bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cell Repertoire Evolution After Allogeneic Bone Marrow Transplantation: An Organizational Perspective
Authors: Meier Jeremy A. , Fawaz Mohamed , Abdeen Hamdi , Reed Jason , Kanakry Christopher G. , Luznik Leo , Toor Amir A. 
Published: May 2018

AbstractHigh throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire. In an attempt to correlate T cell reconstitution with clinical outcomes several measures of T cell repertoire complexity have emerged. However, the associations identified are of a broadly statistical nature, not allowing precise modeling of outcomes based on T cell repertoire development in clinical contexts such as following bone marrow transplantation (BMT). Previous work demonstrated that there is an inherent, mathematically definable order observed in the T cell population that is conserved in a diverse group of donors, and which is perturbed in recipients following BMT. Herein, we use a public database of human leukocyte antigen matched related-donor and recipient T cell receptor (TCR) β sequences to further develop this methodology. TCR β sequencing from unsorted T cells and sorted T cell subsets isolated from peripheral blood samples from BMT donors and recipients show remarkable conservation and symmetry of VJ segment usage in the clonal frequencies, linked to the organization of the gene segments along the TCR locus. This TCR β VJ segment translational symmetry is preserved post-transplant, and even in cases of acute GVHD (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antiges. We also observe that the complexity of the repertoire is significantly diminished after BMT and is not restored even years out post-transplant. The results here provide a new method of quantifying and characterizing post-transplant T cell repertoire reconstitution by further analyzing the mathematical rules governing TCR usage in the context of BMT. This approach may allow for a new means to correlate clinical outcomes with the evolving T cell repertoire post-transplant.
Transformation from auditory to linguistic representations across auditory cortex is rapid and attention dependent for continuous speech
Authors: Brodbeck Christian , Hong L. Elliot , Simon Jonathan Z. 
Published: May 2018

SummaryDuring speech perception, a central task of the auditory cortex is to analyze complex acoustic patterns to allow detection of the words that encode a linguistic message. It is generally thought that this process includes at least one intermediate, phonetic, level of representations [1–6], localized bilaterally in the superior temporal lobe [7–10]. Phonetic representations reflect a transition from acoustic to linguistic information, classifying acoustic patterns into linguistically meaningful units, which can serve as input to mechanisms that access abstract word representations [11–13]. While recent research has identified neural signals arising from successful recognition of individual words in continuous speech [14–17], no explicit neurophysiological signal has been found demonstrating the transition from acoustic/phonetic to symbolic, lexical representations. Here we report a response reflecting the incremental integration of phonetic information for word identification, dominantly localized to the left temporal lobe. The short response latency, approximately 110 ms relative to phoneme onset, suggests that phonetic information is used for lexical processing as soon as it becomes available. Responses also tracked word boundaries, confirming previous reports of immediate lexical segmentation [18,19]. These new results were further investigated using a cocktail-party paradigm [20,21] in which participants listened to a mix of two talkers, attending to one and ignoring the other. Analysis indicates neural lexical processing of only the attended, but not the unattended, speech stream. Thus, while responses to acoustic features reflect attention through selective amplification of attended speech, responses consistent with a lexical processing model reveal categorically selective processing.
The first one hundred nanometers inside the pre-synaptic terminal where calcium diffusion triggers vesicular release
Authors: Guerrier C. , Holcman D. 
Published: May 2018

