription Initiation Sites (TISs) of the H-strand. In addition, we found that the copy numbers of tandem repeats showed a great diversity within an individual, enriching the fundamental knowledge of mitochondrial biology. This sRNA-seq based method uses 5′ and 3′ end small RNAs to annotate nuclear non-coding and mitochondrial genes at 1 bp resolution and can also be used to identify new steady-state RNAs, particularly long non-coding RNAs (lncRNAs). Animal mitochondrial genomes containing one control region only encode two steady-state lncRNAs, which are the Mitochondrial D-loop 1 (MDL1) and its antisense gene (MDL1AS), while all other reported mitochondrial lncRNAs could be degraded fragments of transient RNAs or random breaks during experimental processing. The high-resolution annotations of mitochondrial genomes can be used to study the phylogenetics and molecular evolution of animals or to investigate mitochondrial gene transcription, RNA processing, RNA maturation and several other related topics.
Structures of the Catalytically Activated Yeast Spliceosome Reveal the Mechanism of Branching
Authors: Wan Ruixue , Bai Rui , Yan Chuangye , Lei Jianlin , Shi Yigong
Published: December 2018

Pre-mRNA splicing is executed by the spliceosome. Structural characterization of the catalytically activated complex (B*) is pivotal for mechanistic understanding of catalysis of the branching reaction by the spliceosome. In this study, we assembled the B* complex on two different pre-mRNAs from Saccharomyces cerevisiae and determined the cryo-EM structures of four distinct B complexes at overall resolutions of 2.9-3.8 Å. The duplex between U2 snRNA and the branch point sequence (BPS) is located 13-20 Å away from the 5’-splice site (5’SS) in the B* complexes that are devoid of the step I splicing factors Yju2 and Cwc25. Recruitment of Yju2 into the active site brings the U2/BPS duplex into the vicinity of 5’SS, ready for branching. In the absence of Cwc25, the nucleophile from BPS is positioned about 4 Å away from, and remains to be activated by, the catalytic metal M2. This analysis reveals the functional mechanism of Yju2 and Cwc25 in branching. These four structures constitute compelling evidence for substrate-specific conformations of the spliceosome in a major functional state.
DR-SIP: Protocols for Higher Order Structure Modeling with Distance Restraints- and Cyclic Symmetry-Imposed Packing
Authors: Chan Justin , Zou Jinhao , Chien Chi-Hong Chang , Pan Rong-Long , Yang Lee-Wei
Published: December 2018

Motivation: Quaternary structure determination for proteins is difficult especially for transmembrane proteins. Even if the monomeric constituents of complexes have been experimentally resolved, computational prediction of quaternary structures is a challenging task particularly for higher order complexes. It is essential to have a reliable computational protocol to predict quaternary structures of both transmembrane and soluble proteins leveraging experimentally determined distance restraints and/or cyclic symmetry (Cn symmetry) found in most homo-oligomeric transmembrane proteins. Results: We survey 115 X-ray crystallographically solved structures of homo-oligomeric transmembrane proteins (HoTPs) to discover that 90% of them are Cn symmetric. Given the prevalence of Cn symmetric HoTPs and the benefits of incorporating geometry restraints in aiding quaternary structure determination, we introduce two new filters, the distance-restraints (DR) filter and the Symmetry-Imposed Packing (SIP) filter which takes advantage of the statistically derived tilt angle cutoff and the Cn symmetry of HoTPs without prior knowledge of the number ("n") of monomers. Using only the geometrical filter, SIP, near-native poses of the 115 HoTPs can be correctly identified in the top-5 for 52% of all cases, or 49% among the HoTPs having an n>2 (~60% of the dataset), while ZDOCK alone returns 41% and 24%, respectively. Applying only SIP to three HoTPs with distance restraints, the near-native poses for two HoTPs are ranked 1st and the other 7th among 54,000 possible decoys. With both filters, the two remain 1st while the other improved to 2nd. While a soluble system with distance restraints is recovered at the 1st-ranked pose by applying only DR.
Selective peak inference: Unbiased estimation of raw and standardized effect size at local maxima
Authors: Davenport Samuel J. , Nichols Thomas E.
Published: December 2018

