bluuebunny/crossref_metadata_2025 huggingface dataset:
Haploidentical Hematopoietic Stem Cell Transplant Complicated by Atypical Hemolytic Uremic Syndrome and Kidney Transplant From the Same Donor With No Immunosuppression but C5 Inhibition
Authors: Ardissino Gianluigi , Cresseri Donata , Giglio Fabio , Onida Francesco , Iannuzzella Francesco , Tel Francesca , Giussani Antenore , Messa Piergiorgio , Longhi Selena , Vincenti Daniele , Tedeschi Silvana , Cugno Massimo , Ciceri Fabio
Published: October 2018

Background

Atypical hemolytic uremic syndrome (aHUS) is life-threatening condition particularly when complicating allograft hematopoietic stem cell transplant (HSCT). In the past, the outcome was very poor with the majority of patients reaching end-stage renal disease or dying with little or no chances of kidney transplant (KTx) due to the high risk of relapse. The availability of C5 inhibition has opened up significant therapeutic opportunities and has improved the outcome particularly if complement dysregulation (CD) is the underlying pathogenetic mechanism.

Methods

We describe a peculiar case of a girl with aHUS complicating HSCT and her subsequent successful KTx received from the same donor thus performed without immunosuppression but anti-C5 inhibition.

Results

Soon after HSCT performed for acute lymphoblastic leukemia, the patient developed a TMA due to CD and reached end-stage renal disease. After 2 years on dialysis, the patient received a KTx from her father who was already the HSCT donor. Given the full chimerism, no immunosuppressive agent was prescribed except a short (2 days) course of steroids and eculizumab to prevent aHUS relapse. Nine months after the KTx, the patient is well with normal renal function, no immunosuppression and continues eculizumab prevention of aHUS (1 infusion every 21 days).

Conclusions

All patients with transplant-associated thrombotic microangiopathy should be screened for the causes of CD. C5 inhibition with eculizumab is an important therapeutic resource to manage this complication. When KTx is necessary, immunosuppression can be safely withhold in case of same donor for both grafts and documented full chimerism.
Retransplantation Outcomes at a Large Lung Transplantation Program
Authors: Ren Dewei , Kaleekal Thomas S. , Graviss Edward A. , Nguyen Duc T. , Sinha Neeraj , Goodarzi Amad , Agboli Isioma , Suarez Erik E. , Loebe Matthias , Scheinin Scott A. , Bruckner Brian A.
Published: October 2018

Background

With the increase of primary lung transplantation across major centers worldwide, over the last several years the need of lung retransplant (ReTX) is likely to increase. Therefore, characterization of ReTX patients is prudent and necessary. Our study aimed to investigate and characterize the covariates and outcomes associated with lung ReTX survival in a single large U.S. transplant center.

Methods

Demographic, clinical diagnoses, and comorbidities were analyzed. Kaplan-Meier statistics were used to calculate and predict survival for 30 days and up to 3 years. Cox proportional modeling was used to determine the variables associated with mortality.

Results

Of included 684 lung transplants performed at the Houston Methodist Hospital between January 2009 and December 2015, 49 were lung ReTX. Median age of primary lung transplant (non-ReTX) and ReTx recipients was 62 and 49 years, respectively. Chronic graft rejection in the form of restrictive chronic lung allograft dysfunction and bronchiolitis obliterans syndrome was the main indications for ReTX. Compared with non-ReTX patients, ReTX patients had higher median lung allocation score (46.2 vs 37.0, respectively) and higher mortality after 6 months posttransplant. ReTX, older age, female sex, hospitalization 15 days or longer, estimated glomerular filtration rate less than 60, 6-minute walk distance less than 400 ft, and donor/recipient height ratio less than 1 were significantly associated with decreased 1-year patient and graft survival. Chronic graft rejection was still the major cause of death in the long-term follow-up recipients.

Conclusions

Our findings suggested that lung ReTX recipients have poor long-term survival outcomes. Lung ReTX should only be offered to carefully selected patients.
History and Future Directions of Vision Testing in Head Trauma
Authors: Akhand Omar , Rizzo John-Ross , Rucker Janet C. , Hasanaj Lisena , Galetta Steven L. , Balcer Laura J.
Published: October 2018

Background:

Concussion leads to neurophysiologic changes that may result in visual symptoms and changes in ocular motor function. Vision-based testing is used increasingly to improve detection and assess head injury. This review will focus on the historical aspects and emerging data for vision tests, emphasizing rapid automatized naming (RAN) tasks and objective recording techniques, including video-oculography (VOG), as applied to the evaluation of mild traumatic brain injury.

Methods:

Searches on PubMed were performed using combinations of the following key words: “concussion,” “mild traumatic brain injury,” “rapid automatized naming,” “King-Devick,” “mobile universal lexicon evaluation system,” “video-oculography,” and “eye-tracking.” Additional information was referenced from web sites of vendors of commercial eye-tracking systems and services.