AbstractCalcium diffusion in the thin one hundred nanometers layer located between the plasma membrane and docked vesicles in the pre-synaptic terminal of neuronal cells mediates vesicular fusion and synaptic transmission. Accounting for the narrow-cusp geometry located underneath the vesicle is a key ingredient that defines the probability and the time scale of calcium diffusion to bind calcium sensors for the initiation of vesicular release. We study here the time scale, the calcium binding dynamics and the consequences for asynchronous versus synchronous release. To conclude, threedimensional modeling approaches and the associated coarse-grained simulations can now account efficiently for the precise co-organization of vesicles and Voltage-Gated-Calcium-Channel (VGCC). This co-organization is a key determinant of short-term plasticity and it shapes asynchronous release. Moreover, changing the location of VGCC from few nanometers underneath the vesicle modifies significantly the release probability. Finally, by modifying the calcium buffer concentration, a single synapse can switch from facilitation to depression.
Decreased RORC expression and downstream signaling in HTLV-1-associated Adult T-cell Lymphoma/Leukemia uncovers an antiproliferative IL17 link: a potential target for immunotherapy?
Authors: Subramanian Kritika , Dierckx Tim , Khouri Ricardo , Menezes Soraya Maria , Farre Lourdes , Bittencourt Achilea , Kataoka Keisuke , Ogawa Seishi , Van Weyenbergh Johan 
Published: May 2018

AbstractRetinoic acid-related drugs have shown promising pre-clinical activity in Adult T-cell Leukemia/Lymphoma (ATL), but RORC (Retinoic acid Orphan Receptor C) signaling has not been explored. Therefore, we investigated transcriptome-wide interactions of the RORC pathway in Human T-cell Leukemia Virus-1 (HTLV-1) infection and ATL, using our own and publicly available gene expression data for ATL and other leukemias, HTLV-1-infected individuals and healthy controls. Gene expression data from ATL patients were analyzed using Weighted Gene Correlation Network Analysis (WGCNA) to determine gene modules and their correlation to clinical and molecular data. Both PBMCs and CD4+ T-cells showed decreased RORC expression in four different ATL cohorts. A small subset of RORChi ATL patients was identified with significantly lower pathognomonic CADM1 and HBZ levels but similar levels of other ATL markers (CD4/CD25/CCR4), hinting at a less aggressive ATL subtype. In addition, an age-dependent decrease in RORC expression was found in HTLV-1-infected individuals, but not in healthy controls, suggesting an early molecular event predisposing to leukemogenesis. Genes upstream of RORC signaling were members of a proliferative gene module (containing proliferation markers PCNA/MKI67), whereas downstream members clustered in an antiproliferative gene module. IL17C transcripts showed the strongest negative correlation to PCNA in both ATL cohorts, which was replicated in two large cohorts of T- and B-cell acute leukemias. In conclusion, decreased RORC expression and downstream signaling might represent an early event in ATL pathogenesis. An antiproliferative IL17C/PCNA link is shared between ATL, T-ALL and B-ALL, suggesting (immuno)therapeutic benefit of boosting RORC/IL17 signaling.AbbreviationsHTLV-1Human T-cell Leukemia Virus-1ATLAdult T-cell Leukemia/LymphomaWGCNAWeighted Gene Correlation Network AnalysisATRAAll-trans retinoic acidRARaRetinoic acid receptor alphaRORCRetinoic acid orphan receptor CTBLVType B Leukomogenic VirusAMLAcute Myeloid LeukemiaT-ALLT-cell acute lymphoblastic leukemiaILInterleukinPCNAProliferating cell nuclear antigenIDInfectious Dermatitis
The EVcouplings Python framework for coevolutionary sequence analysis
Authors: Hopf Thomas A. , Green Anna G. , Schubert Benjamin , Mersmann Sophia , Schäerfe Charlotta P. I. , Ingraham John B. , Toth-Petroczy Agnes , Brock Kelly , Riesselman Adam , Kang Chan , Dallago Christian , Sander Chris , Marks Debora S. 
Published: May 2018