The spatial signals in neuroimaging mass univariate analyses can be characterized in a number of ways, but one widely used approach is peak inference: the identification of peaks in the image. Peak locations and magnitudes provide a useful summary of activation and are routinely reported, however, the magnitudes reflect selection bias as these points have both survived a threshold and are local maxima. In this paper we propose the use of resampling methods to estimate and correct this bias in order to estimate both the raw units change as well as standardized effect size measured with Cohen’sdand partialR2. We evaluate our method with a massive open dataset, and discuss how the corrected estimates can be used to perform power analyses.
Integrated Likelihood for Phylogenomics under a No-Common-Mechanism Model
Authors: Tidwell Hunter , Nakhleh Luay
Published: December 2018

The availability of genome-wide sequence data from a large number of species as well as data from multiple individuals within a species has ushered in the era of phylogenomics. In this era, species phylogeny inference is based on models of sequence evolution on gene trees as well as models of gene tree evolution within the branches of species phylogenies. Parsimony, likelihood, Bayesian, and distance methods have been introduced for species phylogeny inference based on such models. All methods, except for the parsimony ones, assume a common mechanism across all loci as captured by a single value of each branch length of the species phylogeny. In this paper, we propose a ``no common mechanism" (NCM) model, where every gene tree evolves according to its own parameters of the species phylogeny. An analogous model was proposed and explored, both mathematically and experimentally, for sites, or characters, in a sequence alignment in the context of the classical phylogeny problem. For example, a famous equivalence between the maximum parsimony and maximum likelihood phylogeny estimates was established under certain NCM models by Tuffley and Steel. Here we derive an analytically integrated likelihood of both species trees and networks given the gene trees of multiple loci under an NCM model. We demonstrate the performance of inference under this integrated likelihood on both simulated and biological data. The model presented here will afford opportunities for exploring connections among various methods for estimating species phylogenies from multiple, independent loci.
An interaction map of transcription factors controlling gynoecium development in Arabidopsis
Authors: Herrera-Ubaldo Humberto , Campos Sergio E. , Luna Garcia Valentin , Zuniga-Mayo Victor M. , Armas-Caballero Gerardo , DeLuna Alexander , Marsch-Martinez Nayelli , de Folter Stefan
Published: December 2018

Flowers are composed of different organs, whose identity is defined at the molecular by the combinatorial activity of transcription factors (TFs). MADS-box TFs interact forming complexes that have been schematized in the quartet model. The gynoecium is the female reproductive part in the flower, crucial for plant reproduction, and fruit and seed production. Once carpel identity is established, a gynoecium containing many tissues arises. Several TFs have been identified as regulators of gynoecium development, and some of these TFs form complexes. However, broad knowledge about the interactions among these TFs is still scarce. In this work, we used a systems biology approach to understand the formation of a complex reproductive unit as the gynoecium by mapping binary interactions between well-characterized TFs. We analyzed over 3500 combinations and detected more than 200 protein-protein interactions (PPIs), resulting in a process specific interaction map. Topological analyses suggest hidden functions and novel roles for many TFs. Furthermore, a relationship between TFs involved in auxin and cytokinin signaling pathways and other TFs was observed. We analyzed the network by combining PPI data, expression and genetic data, allowing us to dissect it into several dynamic spatio-temporal sub-networks related to gynoecium development subprocesses.
Taking advantage of external mechanical work to reduce metabolic cost: the mechanics and energetics of split-belt treadmill walking
Authors: Sanchez Natalia , Simha Surabhi , Donelan J. Maxwell , Finley James Micah
Published: December 2018

In everyday tasks such as walking and running, we exploit the work performed by external sources such as gravity to reduce the work performed by muscles. There has been considerable recent effort to design devices capable of performing mechanical work to improve walking function or reduce effort. The success of these devices relies on the user adapting their natural control strategies to take advantage of assistance provided by the device. Although locomotor adaptation is central to this process, the study of adaptation is often done using approaches that on the surface, seem to have little in common with the use of external assistance. Here, we show that one of the most common approaches for studying this process, which is adaptation to walking on a split-belt treadmill, can be understood from a perspective in which people learn to take advantage of mechanical work performed by the treadmill. During adaptation, people systematically adjust their step lengths, defined as the distance between the feet at heel strike, from one step to the next. Initially, the step length on the slow belt is longer than the step length on the fast belt, measured as a negative step length asymmetry, but people naturally reduce this asymmetry with practice. Here, we demonstrate that these modifications of step length asymmetry allow people to extract positive work from the treadmill belts to reduce the positive work performed by the legs and simultaneously reduce metabolic cost. Moreover, we show that walking with a positive step length asymmetry minimizes metabolic cost, and people prefer to walk in this manner when allowed to select their walking pattern. Together, our results suggest that split-belt adaptation can be interpreted as a process by which people learn to take advantage of mechanical work performed by an external device to improve walking economy.
LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription
Authors: LeRoy Gary , Oksuz Ozgur , Descostes Nicolas , Aoi Yuki , Ganai Rais , Ortabozkoyun Havva , Yu Jia-Ray , Lee Chul-Hwan , Stafford James , Shilatifard Ali , Reinberg Danny
Published: December 2018