Results:

Tests of rapid number, picture, or symbol naming, termed RAN tasks, have been used in neuropsychological studies since the early 20th century. The visual system contains widely distributed networks that are readily assessed by a variety of functionally distinct RAN tasks. The King-Devick test, a rapid number naming assessment, and several picture-naming tests, such as the Mobile Universal Lexicon Evaluation System (MULES) and the modified Snodgrass and Vanderwart image set, show capacity to identify athletes with concussion. VOG has gained widespread use in eye- and gaze-tracking studies of head trauma from which objective data have shown increased saccadic latencies, saccadic dysmetria, errors in predictive target tracking, and changes in vergence in concussed subjects. Performance impairments on RAN tasks and on tasks recorded with VOG are likely related to ocular motor dysfunction and to changes in cognition, specifically to attention, memory, and executive functioning. As research studies on ocular motor function after concussion have expanded, so too have commercialized eye-tracking systems and assessments. However, these commercial services are still investigational and all vision-based markers of concussion require further validation.

Conclusions:

RAN tasks and VOG assessments provide objective measures of ocular motor function. Changes in ocular motor performance after concussion reflect generalized neurophysiologic changes affecting a variety of cognitive processes. Although these tests are increasingly used in head injury assessments, further study is needed to validate them as adjunctive diagnostic aids and assessments of recovery.
The evolution of class-dependent reproductive effort in humans and other animals
Authors: Rodrigues António M. M.
Published: October 2018

Reproductive effort is a major life history trait that largely determines an organism’s reproductive and survival schedule, and therefore it has a significant impact on lifetime fitness. A wealth of theoretical models have identified a wide range of factors that provide adaptive explanations for reproductive effort, including senescence, differential adult and offspring survival, and inter-generational competition. This work, however, is inadequate for explaining the levels of variation in reproductive effort found in stratified societies characterised by complex social dynamics. Rank and class-based societies are widespread in the natural world and common in social species, from insects and birds to humans and other mammals. In this article, I investigate how class and intra-generational social mobility influence the allocation of resources between fecundity and somatic tissue. I find that social mobility causes lower-class mothers to preferentially invest in survival, but only if class is associated with additional reproductive resources. If, by contrast, class is associated with extra survival resources, then upper-class mothers are always favoured to invest more in somatic maintenance, whilst lower-class mothers are always favoured to invest less in somatic maintenance, irrespective of social mobility. Moreover, I find that class-dependent reproductive effort leads to the emergence of distinct class-specific life-history syndromes, with each syndrome being associated with a suite of contrasting life-history traits. Finally, I find that these life-history syndromes are in close agreement with those observed in a human contemporary population. These findings lend support to the idea that evolutionary models can bridge the gap between the animal-human divide, and therefore be a valuable tool for public health decision-making and other human affairs.
A Cyclin A – Myb-MuvB – Aurora B network regulates the choice between mitotic cycles and polyploid endoreplication cycles
Authors: Rotelli Michael D. , Policastro Robert A. , Bolling Anna M. , Killion Andrew W. , Weinberg Abraham J. , Dixon Michael J. , Zentner Gabriel E. , Walczak Claire E. , Lilly Mary A. , Calvi Brian R.
Published: October 2018

Cells switch to polyploid endoreplication cycles during development, wound healing, and cancer. We used integrated approaches inDrosophilato determine how mitotic cycles are remodeled into endoreplication cycles, and how similar this remodeling is between developmental and induced endoreplicating cells (devECs and iECs). We found that while only devECs had a dampened E2F1 transcriptome, repression of a Cyclin A - Myb-MuvB - Aurora B mitotic network promoted endoreplication in both devECs and iECs. Cyclin A associated with and activated Myb-MuvB to induce transcription of mitotic genes, with expression of one, Aurora B, being key for mitotic commitment. Knockdown of Cyclin A, Myb, Aurora B, or downstream cytokinetic proteins induced distinct types of endoreplication, suggesting that repression of different mitotic network steps may explain the known diversity of polyploid cycles. These findings reveal how remodeling of a mitotic network promotes polyploid cycles that contribute to development, wound healing, and cancer.
Satb1integrates DNA sequence,shape, motif densityand torsional stressto differentially bind targets in nucleosome-dense regions
Authors: Ghosh Rajarshi P. , Shi Quanming , Yang Linfeng , Reddick Michael P. , Nikitina Tatiana , Zhurkin Victor B. , Fordyce Polly , Stasevich Timothy J. , Chang Howard Y. , Greenleaf William J. , Liphardt Jan T.
Published: October 2018

Satb1 is a genome organizer that regulates multiple cellular and developmental processes. It is not yet clear how Satb1 selects different sets of targets throughout the genome. We used live-cell single molecule imaging and deep sequencing to assess determinants of Satb1 binding-site selectivity. We found that Satb1 preferentially targets nucleosome-dense regions and can directly bind consensus motifs within nucleosomes. Some genomic regions harbor multiple regularly spaced Satb1 binding motifs (typical separation ∼1 turn of the DNA helix), characterized by highly cooperative binding. The Satb1 homeodomain is dispensable for high-affinity binding but is essential for specificity. Finally, Satb1⇔DNA interactions are mechanosensitive: increasing negative torsional stress in DNA enhances Satb1 binding and Satb1 stabilizes base unpairing regions (BURs) against melting by molecular machines. The ability of Satb1 to control diverse biological programs may reflect its ability to combinatorially use multiple site selection criteria.
Evaluation of FlowVR: a virtual reality game for improvement of depressive mood
Authors: Bittner Lukas , Mostajeran Fariba , Steinicke Frank , Gallinat Jürgen , Kühn Simone
Published: October 2018

Objective

This study evaluated the efficacy of FlowVR, a virtual reality (VR) game designed to improve mood and reduce feelings of depression. The aim is to contribute to the question of whether and how VR could be used for depression therapy, as research in this area is quite rare.