AbstractSummaryCoevolutionary sequence analysis has become a commonly used technique for de novo prediction of the structure and function of proteins, RNA, and protein complexes. This approach requires extensive computational pipelines that integrate multiple tools, databases, and data processing steps. We present the EVcouplings framework, a fully integrated open-source application and Python package for coevolutionary analysis. The framework enables generation of sequence alignments, calculation and evaluation of evolutionary couplings (ECs), and de novo prediction of structure and mutation effects. The application has an easy to use command line interface to run workflows with user control over all analysis parameters, while the underlying modular Python package allows interactive data analysis and rapid development of new workflows. Through this multi-layered approach, the EVcouplings framework makes the full power of coevolutionary analyses available to entry-level and advanced users.Availabilityhttps://github.com/debbiemarkslab/evcouplingsContactsander.research@gmail.com, debbie@hms.harvard.edu
Comprehensive profiling of translation initiation in influenza virus infected cells
Authors: Machkovech Heather M. , Bloom Jesse D. , Subramaniam Arvind R. 
Published: May 2018

AbstractTranslation can initiate at alternate, non-canonical start codons in response to stressful stimuli in mammalian cells. Recent studies suggest that viral infection and anti-viral responses alter sites of translation initiation, and in some cases, lead to production of novel immune epitopes. Here we systematically investigate the extent and impact of alternate translation initiation in cells infected with influenza virus. We perform evolutionary analyses that suggest selection against non-canonical initiation at CUG codons in influenza virus lineages that have adapted to mammalian hosts. We then use ribosome profiling with the initiation inhibitor lactidomycin to experimentally delineate translation initiation sites in a human lung epithelial cell line infected with influenza virus. We identify several candidate sites of alternate initiation in influenza mRNAs, all of which occur at AUG codons that are downstream of canonical initiation codons. One of these candidate downstream start sites truncates 14 amino acids from the N-terminus of the N1 neuraminidase protein, resulting in loss of its cytoplasmic tail and a portion of the transmembrane domain. This truncated neuraminidase protein is expressed on the cell surface during influenza virus infection, is enzymatically active, and is conserved in most N1 viral lineages. Host transcripts induced by the anti-viral response are enriched for translation initiation at non-canonical start sites and non-AUG start codons. Together, our results systematically map the landscape of translation initiation during influenza virus infection, and shed light on the evolutionary forces shaping this landscape.
Mitochondrial ClpX activates an essential metabolic enzyme through partial unfolding
Authors: Kardon Julia R. , Moroco Jamie A. , Engen John R. , Baker Tania A. 
Published: May 2018

ABSTRACTMitochondria can control the activity, quality, and lifetime of their proteins with their autonomous system of chaperones, but the signals that direct substrate-chaperone interaction and outcome are poorly understood. We previously discovered that the mitochondrial AAA+ protein unfoldase ClpX (mtClpX) activates the initiating enzyme for heme biosynthesis, 5-aminolevulinic acid synthase (ALAS), by promoting incorporation of cofactor. Here, we ask how unfolding by mtClpX directs activation. We identified sequence and structural features in ALAS that position mtClpX and provide a grip for acting on ALAS. Observation of ALAS undergoing remodeling by mtClpX revealed that unfolding was limited to a subdomain extending from the mtClpX-binding site to the active site. Unfolding along this path was required for mtClpX to gate cofactor access to the ALAS active site. This targeted unfolding contrasts with the global unfolding canonically executed by ClpX homologs and suggests how substrate-chaperone interactions can direct the outcome of remodeling.
Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins
Authors: Ballesteros Angela , Fenollar-Ferrer Cristina , Swartz Kenton J. 
Published: May 2018

AbstractThe hair cell mechanotransduction (MET) channel complex is essential for hearing, yet it’s molecular identity and structure remain elusive. The transmembrane channel-like 1 (TMC1) protein localizes to the site of the MET channel, interacts with the tip-link responsible for mechanical gating, and genetic alterations in TMC1 alter MET channel properties and cause deafness, supporting the hypothesis that TMC1 forms the MET channel. We generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that also harbors the Beethoven mutation, suggesting that it could function as a permeation pathway. We also find that hair cells are permeable to 3 kDa dextrans, and that dextran permeation requires TMC1/2 proteins and functional MET channels, supporting the presence of a large permeation pathway and the hypothesis that TMC1 is a pore forming subunit of the MET channel complex.
Urine proteome changes in a TNBS-induced colitis rat model
Authors: Qin Weiwei , Wang Ting , Li Lujun , Huang He , Gao Youhe 
Published: May 2018