FACT (facilitates chromatin transcription) is a protein complex that allows RNAPII to overcome the nucleosome-induced barrier to transcription. While abundant in undifferentiated cells and many cancers, FACT is not abundant or is absent in most tissues. Therefore, we screened for additional proteins that might replace FACT upon differentiation. Here we report the identification of two such proteins, LEDGF and HDGF2, each containing two HMGA-like AT-hooks and a PWWP methyl-lysine reading domain known to bind to H3K36me2 and H3K36me3. LEDGF and HDGF2 localize with H3K36me2/3 at genomic regions containing active genes, usually adjacent to H3K27me3 domains. In myoblasts, where FACT expression is low, LEDGF and HDGF2 are enriched on most active genes. Upon differentiation to myotubes, LEDGF levels decrease across the genome while HDGF2 levels are maintained. Moreover, HDGF2 is recruited to the majority of myotube up-regulated genes and is required for their proper expression. HDGF2 knockout myoblasts exhibit an accumulation of paused RNAPII proximal to the first nucleosome within the transcribed region of many HDGF2 target genes, indicating a defect in early elongation. We propose that LEDGF and HDGF2 substitute for FACT in differentiated tissues and that their distribution on the genome helps maintain transcriptional programs unique to particular cell types.
The Landscape Of Circular RNA Expression In The Human Brain
Authors: Gokoolparsadh Akira , Anwar Firoz , Voineagu Irina
Published: December 2018

Circular RNAs (circRNAs) are enriched in the mammalian brain and are upregulated in response to neuronal differentiation and depolarisation. These RNA molecules, formed by non-canonical back-splicing, have both regulatory and translational potential. Here, we carried out an extensive characterisation of circRNA expression in the human brain, in nearly two hundred human brain samples, from both healthy individuals and autism cases. We identify hundreds of novel circRNAs and demonstrate that circRNAs are not expressed stochastically, but rather as major isoforms. We characterise inter-individual variability of circRNA expression in the human brain and show that inter-individual variability is less pronounced than variability between cerebral cortex and cerebellum. We also find that circRNA expression is dynamic during cellular maturation in brain organoids, but remains largely stable across the adult lifespan. Finally, we identify a circRNA co-expression module upregulated in autism samples, thereby adding another layer of complexity to the transcriptome changes observed in autism brain. These data provide a comprehensive catalogue of circRNAs as well as a deeper insight into their expression in the human brain, and are available as a free resource in browsable format at: http://www.voineagulab.unsw.edu.au/circ_rna
Structural analysis of phosphorylation-associated interactions of MCC to Scribble PDZ domains
Authors: Caria Sofia , Stewart Bryce Z , Humbert Patrick O , Kvansakul Marc
Published: December 2018

Scribble is a crucial adaptor protein that plays a pivotal role during establishment and control of cell polarity, impacting many physiological processes ranging from cell migration to immunity and organization of tissue architecture. Scribble harbors a leucine-rich repeat domain and four PDZ domains, which mediate most of Scribbles interactions with other proteins. It has become increasingly clear that posttranslational modifications substantially impact Scribble-ligand interactions, with phosphorylation being a major modulator of binding to Scribble. To better understand how Scribble PDZ domains direct cell polarity signalling and how phosphorylation impacts this process, we investigated Scribble interactions with MCC (mutated in colorectal cancer). We systematically evaluated the ability of all four individual Scribble PDZ domains to bind the PDZ-binding motif (PBM) of wild-type MCC as well as MCC phosphorylated at the -1 Ser position. We show that Scribble PDZ1 and PDZ3 are the major interactors with MCC, and that modifications to Ser at the -1 position in the MCC PBM only has a modest effect on binding to Scribble PDZ domains. We then examined the structural basis for these observations by determining the crystal structures of Scribble PDZ1 domain bound to both the wild-type MCC PBM as well as phosphorylated MCC. Our structures indicated that phospho-Ser at the -1 position in MCC is not involved in major contacts with Scribble PDZ1, and in conjunction with our affinity measurements suggest that the impact of phosphorylation at the -1 position of MCC extends beyond a simple modulation of the affinity for Scribble PDZ domains.
Proteomic Analyses of Morphological Variants ofBorrelia burgdorferiShed New Light on Persistence Mechanisms: Implications for Pathogenesis, Diagnosis and Treatment
Authors: Feng Jie , Zhang Ying
Published: December 2018