Method

18 healthy participants (9 female; Mage = 25.9) underwent three conditions, playing FlowVR in VR with a head-mounted display, playing FlowVR on a tablet or reading a text on a tablet. For each condition, they were tested on a separate day at the same time of day within a two-week period. Before and after every condition participants completed the Becks Depression Inventory II (BDI-II), the state part of the State-Trait-Anxiety-Depression-Inventory (STADI(S)) and the Positive Affect Negative Affect Schedule-Expanded Form (PANAS-X).

Results

While the participants showed only a reduction in acute anxiety in the control and the tablet conditions, they showed improved affectivity in all variables measured in the VR condition. In addition, VR had significantly better results than the control condition in improving positive affectivity, negative affectivity and acute feelings of depression. Using a less conservative statistical approach, these significant differences could also be found between the tablet and the VR condition. There were no significant differences between the tablet and the control condition.

Conclusion

The results indicate that due to its immersive nature, VR can be used effectively to improve mood and temporarily reduce feelings of depression. Long-term effects of FlowVR on participants with depression must be investigated in consecutive research.
SpliceVisuL: Visualization of Bidirectional Long Short-term Memory Networks for Splice Junction Prediction
Authors: Dutta Aparajita , Dalmia Aman , Athul R , Singh Kusum Kumari , Anand Ashish
Published: October 2018

Neural models have been able to obtain state-of-the-art performances on several genome sequence-based prediction tasks. Such models take only nucleotide sequences as input and learn relevant features on its own. However, extracting the interpretable motifs from the model remains a challenge. This work explores various existing visualization techniques in their ability to infer relevant sequence information learned by a recurrent neural network (RNN) on the task of splice junction identification. The visualization techniques have been modulated to suit the genome sequences as input. The visualizations inspect genomic regions at the level of a single nucleotide as well as a span of consecutive nucleotides. This inspection is performed based on modification of input sequences (perturbation-based) or the embedding space (back-propagation based). We infer features pertaining to both canonical and non-canonical splicing from a single neural model. Results indicate that the visualization techniques produce comparable performance for branchpoint detection. However, in case of canonical donor and acceptor junction motifs, perturbation based visualizations perform better than back-propagation based visualizations and vice-versa for non-canonical motifs.
Pinnularia baeticasp. nov. (Bacillarophyceae): a new diatom species found in an alkaline mountain lagoon in the south of Europe (Granada, Spain)
Authors: Fernádez-Moreno David , Luís Ana T. , Sánchezcastillo Pedro M.
Published: October 2018

A new benthic freshwater diatom species belonging to the genusPinnulariawas found in Laguna Seca of Sierra Seca in the north of the province of Granada, Spain.Pinnularia baeticasp.nov. is proposed as a new species based on observations under light (LM) and scanning electron microscopy (SEM) and its special ecology typical of a calcareous lagoon. The most similar taxa toP. baeticaisP. atlasiiand with more differencesP. infirmaand the last two were studied through material obtained in lagoons of northern Morocco. Although there are similarities in the morphological characters of the frustule, it was possible to verify through LM and SEM micrographs, evident differences between P. baetica and the other two taxa; on the one end,P. baeticahas a panduriform shape more pronounced thanP. infirmaand bigger size. On the other hand, the absence of spines inP. baeticaand the more convergent striation at the poles are the main differences with P. atlasi.

Phylum Ochrophyta Caval.-Sm. (Cavalier-Smith 1995)

Class Bacillariophyceae Haeckel emend. Medlin & Kaczmarska (Medlin & Kaczmarska 2004)

SubclassBacillariophycidaeRound (Round et al. 1990)

OrderNaviculales(Bessey 1907 sensu emend)

Family Pinnulariaceae D.G. Mann, 1990, GenusPinnulariaC.G. Ehrenberg, 1843

Pinnularia baeticaFernández Moreno & Sánchez Castillo sp. nov
Bayesian inference of neuronal ensembles
Authors: Diana Giovanni , Sainsbury Thomas T. J. , Meyer Martin P.
Published: October 2018

In many areas of the brain, both spontaneous and stimulus-evoked activity can manifest as synchronous activation of neuronal ensembles. The characterization of ensemble structure and dynamics provides important insights into how brain computations are distributed across neural networks. The proliferation of experimental techniques for recording the activity of neuronal ensembles calls for a comprehensive statistical method to describe, analyze and characterize these high dimensional datasets. Here we introduce a generative model of synchronous activity to describe spontaneously active neural ensembles. Unlike existing methods, our analysis provides a simultaneous estimation of ensemble composition, dynamics and statistical features of these neural populations, including ensemble noise and activity rate. We also introduce ensemble “coherence” as a measure of within-ensemble synchrony. We have used our method to characterize population activity throughout the tectum of larval zebrafish, allowing us to make statistical inference on the spatiotemporal organization of tectal ensembles, their composition and the logic of their interactions. We have also applied our method to functional imaging and neuropixels recordings from the mouse, allowing us to relate the activity of identified ensembles to specific behaviours such as running or changes in pupil diameter.
Altered protein quality control contributes to noise-induced hearing loss
Authors: Jongkamonwiwat Nopporn , Wong Ann C. Y. , Ramirez Miguel A , Pak Kwang , Wang Yi-Zhi , Ryan Allen F. , Savas Jeffrey N.
Published: October 2018