AbstractUrine is an important resource for biomarker research. Without homeostasis, urine accumulates markers of all the changes in the body. Urine proteins reflect not only renal diseases but also changes in other organs in the body. However, urine has rarely been used to reflect inflammatory bowel disease. In the present study, a trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model was used to mimic the human inflammatory bowel disease Crohn’s disease (CD). Urine samples from a control group (n=3), a TNBS 2-day group (n=3) and a TNBS 7-day group (n=3) were analyzed for candidate biomarker discovery by label-free and TMT-labeled proteomic quantitative methods. Seventy-seven urinary proteins were significantly changed in the colitis rats compared with that in the controls. These proteins were further validated by parallel reaction monitoring (PRM) targeted proteomic quantitative methods. Urine samples from the control group (n=8), the TNBS 2-day group (n=11) and the TNBS 7-day group (n=11) were analyzed by PRM. This led to the identification of 9 significantly differential expressed urinary proteins: CAH1, G3P, MMP-8, MANBA, NGAL, RNS1G, SLC31, S6A18, and TMM27. Based on the human protein tissue atlas, CAH1, RNS1G and SLC31 are highly enriched in the gastrointestinal tract. Among the 9 PRM-validated proteins, CAH1, MMP-8 and NGAL were previously reported as IBD-associated proteins (all exhibiting consistent trends with our observation), whereas the others are newly discovered by this study. Our results provide valuable clues for future study of urine biomarker of inflammatory bowel disease and Crohn’s disease.
Modeling effects of crop production, energy development and conservation-grassland loss on avian habitat
Authors: Shaffer Jill A. , Roth Cali L. , Mushet David M. 
Published: May 2018

AbstractBirds are essential components of most ecosystems and provide many services valued by society. However, many populations have undergone striking declines as habitats have been lost or degraded by human activities. Terrestrial grasslands are vital habitat for birds in the North American Prairie Pothole Region (PPR), but grassland conversion and fragmentation from agriculture and energy-production activities have destroyed or degraded millions of hectares. Conservation grasslands can provide alternate habitat. In the United States, the Conservation Reserve Program (CRP) is the largest program maintaining conservation grasslands on agricultural lands, but conservation grasslands in the PPR have declined by over 1 million ha since the program’s zenith in 2007. We used an ecosystem-services model (InVEST) parameterized for the PPR to quantify grassland-bird habitat remaining in 2014 and to assess degradation status of this remaining habitat as influenced by crop and energy (i.e., oil, natural gas, and wind) production. We compared our resultant habitat-quality ratings to grassland-bird abundance data from the North American Breeding Bird Survey to confirm that ratings were related to grassland-bird abundance. Of the grassland-bird habitat remaining in 2014, about 18% was degraded by nearby crop production, whereas energy production degraded an additional 16%. We further quantified changes in availability of grassland-bird habitat under various land-cover scenarios representing incremental losses (10%, 25%, 50%, 75%, and 100%) of CRP grasslands from 2014 levels. Our model identified 1 million ha (9%) of remaining grassland-bird habitat in the PPR that would be lost or degraded if all CRP conservation grasslands were returned to crop production. In addition to direct losses, an economic climate favoring energy and commodity production over conservation has resulted in substantial degradation of remaining grassland-bird habitat across the PPR. Other grassland regions of the world face similar challenges in maintaining avian habitat.
Reinterpretation of the localization of the ATP binding cassette transporter ABCG1 in insulin-secreting cells and insights regarding its trafficking and function
Authors: Harris Megan T. , Hussain Syed Saad , Inouye Candice M. , Castle Anna M. , Castle J. David 
Published: May 2018