Borrelia burgdorfericauses Lyme disease, which is the most common vector borne disease in the United States and Europe. Although 2-4 week antibiotic treatment for Lyme disease is effective in the majority of cases, about 10–20% patients suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the mechanisms of PTLDS are unclear, persisting organisms not killed by current Lyme antibiotics has been suggested as a possible explanation.B. burgdorferican spontaneously develop different morphological variant forms under stress or in stationary phase with increased persistence to antibiotics. To shed light on the possible mechanisms by which these variant forms develop persistence, here, we isolated threeB. burgdorferiforms, log phase spirochetal form, stationary phase planktonic form, and stationary phase aggregated biofilm-like microcolony form. We showed that the two separated stationary phase forms especially microcolony form have more persistence to antibiotics than the log phase spirochetal form. Then, we performed mass spectrometry (MS/MS) analysis to determine the proteomic profiles of the three different forms to reveal the mechanisms of persistence inB. burgdorferi. We identified 1023 proteins in the threeB. burgdorferiforms, with 642 proteins (63%) differentially expressed. Compared with the log phase spirochetal form ofB. burgdorferi, a total of 143 proteins were upregulated in both stationary phase planktonic form and microcolony form. Among these common upregulated proteins, 90 proteins had predicted functions and were mapped to different pathways involved in infection and virulence, DNA repair, heat shock, transport, sporulation, cell envelope and metabolism, many of which are consistent with persister mechanisms in other bacteria. A particularly interesting observation is that infection and virulence related proteins are highly up-regulated in stationary phase planktonic form and microcolony form compared with log phase spirochetal form. These findings shed new light on the mechanisms ofB. burgdorferipersistence and offer novel targets for developing more effective diagnostics, vaccines and treatments.
Nucleotide Archival Format (NAF) enables efficient lossless reference-free compression of DNA sequences
Authors: Kryukov Kirill , Ueda Mahoko Takahashi , Nakagawa So , Imanishi Tadashi
Published: December 2018

DNA sequence databases use compression such as gzip to reduce the required storage space and network transmission time. We describe Nucleotide Archival Format (NAF) – a new file format for lossless reference-free compression of FASTA and FASTQ-formatted nucleotide sequences. NAF compression ratio is comparable to the best DNA compressors, while providing dramatically faster decompression. We compared our format with DNA compressors: DELIMINATE and MFCompress, and with general purpose compressors: gzip, bzip2, xz, brotli, and zstd.

Availability

NAF compressor and decompressor, as well as format specification are available at https://github.com/KirillKryukov/naf. Format specification is in public domain. Compressor and decompressor are open source under the zlib/libpng license, free for nearly any use.

Contact

kkryukov@gmail.com
Soil respiration in a tropical montane grassland ecosystem is largely heterotroph-driven and increases under simulated warming
Authors: Tiruvaimozhi Yadugiri V , Sankaran Mahesh
Published: December 2018