Exposure to damaging levels of noise is the most common cause of hearing loss and impairs high frequency hearing in more than 15 % of adult Americans. Using mice exposed to increasing levels of noise in combination with quantitative proteomics, we tested how noise insults remodel the cochlear proteome both acutely and after a two-week recovery period. We used ABR & DPOAE recordings to define the intensity of noise exposure necessary to produce temporary or permanent threshold shifts (TTS, PTS) in young adult mice and found noise at 94 and 105 dB SPL levels for 30 minutes elicits TTS and PTS, respectively. We quantified thousands of proteins and found that noise insults cause a rapid increase rather than a decrease in the levels of many proteins involved with protein homeostasis, myelin, cytoskeletal structures, and cell junctions such as the synapse. The vast majority of proteins with increased levels immediately after noise exposure showed normal levels after two weeks of recovery. However, several proteins involved in oxidative stress and neuroprotection had significantly increased levels only after the recovery period suggesting they play in important role in regeneration. Interestingly, a small panel of mitochondrial proteins were significantly altered only in PTS conditions suggesting potential discrete protein mechanisms. Our discovery-based proteomic analysis extends the recent description of noise-induced cochlear synaptopathy and shows that noise insults drive a robust proteostasis response. These data provide a new understanding of noise sensitive proteins and may inform the development of effective preventiative strategies or therapies for NIHL.
PROCYCLIC Trypanosoma brucei CELL CYCLE is IMPAIRED at the G1 STAGE by the PRESENCE of POLY (ADP-RIBOSE) in the NUCLEUS
Authors: Schlesinger Mariana , Vilchez Larrea Salomé C. , Fernández Villamil Silvia H.
Published: October 2018

Previously we demonstrated that an excess of poly (ADP-ribose) in the nucleus makes procyclic parasites more sensitive to hydrogen peroxide. However, the effect of an altered-PAR metabolism under standard conditions has not been addressed yet. Here we have analyzed the behavior of the growth curve of transgenic parasites that present this phenotype and studied cell cycle progression in synchronized cultures by flow cytometry and immunofluorescence. We have demonstrated that an excess of nuclear poly (ADP-ribose) produces a delay in the G1 phase of the cell cycle. Moreover, for the first time we have shown that poly (ADP-ribose) occurs at specific points very close to the mature basal body, suggesting there could be a link between the kinetoplast and poly (ADP-ribose) metabolism.
Robust estimation of sulcal morphology
Authors: Madan Christopher R.
Published: October 2018

While it is well established that cortical morphology differs in relation to a variety of inter-individual factors, it is often characterized using estimates of volume, thickness, surface area, or gyrification. Here we developed a computational approach for estimating sulcal width and depth that relies on cortical surface reconstructions output by FreeSurfer. While other approaches for estimating sulcal morphology exist, studies often require the use of multiple brain morphology programs that have been shown to differ in their approaches to localize sulcal landmarks, yielding morphological estimates based on inconsistent boundaries. To demonstrate the approach, sulcal morphology was estimated in three large sample of adults across the lifespan, in relation to aging. A fourth sample is additionally used to estimate test-retest reliability of the approach. This toolbox is now made freely available as supplemental to this paper: https://cmadan.github.io/calcSulc/.
Characterizing noncompliance in conservation: a multidimensional Randomized Response Technique for multinomial responses
Authors: Cerri Jacopo , Scuffi Lapo , Nocita Annamaria , Zaccaroni Marco , Lenuzza Andrea , Cruyff Maarten
Published: October 2018

Rule violation is critical for biological conservation worldwide. Conventional questionnaires are not suitable to survey these violations and specialized questioning techniques that preserve respondents’ privacy, like the forced-response RRT, have been increasingly adopted by conservationists. However, most of these approaches do not measure multinomial answers and conservationists need a specialized questioning technique for real-world settings where non-compliance could occur in different forms. We developed a multidimensional, statistically-efficient, RRT which is suitable for multinomial answers (mRRT) and which allows researchers to test for respondents’ noncompliance during completion. Then, we applied it to measure the frequency of the various forms of illegal restocking of European catfish from specialized anglers in Italy, developing an operational code for the statistical software R. A total of 75 questionnaires were administered at a large fishing fair in Northern Italy, in winter 2018. Our questionnaires were easily compiled and the multinomial model revealed that around 6% of respondents had moved catfish across public freshwater bodies and private ponds. Future studies should better address their characteristics, and the mRRT could allow for modeling the effect of co-variates over restocking behavior. The multinomial mRRT could be adopted to measure many forms of rule violation in conservation that could take different forms, like various forms of fish restocking or different modes of wildlife persecution.
Genetic distance and social compatibility in the aggregation behavior of Japanese toad tadpoles
Authors: Hase Kazuko , Abe Masato S. , Shimada Masakazu
Published: October 2018

