bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in Number and Composition of Sex Partners Among Men Who Have Sex With Men in the United States, National HIV Behavioral Surveillance, 2008–2014
Authors: Chapin-Bardales Johanna , Rosenberg Eli S. , Sullivan Patrick S. , Jenness Samuel M. , Paz-Bailey Gabriela ,   for the NHBS Study Group
Published: March 2019

Background:

Social and legal acceptance of long-term same-sex partnerships in the United States has increased over the past decade which may impact sexual partnering among men who have sex with men (MSM). Identifying whether and how partnering trends have evolved at a national level could improve understanding of HIV transmission and prevention among MSM partnerships.

Methods:

We used Centers for Disease Control and Prevention's National HIV Behavioral Surveillance data (2008, 2011, and 2014) to study trends in the number and partner type composition (main/casual) of male sex partners among US MSM. Changes over time were assessed in Poisson regression models with the link function tailored to the count and binary outcomes.

Results:

The mean total number of partners in the past year increased, while the mean number of main partners remained stable. The percentage of MSM with both main and casual partners increased, and we observed a shift from having ≥1 main and 0 casual partners to having ≥1 main and ≥2 casual partners. Condomless anal sex in the past year increased regardless of partner composition.

Discussion:

Findings suggest casual partnering among MSM has increased in recent years, including among those with ≥1 main partners. Both partner-based and individual prevention programs remain critical to reaching MSM.
Clinical Relevance of Posttransplant DSAs in Patients Receiving Desensitization for HLA-incompatible Kidney Transplantation
Authors: Vo Ashley A. , Aubert Olivier , Haas Mark , Huang Edmund , Zhang Xiaohai , Choi Jua , Peng Alice , Najjar Reiad , Sethi Supreet , Ammerman Nori , Lim Kathlyn , Jordan Stanley C.
Published: March 2019

Background.

Highly HLA-sensitized (HS) patients have an increased risk for the development of donor-specific antibodies (DSA) and antibody-mediated rejection (AMR) posttransplant. Here, we examined the risk for AMR in HS patients transplanted after desensitization (DES) who were DSA+ versus DSA− at transplant. We also examined the incidence and clinical impact of de novo DSAs (dnDSAs) and compared with dnDSA− patients.

Methods.

From January 2013 to October 2016, 90 HS patients (PRA > 80%, DSA+ = 50 versus DSA− = 40) received kidney transplantation after DES with IVIG + rituximab ± PLEX (plasma exchange) ± tocilizumab. DSAs were monitored at transplant and at 1, 3, 6, 12, 24, 36, and 48 months posttransplant.

Results.

Patients were divided into 4 groups: DSA+/+ (n = 31), DSA+/− (n=19), DSA−/+ (n=10), and DSA−/− (n = 30). Median follow-up time was 2.9 years. DSA-negative patients who developed dnDSA had the highest incidence of AMR (70%) compared with the DSA+/+ (45%), DSA+/− (11%), and DSA−/− (10%) patients (P < 0.0001). Among patients who developed AMR, Banff 2013 AMR scores did not differ among the 4 groups. Graft survival and estimated glomerular filtration rate determinations at 4 years were similar.

Conclusions.

Persistence of preexisting DSAs or development of dnDSA after transplant is associated with an increased risk for AMR. Despite this, we did not observe a difference in Banff biopsy scores, graft survival, or patient survival compared with those without DSAs after transplant. Thus, for HS patients undergoing HLA-incompatible kidney transplant, DES therapy and frequent monitoring for dnDSAs appears critical for good long-term survival in at-risk groups.
Should I stay or should I go? Individual movement decisions during group departures in red-fronted lemurs
Authors: Sperber Anna Lucia , Kappeler Peter M. , Fichtel Claudia
Published: March 2019