AbstractThe ABC transporter ABCG1 regulates intracellular cholesterol. We showed previously that ABCG1 deficiency inhibits insulin secretion by pancreatic beta cells and, based on its immunolocalization to insulin granules, proposed its essential role in forming cholesterol-enriched granule membranes. While we confirm elsewhere that ABCG1, alongside ABCA1 and oxysterol binding protein OSBP, supports insulin granule formation, the aim here is to update our localization and to provide added insight regarding ABCG1’s trafficking and sites of function. We show that stably expressed GFP-tagged ABCG1 closely mimics the distribution of endogenous ABCG1 in pancreatic INS1 cells and accumulates in the trans-Golgi network (TGN), endosomal recycling compartment (ERC) and on the cell surface but not on insulin granules, early or late endosomes. Notably, ABCG1 is short-lived, and proteasomal and lysosomal inhibitors both decrease its degradation. Following blockade of protein synthesis, GFP-ABCG1 first disappears from the ER and TGN and later from the ERC and plasma membrane. Beyond aiding granule formation, our findings raise the prospect that ABCG1 may act beyond the TGN to regulate activities involving the endocytic pathway, especially as the amount of transferrin receptor is increased in ABCGI-deficient cells. Thus, ABCG1 may function at multiple intracellular sites and the plasma membrane as a roving sensor and modulator of cholesterol distribution and membrane trafficking.
Developmental factors associated with decline in grip strength from midlife to old age: a British birth cohort study
Authors: Kuh D , Hardy R , Blodgett JM , Copper R 
Published: May 2018

AbstractMaintenance of muscle strength is important for healthy ageing, protecting against chronic disease and enabling independent living. We tested whether developmental factors were associated with grip strength trajectories between 53 and 69 years, and operated independently or on the same pathway/s as adult factors, in 3058 participants from a British birth cohort. Grip strength (kg) at ages 53, 60-64 and 69, was analysed using multilevel models, testing for age and sex interactions, to estimate associations with developmental factors (birthweight, growth parameters, motor and cognitive development) and childhood socioeconomic position (SEP) and investigate potential adult mediators. Heavier birthweight, beginning to walk on time, later puberty and greater weight 0-26 years in men, and earlier age at first standing in women, were associated with stronger grip but not with its decline; these associations were independent of adult factors. The slower decline in grip strength (by 0.068kg/year, 95% confidence interval (CI) 0.024,0.11 per 1SD, p=.003) in men with higher childhood cognition was attenuated by adult verbal memory which became increasingly positively associated with grip strength at older ages. Thus grip strength may increasingly reflect neural ageing processes. Targeting developmental factors to promote muscle development should increase the chance of independence in old age.
Model-driven design and evolution of non-trivial synthetic syntrophic pairs
Authors: Lloyd Colton J. , King Zachary A. , Sandberg Troy E. , Hefner Ying , Olson Connor A. , Phaneuf Patrick V. , O’brien Edward J. , Feist Adam M. 
Published: May 2018

AbstractSynthetic microbial communities are attractive for applied biotechnology and healthcare applications through their ability to efficiently partition complex metabolic functions. By pairing auxotrophic mutants in co-culture, nascentE. colicommunities can be established where strain pairs are metabolically coupled. Intuitive synthetic communities have been demonstrated, but the full space of cross-feeding metabolites has yet to be explored. A novel algorithm, OptAux, was constructed to design 66 multi-knockoutE. coliauxotrophic strains that require significant metabolite cross-feeding when paired in co-culture. Three OptAux predicted auxotrophic strains were co-cultured with an L-histidine auxotroph and validated via adaptive laboratory evolution (ALE). Time-course sequencing revealed the genetic changes employed by each strain to achieve higher community fitness and provided insights on mechanisms for sharing and adapting to the syntrophic niche. A community model of metabolism and gene expression was utilized to predict the relative community composition and fundamental characteristics of the evolved communities. This work presents a novel computational method to elucidate metabolic changes that empower community formation and thus guide the optimization of co-cultures for a desired application.