From microorganism to vertebrates, living things often exhibit social aggregation. One of anuran larvae, dark-bodied toad tadpoles (genus Bufo) are known to aggregate against predators. When individuals share genes from a common ancestor for whom social aggregation was a functional trait, they are also likely to share common recognition cues regarding association preferences, while greater genetic distances make cohesive aggregation difficult. In this study, we conducted quantitative analyses to examine aggregation behavior among three lineages of toad tadpoles: Bufo japonicus japonicus, B. japonicus formosus, and B. gargarizans miyakonis. To determine whether there is a correlation between cohesiveness and genetic similarity among group members, we conducted an aggregation test using 42 cohorts consisting of combinations drawn from a laboratory-reared set belonging to distinct clutches. As genetic indices, we used mitochondrial DNA (mtDNA) and major histocompatibility complex (MHC) class II alleles. The results clearly indicated that aggregation behavior in toad tadpoles is directly influenced by genetic distances based on mtDNA sequences and not on MHC haplotypes. Cohesiveness among heterogeneous tadpoles is negatively correlated with the geographic dispersal of groups. Our findings suggest that social incompatibility among toad tadpoles reflects phylogenetic relationships.
Integrity and stability of virulence plasmids fromPseudomonas syringaeare modulated by mobile genetic elements and multiple toxin-antitoxin systems
Authors: Bardaji Leire , Añorga Maite , Echeverría Myriam , Ramos Cayo , Murillo Jesús
Published: October 2018

Background

Virulence plasmids are critically exposed to genetic decay and loss, particularly inPseudomonas syringaestrains because of their high content of mobile genetic elements and their exploitation of environmental niches outside of the plant host. The demonstrated high plasticity and adaptability of P. syringae plasmids, involving the acquisition and loss of large DNA regions, contrasts with their usual high stability and the maintenance of key virulence genes in free living conditions. The identification of plasmid stability determinants and mechanisms will help to understand their evolution and adaptability to agroecosystems as well as to develop more efficient control measures.

Results

We show that the three virulence plasmids ofP. syringaepv. savastanoi NCPPB 3335 contain diverse functional stability determinants, including three toxin-antitoxin systems (TA) in both pPsv48A and pPsv48C, whereas one of the two replicons of pPsv48C can confer stable inheritance by itself. Loss of pPsv48A increased by two orders of magnitude upon functional inactivation of its TA systems. However, inactivation of the TA systems from pPsv48C did not result in its curing but led to the recovery of diverse deletion derivatives. One type consisted in the deletion of an 8.3 kb fragment, with a frequency of 3.8 ± 0.3 × 10−3, by recombination between two copies of MITEPsy2. Likewise, IS801promoted the occurrence of deletions of variable size by one-ended transposition with a frequency of 5.5 ± 2.1 × 10−4, 80 % of which resulted in the loss of virulence geneidi. These deletion derivatives were stably maintained in the population by replication mediated byrepJ, which is adjacent to IS801. IS801also promoted deletions in plasmid pPsv48A, either by recombination or one-ended transposition. In all cases, functional TA systems contributed significantly to reduce the occurrence of plasmid deletionsin vivo.

Conclusions

Virulence plasmids fromP. syringaeharbour a diverse array of stability determinants with a variable contribution to plasmid persistence. Additionally, multiple TA systems favour the long-term survival and integrity of virulence plasmids, as well as the maintenance of pathogenicity genes in free-living conditions. This strategy is likely widespread amongst native plasmids ofP. syringaeand other bacteria.
Unravelling intra- and intersegmental neuronal connectivity between central pattern generating networks in a multi-legged locomotor system
Authors: Daun Silvia , Mantziaris Charalampos , Tóth Tibor I. , Büschges Ansgar , Rosjat Nils
Published: October 2018

Animal walking results from a complex interplay of central pattern generating networks (CPGs), local sensory signals expressing position, velocity and forces generated in the legs, and coordinating signals between neighboring ones. In the stick insect, in particular, intra- and intersegmental coordination is conveyed by these sensory signals. The rhythmic activity of the CPGs, hence of the legs, can be modified by the aforementioned sensory signals. However, the precise nature of the interaction between the CPGs and these sensory signals has remained largely unknown. Experimental methods aiming at finding out details of these interactions, often apply the muscarinic acetylcholine receptor agonist, pilocarpine in order to induce rhythmic activity in the CPGs, hence in the motoneurons of the segmental ganglia. Using this general approach, we removed the influence of sensory signals and investigated the putative connections between CPGs associated with the coxa-trochanter (CTr)-joint in the different segments (legs) in more detail. The experimental data underwent phase-difference analysis and Dynamic Causal Modelling (DCM). These methods can uncover the underlying coupling structure and strength between pairs of segmental ganglia (CPGs). We set up different coupling schemes (models) for DCM and compared them using Bayesian Model Selection (BMS). Models with contralateral connections in each segment and ipsilateral connections on both sides, as well as the coupling from the meta- to the ipsilateral prothoracic ganglion were preferred by BMS to all other types of models tested. Moreover, the intrasegmental coupling strength in the mesothoracic ganglion was the strongest and most stable in all three ganglia.
Testosterone modulates status-specific patterns of cooperation in a social network
Authors: Ryder T. Brandt , Dakin Roslyn , Vernasco Ben J. , Evans Brian S. , Horton Brent M. , Moore Ignacio T.
Published: October 2018