Collective movements are essential for maintaining group cohesion. However, group members can have different optimal departure times, depending on individual, social and contextual factors whose relative importance remains poorly known. We, therefore, studied collective departures in four groups of red-fronted lemurs (
Eulemur rufifrons
) in Kirindy Forest, Madagascar, to investigate the influence of an individual's age, sex, their affiliative relationships and their proximity to other group members at the time of departure on their individual departure decision. We recorded behavioural and spatial data on individual departures during 167 group movements and conducted group scans (181–279 per group) to assess affiliative relationships. All factors influenced individual departures. Both affiliation and proximity determined a mimetic joining process in which dyads with stronger affiliative bonds departed in closer succession, and individuals followed the initiator and predecessors more quickly when they were in closer proximity at departure. While the influence of affiliation is common, the effect of inter-individual distance has rarely been considered in groups with heterogeneous social relationships. Although local rules influenced joining, the overall movement pattern was mainly determined by individual traits: juveniles took protected central positions, while females made up the van and males brought up the rear. Individual needs, expressed in the departure order, to an extent overruled the effect of affiliation. These results highlight the importance of considering individual, social and contextual factors collectively in the study of collective movements.
How real are observed trends in small correlated datasets?
Authors: Salamon S. J. , Hansen H. J. , Abbott D.
Published: March 2019

The eye may perceive a significant trend in plotted time-series data, but if the model errors of nearby data points are correlated, the trend may be an illusion. We examine generalized least-squares (GLS) estimation, finding that error correlation may be underestimated in highly correlated small datasets by conventional techniques. This risks indicating a significant trend when there is none. A new correlation estimate based on the Durbin–Watson statistic is developed, leading to an improved estimate of autoregression with highly correlated data, thus reducing this risk. These techniques are generalized to randomly located data points in space, through the new concept of the nearest new neighbour path. We describe tests on the validity of the GLS schemes, allowing verification of the models employed. Examples illustrating our method include a 40-year record of atmospheric carbon dioxide, and Antarctic ice core data. While more conservative than existing techniques, our new GLS estimate finds a statistically significant increase in background carbon dioxide concentration, with an accelerating trend. We conclude with an example of a worldwide empirical climate model for radio propagation studies, to illustrate dealing with spatial correlation in unevenly distributed data points over the surface of the Earth. The method is generally applicable, not only to climate-related data, but to many other kinds of problems (e.g. biological, medical and geological data), where there are unequally (or randomly) spaced observations in temporally or spatially distributed datasets.
A ctenophore (comb jelly) employs vortex rebound dynamics and outperforms other gelatinous swimmers
Authors: Gemmell Brad J. , Colin Sean P. , Costello John H. , Sutherland Kelly R.
Published: March 2019

Gelatinous zooplankton exhibit a wide range of propulsive swimming modes. One of the most energetically efficient is the rowing behaviour exhibited by many species of schyphomedusae, which employ vortex interactions to achieve this result. Ctenophores (comb jellies) typically use a slow swimming, cilia-based mode of propulsion. However, species within the genusOcyropsishave developed an additional propulsive strategy of rowing the lobes, which are normally used for feeding, in order to rapidly escape from predators. In this study, we used high-speed digital particle image velocimetry to examine the kinematics and fluid dynamics of this rarely studied propulsive mechanism. This mechanism allowsOcyropsisto achieve size-adjusted speeds that are nearly double those of other large gelatinous swimmers. The investigation of the fluid dynamic basis of this escape mode reveals novel vortex interactions that have not previously been described for other biological propulsion systems. The arrangement of vortices during escape swimming produces a similar configuration and impact as that of the well-studied ‘vortex rebound’ phenomenon which occurs when a vortex ring approaches a solid wall. These results extend our understanding of how animals use vortex–vortex interactions and provide important insights that can inform the bioinspired engineering of propulsion systems.
On the equivalence of the two foundational formulations for atomistic flux in inhomogeneous transport processes
Authors: Diaz Adrian , Davydov Denis , Chen Youping
Published: March 2019

Although there are numerous formulae for atomic-level fluxes, they are expressed either in terms of a singlet density, resulting from Irving and Kirkwood's statistical mechanics formulation of hydrodynamical equations, or a pair density, proposed in kinetic theories of transport processes. Flux formulae using singlet density have been further developed and widely implemented in molecular dynamics (MD) simulations by either replacing the Dirac delta with a volumetric averaging function or performing a surface average of the flux operators. Pair density-based flux formulae have also been further developed by using spatial-averaging kernels; these formulae, however, have rarely been implemented or used in modern MD. In this work, distributional calculus is used to reformulate the fluxes in momentum and energy transport processes. The formulation results demonstrate that these two types of existing flux formulae are mathematically equivalent when expressed with the Dirac delta. The lasting confusion regarding these two different types of flux formulae from two different formalisms is thus resolved.
Propagation direction of the bistable travelling wavefront for delayed non-local reaction diffusion equations
Authors: Ma Manjun , Yue Jiajun , Ou Chunhua
Published: March 2019