Soil respiration, a major source of atmospheric carbon (C), can feed into climate warming, which in turn can amplify soil CO2 efflux by affecting root, arbuscular mycorrhizal fungal (AMF) and other heterotrophic respiration. Although tropical ecosystems contribute >60% of the global soil CO2 efflux, there is currently a dearth of data on tropical soil respiration responses to temperature rise. We set up a simulated warming and soil respiration partitioning experiment in tropical montane grasslands in the Western Ghats in southern India, to (a) evaluate soil respiration responses to warming, (b) assess the relative contributions of autotrophic and heterotrophic components to soil respiration, and (c) assess the roles of soil temperature and soil moisture in influencing soil respiration in this system. Our results show that soil respiration was tightly coupled with soil moisture availability, with CO2 efflux levels peaking during the wet season. Soil warming by ~1.4 °C nearly doubled soil respiration from ~0.64 g CO2 m-2 hr-1 on average under ambient conditions to ~1.17 g CO2 m-2 hr-1 under warmed conditions. However, warming effects on soil CO2 efflux were contingent on water availability, with greater relative increases in soil respiration observed under conditions of low, compared to high, soil moisture. Hetrotrophs contributed to the majority of soil CO2 efflux, with respiration remaining unchanged when roots and/or AMF hyphae were excluded. Overall, our results indicate that future warming is likely to substantially increase the largely heterotroph-driven soil C fluxes in this tropical montane grassland ecosystem.
MicroRNA-deficient embryonic stem cells acquire a functional Interferon response
Authors: Witteveldt Jeroen , Knol Lisanne , Macias Sara
Published: December 2018

When mammalian cells detect a viral infection, they initiate a type-I Interferon (IFNs) response as part of their innate immune system. This antiviral mechanism is conserved in virtually all cell types, except for embryonic stem cells (ESCs) and oocytes which are intrinsically incapable of producing IFNs. Despite the importance of the IFN response to fight viral infections, the mechanisms regulating this pathway during pluripotency are still unknown. Here we show that, in the absence of miRNAs, ESCs acquire an active IFN response. Proteomic analysis identified MAVS, a central component of the IFN pathway, to be actively silenced by miRNAs and responsible for suppressing IFN expression in ESCs. Furthermore, we show that knocking out a single miRNA, miR-673, restores the antiviral response in ESCs through MAVS regulation. Our findings suggest that the interaction between miR-673 and MAVS acts as a switch to suppress the antiviral IFN during pluripotency and present genetic approaches to enhance their antiviral immunity.
PrimPol is required for the maintenance of efficient nuclear and mitochondrial DNA replication in human cells
Authors: Bailey Laura , Bianchi Julie , Doherty Aidan
Published: December 2018

Eukaryotic Primase-Polymerase (PrimPol) is an enzyme that maintains efficient DNA duplication by repriming replication restart downstream of replicase stalling lesions and structures. To elucidate the cellular requirements for PrimPol in human cells, we generated PrimPol-deleted cell lines and show that it plays key roles in maintaining active replication in both the nucleus and mitochondrion, even in the absence of exogenous damage. Human cells lacking PrimPol exhibit delayed recovery after UV-C damage and increased mutation rates, micronuclei and sister chromatin exchanges but are not sensitive to genotoxins. PrimPol is also required during mitochondrial replication, with PrimPol-deficient cells having increased mtDNA copy number but displaying a significant decrease in replication rates. Deletion of PrimPol in XPV cells, lacking functional Pol Eta, causes an increase in DNA damage sensitivity and pronounced fork stalling after UV-C treatment. We show that, unlike canonical TLS polymerases, PrimPol is important for allowing active replication to proceed, even in the absence of exogenous damage, thus preventing the accumulation of excessive fork stalling and genetic mutations. Together, these findings highlight the importance of PrimPol for maintaining efficient DNA replication in unperturbed cells and its complementary roles, with Pol Eta, in damage tolerance in human cells.
Using ribosome profiling to quantify differences in protein expression: a case study in Saccharomyces cerevisiae oxidative stress conditions
Authors: Blevins William R. , Tavella Teresa , Moro Simone G. , Blasco-Moreno Bernat , Closa-Mosquera Adrià , Díez Juana , Carey Lucas B. , Albà M. Mar
Published: December 2018