Stable cooperation requires plasticity whereby individuals are able to express competitive or cooperative behaviors depending on social context. To date, however, the physiological mechanisms that underlie behavioral variation in cooperative systems are poorly understood. We studied hormone-mediated behavior in the wire-tailed manakin (Pipra filicauda), a gregarious songbird whose cooperative partnerships are crucial for fitness. We used automated telemetry to monitor > 36,000 cooperative interactions among male manakins over three field seasons, and we examined how circulating testosterone affects cooperation using > 500 hormone samples. Observational data show that in non-territorial floater males, high testosterone is associated with increased cooperative behaviors and subsequent ascension to territorial status. In territory-holding males, however, both observational and experimental evidence demonstrate that high testosterone antagonizes cooperation. Moreover, circulating testosterone explains significant variation (2-8%) in social behavior within each status class. Collectively, our findings show that the hormonal control of cooperation depends on a male’s social status. We propose that the status-dependent reorganization of hormone-regulatory pathways can facilitate stable cooperative partnerships, and thus provide direct fitness benefits for males.
N-terminal β-strand underpins biochemical specialization of an ATG8 isoform
Authors: Zess Erin K. , Jensen Cassandra , Cruz-Mireles Neftaly , De la Concepcion Juan Carlos , Sklenar Jan , Imre Richard , Roitinger Elisabeth , Hughes Richard , Belhaj Khaoula , Mechtler Karl , Menke Frank L.H. , Bozkurt Tolga , Banfield Mark J. , Kamoun Sophien , Maqbool Abbas , Dagdas Yasin F.
Published: October 2018

ATG8 is a highly-conserved ubiquitin-like protein that modulates autophagy pathways by binding autophagic membranes and numerous proteins, including cargo receptors and core autophagy components. Throughout plant evolution, ATG8 has expanded from a single protein in algae to multiple isoforms in higher plants. However, the degree to which ATG8 isoforms have functionally specialized to bind distinct proteins remains unclear. Here, we describe a comprehensive protein-protein interaction resource, obtained using in planta immunoprecipitation followed by mass spectrometry, to define the potato ATG8 interactome. We discovered that ATG8 isoforms bind distinct sets of plant proteins with varying degrees of overlap. This prompted us to define the biochemical basis of ATG8 specialization by comparing two potato ATG8 isoforms using both in vivo protein interaction assays and in vitro quantitative binding affinity analyses. These experiments revealed that the N-terminal β-strand—and, in particular, a single amino acid polymorphism—underpins binding specificity to the substrate PexRD54 by shaping the hydrophobic pocket that accommodates this protein’s ATG8 interacting motif. Additional proteomics experiments indicated that the N-terminal β-strand shapes the ATG8 interactor profiles, defining interaction specificity with about 80 plant proteins. Our findings are consistent with the view that ATG8 isoforms comprise a layer of specificity in the regulation of selective autophagy pathways in plants.
The RED scheme: Rate-constant estimation from pre-steady state weighted ensemble simulations
Authors: DeGrave Alex J. , Bogetti Anthony T. , Chong Lillian T.
Published: October 2018

We present the Rate from Event Durations (RED) scheme, a new scheme that more efficiently calculates rate constants using the weighted ensemble path sampling strategy. This scheme enables rate-constant estimation from shorter trajectories by incorporating the probability distribution of event durations, or barrier crossing times, from a simulation. We have applied the RED scheme to weighted ensemble simulations of a variety of rare-event processes that range in complexity: residue-level simulations of protein conformational switching, atomistic simulations of Na+/Cl− association in explicit solvent, and atomistic simulations of protein-protein association in explicit solvent. Rate constants were estimated with up to 50% greater efficiency than the original weighted ensemble scheme. Importantly, our method accounts for systematic error when using data from the entire simulation. The RED scheme is relevant to any simulation strategy that involves unbiased trajectories of similar length to the most probable event duration, including weighted ensemble, milestoning, and standard simulations as well as the construction of Markov state models.
eIF3b and eIF3i relocate together to the ribosomal subunit interface during translation initiation and modulate start codon selection
Authors: Llácer Jose L. , Hussain Tanweer , Dong Jinsheng , Gordiyenko Yuliya , Hinnebusch Alan G.
Published: October 2018

During eukaryotic translational initiation, the 48S ribosomal pre-initiation complex (PIC) scans the 5’ untranslated region of mRNA until it encounters a start codon. We present a single particle electron cryomicroscopy (cryo-EM) reconstruction of a yeast 48S PIC in an open scanning-competent state in which eIF3b is observed bound on the 40S subunit interface. eIF3b is re-located with eIF3i from their solvent-interface locations observed in other PIC structures; however, eIF3i is not in contact with the 40S. Re-processing of micrographs of our previous 48S PIC in a closed state using currently available tools reveal a similar re-location of eIF3b and eIF3i from the solvent to subunit interface. Genetic analysis indicates that high fidelity initiation in vivo depends strongly on eIF3b interactions at the subunit interface that either promote the closed conformation of the PIC on start codon selection or facilitate subsequent relocation back to the solvent side of the 40S subunit.
Patterned expression of Pannexin 1 channels in the adult cerebellar Purkinje cells
Authors: Ady Visou , Dubayle David , Blanc Pascale Le , Shestopalov Valery , Meunier Claude , Levenes Carole
Published: October 2018

Pannexin1 (PanX1) are recently discovered proteins that can form large pore channels at the cell surface. They have been implicated in ATP-dependent cell-to-cell communication and in several pathophysiological processes such as inflammation, cell death and epilepsy. Using immunohistochemistry in the adult mouse, we describe the presence of PanX1 in the deep cerebellar nuclei, in large cells of the granular layer, presumably Golgi interneurones, in some Bergmann glia radial processes as well as in the soma and dendrites of Purkinje cells. In the latter, PanX1, like many other proteins, distribute heterogeneously. Only Zebrin II-positive Purkinje cells express PanX1, in accordance with the so-called “zebra-striped” modular architecture of the cerebellum. This distribution in zebra-stripes suggest that PanX1 may contribute to the control of ensemble activity within cerebellar microdomains or to the response of Purkinje cell to excitotoxicity and cell-death messages.
Cyclic, condition-independent activity in primary motor cortex predicts corrective movement behavior
Authors: Rouse Adam G. , Schieber Marc H. , Sarma Sridevi V.
Published: October 2018

Reaching movements are known to have large condition-independent neural activity and cyclic neural dynamics. A new precision center-out task was performed by rhesus macaques to test the hypothesis that cyclic, condition-independent neural activity in the primary motor cortex (M1) occurs not only during initial reaching movements but also during subsequent corrective movements. Corrective movements were observed to be discrete with time courses and bell-shaped speed profiles similar to the initial movements. Condition-independent cyclic neural trajectories were similar and repeated for initial and each additional corrective submovement. The phase of the cyclic condition-independent neural activity predicted the time of peak movement speed more accurately than regression of instantaneous firing rate, even when the subject made multiple corrective movements. Rather than being controlled as continuations of the initial reach, a discrete cycle of motor cortex activity encodes each corrective submovement.

Significance Statement

During a precision center-out task, initial and subsequent corrective movements occur as discrete submovements with bell-shaped speed profiles. A cycle of condition-independent activity in primary motor cortex neuron populations corresponds to each submovement, such that the phase of this cyclic activity predicts the time of peak speeds—both initial and corrective. These submovements accompanied by cyclic neural activity offer important clues into how we successfully execute precise, corrective reaching movements and may have implications for optimizing control of brain-computer interfaces.
Visual cue-related activity of cells in the medial entorhinal cortex during navigation in virtual reality
Authors: Kinkhabwala Amina A. , Gu Yi , Aronov Dmitriy , Tank David W.
Published: October 2018

During spatial navigation, animals use self-motion to estimate positions through path integration. However, estimation errors accumulate over time and it is unclear how they are corrected. Here we report a new cell class (“cue cell”) in mouse medial entorhinal cortex (MEC) that encoded visual cue information that could be used to correct errors in path integration. Cue cells accounted for a large fraction of unidentified MEC cells. They exhibited firing fields only near visual cues during virtual navigation and spatially stable activity during navigation in a real arena. Cue cells’ responses occurred in sequences repeated at each cue and were likely driven by visual inputs. In layers 2/3 of the MEC, cue cells formed clusters. Anatomically adjacent cue cells responded similarly to cues. These cue cell properties demonstrate that the MEC circuits contain a code representing spatial landmarks that could play a significant role in error correction during path integration.
Effective Degrees of Freedom of the Pearson’s Correlation Coefficient under Autocorrelation
Authors: Afyouni Soroosh , Smith Stephen M. , Nichols Thomas E.
Published: October 2018

The dependence between pairs of time series is commonly quantified by Pearson’s correlation. However, if the time series are themselves dependent (i.e. exhibit temporal autocorrelation), the effective degrees of freedom (EDF) are reduced, the standard error of the sample correlation coefficient is biased, and Fisher’s transformation fails to stabilise the variance. Since fMRI time series are notoriously autocorrelated, the issue of biased standard errors – before or after Fisher’s transformation – becomes vital in individual-level analysis of resting-state functional connectivity (rsFC) and must be addressed anytime a standardized Z-score is computed. We find that the severity of autocorrelation is highly dependent on spatial characteristics of brain regions, such as the size of regions of interest and the spatial location of those regions. We further show that the available EDF estimators make restrictive assumptions that are not supported by the data, resulting in biased rsFC inferences that lead to distorted topological descriptions of the connectome on the individual level. We propose a practical “xDF” method that accounts not only for distinct autocorrelation in each time series, but instantaneous and lagged cross-correlation. We find the xDF correction varies substantially over node pairs, indicating the limitations of global EDF corrections used previously. In addition to extensive synthetic and real data validations, we investigate the impact of this correction on rsFC measures in data from the Young Adult Human Connectome Project, showing that accounting for autocorrelation dramatically changes fundamental graph theoretical measures relative to no correction.
Multi-Center Study of Resectable Lung Lesions by Ultra-Deep Sequencing of Targeted Genes in Plasma Cell-Free DNA to Assess Nodule Malignancy and Detect Lung Cancers
Authors: Peng Muyun , Xie Yuancai , Li Xiaohua , Qian Youhui , Tu Xiaonian , Yao Xumei , Cheng Fangsheng , Xu Feiyue , Kong Deju , He Bing , Liu Chaoyu , Cao Fengjun , Yang Haoxian , He Jiankui , Yu Fenglei , Xu Chuanbo , Tian Geng
Published: October 2018