Cells respond to changes in the environment by modifying the concentration of specific proteins. Paradoxically, the cellular response is usually examined by measuring variations in transcript abundance by high throughput RNA sequencing (RNA-Seq), instead of directly measuring protein concentrations. This happens because RNA-Seq-based methods provide better quantitative estimates, and more extensive gene coverage, than proteomics-based ones. However, variations in transcript abundance do not necessarily reflect changes in the corresponding protein abundance. How can we close this gap? Here we explore the use of ribosome profiling (Ribo-Seq) to perform differentially gene expression analysis in a relatively well-characterized system, oxidative stress in baker’s yeast. Ribo-Seq is an RNA sequencing method that specifically targets ribosome-protected RNA fragments, and thus is expected to provide a more accurate view of changes at the protein level than classical RNA-Seq. We show that gene quantification by Ribo-Seq is indeed more highly correlated with protein abundance, as measured from mass spectrometry data, than quantification by RNA-Seq. The analysis indicates that, whereas a subset of genes involved in oxidation-reduction processes is detected by both types of data, the majority of the genes that happen to be significant in the RNA-Seq-based analysis are not significant in the Ribo-Seq analysis, suggesting that they do not result in protein level changes. The results illustrate the advantages of Ribo-Seq to make inferences about changes in protein abundance in comparison with RNA-Seq.
CRUP: A comprehensive framework to predict condition-specific regulatory units
Authors: Ramisch Anna , Heinrich Verena , Glaser Laura V. , Fuchs Alisa , Yang Xinyi , Benner Philipp , Schöpflin Robert , Li Na , Kinkley Sarah , Hillmann Anja , Longinotto John , Heyne Steffen , Czepukojc Beate , Kessler Sonja M. , Kiemer Alexandra K. , Cadenas Cristina , Arrigoni Laura , Gasparoni Nina , Manke Thomas , Pap Thomas , Pospisilik Andrew , Hengstler Jan , Walter Jörn , Meijsing Sebastiaan H. , Chung Ho-Ryun , Vingron Martin
Published: December 2018

We present the software CRUP (Condition-specific Regulatory Units Prediction) to infer from epigenetic marks a list of regulatory units consisting of dynamically changing enhancers with their target genes. The workflow consists of a novel pre-trained enhancer predictor that can be reliably applied across cell lines and species, solely based on histone modification ChIP-seq data. Enhancers are subsequently assigned to different conditions and correlated with gene expression to derive regulatory units. We thoroughly test and then apply CRUP to a rheumatoid arthritis model, identifying enhancer-gene pairs comprising known disease genes as well as new candidate genes.

Availability

https://github.com/VerenaHeinrich/CRUP
Metal-induced abnormalities in diatom girdle bands
Authors: Olenici Adriana , Blanco Saul , Borrego-Ramos Maria , Jimenez-Gomez Francisco , Guerrero Francisco , Momeu Laura , Baciu Calin
Published: December 2018

There have been a number of studies that described a serial of type of teratology occurring in different diatom taxa and that highlight the relation between metal concentration and diatom deformities, but this subject still remain not deeply understood. The present study refers to the effect of metal pollution on the diatom Achnanthidium minutissimum s.l. by describing a new form of teratology. The samples were collected in a mine area, Rosia Montana, from Romania. We observed that, exposed to environmental stress, the frustule of diatom cells appeared altered in several ways, with abnormal forms occurring in different diatom species that presented deformed valve outlines, modifications of the raphe canal system, irregular striation or mixed teratologies. In a particular sampling location where A. minutissimum s.l. was identified as the dominant species, 20.53% of the individuals presented an unreported type of deformity. This kind of teratology affects the cingulum, the valvocopula more exactly, by becoming markedly undulate.
A computational platform for high-throughput analysis of RNA sequences and modifications by mass spectrometry
Authors: Wein Samuel , Andrews Byron , Sachsenberg Timo , Santos-Rosa Helena , Kohlbacher Oliver , Kouzarides Tony , Garcia Benjamin A. , Weisser Hendrik
Published: December 2018

The field of epitranscriptomics is growing in importance, with chemical modification of RNA being associated with a wide variety of biological phenomena. A pivotal challenge in this area is the identification of modified RNA residues within their sequence contexts. Next-generation sequencing approaches are generally unable to capture modifications, although workarounds for some epigenetic marks exist. Mass spectrometry (MS) offers a comprehensive solution by using analogous approaches to shotgun proteomics. However, software support for the analysis of RNA MS data is inadequate at present and does not allow high-throughput processing. In particular, existing software solutions lack the raw performance and statistical grounding to efficiently handle the large variety of modifications present on RNA. We present a free and open-source database search engine for RNA MS data, called NucleicAcidSearchEngine (NASE), that addresses these shortcomings. We demonstrate the capability of NASE to reliably identify a wide range of modified RNA sequences in three original datasets of varying complexity. In a human tRNA sample, we characterize over 20 different modification types simultaneously and find many cases of incomplete modification.