BACKGROUND

Early detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumor DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery.

METHODS

The multi-center clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white blood cell genomic DNA (gDNA) and tumor tissue gDNA of each patient were analyzed by ultra-deep sequencing to an average of 35,000X of the coding regions of 65 lung cancer-related genes.

RESULTS

The cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients is at Stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for Stage I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harbored mutations in the lung cancer patients with the largest number found in TP53 (30% plasma and 62% tumor tissue samples) and EGFR (20% and 40%, respectively).

CONCLUSION

Plasma ctDNA was analyzed in lung nodule assessment and early cancer detection while an algorithm combining clinical information enhanced the test performance.
Stromal fibroblast activation and inflammation in frozen shoulder
Authors: Akbar Moeed , McLean Michael , Garcia-Melchor Emma , Crowe Lindsay AN , McMillan Paul , Fazzi Umberto G , Martin David , Arthur Angus , Reilly James H , McInnes Iain B , Millar Neal L
Published: October 2018

Introduction

Frozen shoulder is a common, fibro-proliferative disease characterised by the insidious onset of pain and progressively restricted range of shoulder movement. Despite the prevalence of this disease, there is limited understanding of the molecular mechanisms underpinning the pathogenesis of this debilitating disease. Previous studies have identified increased myofibroblast differentiation and proliferation, immune cell influx and dysregulated cytokine production. We hypothesised that subpopulations within the stromal compartment may take on an activated phenotype, thus initiating the inflammatory processes observed in frozen shoulder. Therefore, we sought to evaluate the presence and possible pathogenic role of known stromal activation proteins in Frozen shoulder,

Methods

Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients undergoing shoulder stabilisation surgery. Stromal activation marker expression (CD248, CD146, VCAM and PDPN, FAP) was quantified using immunohistochemistry. Control and diseased fibroblasts were cultured for in vitro studies from capsule biopsies from instability and frozen shoulder surgeries, respectively. The inflammatory profile and effects of IL-1β upon diseased and control fibroblasts was assessed using ELISA, immunohistochemistry and qPCR.

Results

Immunohistochemistry demonstrated increased expression of stromal activation markers CD248, CD146, VCAM and PDPN in the frozen shoulder group compared with control (p < 0.05). Fibroblasts cultured from diseased capsule produced elevated levels of inflammatory protein (IL-6, IL-8 & CCL-20) in comparison to control fibroblasts. Exposing control fibroblasts to an inflammatory stimuli, (IL-1ß) significantly increased stromal activation marker transcript and protein expression (CD248, PDPN and VCAM).

Conclusions

These results show that stromal fibroblasts have an activated phenotype in frozen shoulder and this is associated with inflammatory cytokine dysregulation. Furthermore, it supports the hypothesis that activated stromal fibroblasts may be involved in regulating the inflammatory and fibrotic processes involved in this disease.
The Maudsley Environmental Risk Score for Psychosis
Authors: Vassos Evangelos , Sham Pak , Kempton Matthew , Trotta Antonella , Stilo Simona A. , Gayer-Anderson Charlotte , Forti Marta Di , Lewis Cathryn M , Murray Robin M , Morgan Craig
Published: October 2018

Risk prediction algorithms have long been used in health research and practice (e.g., in prediction of cardiovascular disease, diabetes, etc.) However, similar tools have not been developed for mental health problems, despite extensive research on risk factors. For example, for psychotic disorders, attempts to sum environmental risk are rare, usually unsystematic and dictated by available data. In light of this, we sought to develop a valid, easy to use measure of the total environmental risk for psychotic disorders, which can be used in research and clinical practice.

We first reviewed the literature to identify well-replicated and validated environmental risk factors for psychosis and, then, used the largest available meta-analyses to derive current best estimates of risk. We devised a method of scoring individuals based on the level of exposure to each risk factor, using odds ratios from the meta-analyses, to produce an Environmental Risk Score (ERS).

Six risk factors (ethnic minority status, urbanicity, high paternal age, obstetric complications, cannabis use, and childhood adversity) were used to generate the ERS. A distribution for different levels of risk based on permuted data showed that most of population would be at low/moderate risk with a small minority at increased environmental risk for psychosis.

This is the first systematic approach to develop an aggregate measure of environmental risk for psychoses. This can be used as a continuous measure of liability to disease or transformed to a relative risk. Its predictive ability will improve with the collection of additional, population specific data.