For delayed non-local reaction–diffusion equations arising from population biology, selection mechanisms of the speed sign for the bistable travelling wavefront have not been found. In this paper, based on the theory of asymptotic speeds of spread for monotone semiflows, we firstly provide an interval of values of wave speed and a novel general condition for determining the speed sign by applying the comparison principle and the globally asymptotic stability of the bistable travelling wave. Moreover, through constructing novel upper/lower solutions, we give explicit conditions for the speed sign to be positive or negative. The obtained results are efficiently applied to three classical forms of the kernel functions.
Two fiber pathways connecting amygdala and prefrontal cortex in humans and monkeys
Authors: Folloni Davide , Sallet Jérôme , Khrapitchev Alexandre A. , Sibson Nicola R. , Verhagen Lennart , Mars Rogier B.
Published: March 2019

The interactions between amygdala and prefrontal cortex are pivotal to many neural processes involved in learning, decision-making, emotion, and social regulation. The broad functional role of amygdala-prefrontal interplay may reflect the diversity of its anatomical connections. Little, however, is known of the structural wiring linking amygdala and prefrontal cortex in humans. Using diffusion imaging techniques, we reconstructed connections between amygdala, anterior temporal and prefrontal cortex in human and macaque brains. First, by studying macaques we were able to assess which aspects of connectivity known from tracer studies could be identified with diffusion imaging. Second, by comparing diffusion imaging results in humans and macaques we were able to estimate amygdala-prefrontal connection patterns in humans and compare them with those in the monkey. We observed a prominent and well-preserved bifurcation of connections between amygdala and frontal lobe into two fiber networks – an amygdalofugal path and an uncinate fascicle path – in both species.
Epstein-Barr virus inactivates the transcriptome and disrupts the chromatin architecture of its host cell in the first phase of lytic reactivation
Authors: Buschle Alexander , Mrozek-Gorska Paulina , Krebs Stefan , Blum Helmut , Cernilogar Filippo M. , Schotta Gunnar , Pich Dagmar , Straub Tobias , Hammerschmidt Wolfgang
Published: March 2019

Epstein-Barr virus (EBV), a herpes virus also termed HHV 4 and the first identified human tumor virus, establishes a stable long-term latent infection in human B cells, its preferred host. Upon induction of EBV’s lytic phase the latently infected cells turn into a virus factory, a process, that is governed by EBV. In the lytic, productive phase all herpesviruses ensure the efficient induction of all lytic viral genes to produce progeny, but certain of these genes also repress the ensuing antiviral responses of the virally infected host cells, regulate their apoptotic death or control the cellular transcriptome. We now find that EBV causes previously unknown massive and global alterations in the chromatin of its host cell upon induction of the viral lytic phase and prior to the onset of viral DNA replication. The viral initiator protein of the lytic cycle, BZLF1, binds to >105binding sites with different sequence motifs in cellular chromatin and in a concentration dependent manner. Concomitant with DNA binding, silent chromatin opens locally as shown by ATAC-seq experiments, while previously wide-open cellular chromatin becomes inaccessible on a global scale within hours. While viral transcripts increase drastically, the induction of the lytic phase results in a massive reduction of cellular transcripts and a loss of chromatin-chromatin interactions of cellular promoters with their distal regulatory elements as shown in Capture-C experiments. Our data document that EBV’s lytic cycle induces discrete early processes that disrupt the architecture of host cellular chromatin and repress the cellular epigenome and transcriptome likely supporting the efficientde novosynthesis of this herpesvirus.
A stable pollination environment limits current but not potential evolution of floral traits
Authors: Castellanos Maria Clara , Montero-Pau Javier , Ziarsolo Peio , Blanca Jose Miguel , Cañizares Joaquin , Pausas Juli G.
Published: March 2019

The vast variation in floral traits at a macroevolutionary level is often interpreted as the result of adaptation to pollinators. However, studies in wild populations often find no evidence of pollinator-mediated selection on flowers. Evolutionary theory predicts this could be the outcome of long periods of stasis under stable conditions, followed by shorter periods of pollinator change that provide selection for innovative phenotypes. We asked if periods of stasis are caused by stabilizing selection, absence of other forms of selection on floral traits, or by low trait ability to respond even if selection is present. We studiedUlex parviflorus, a plant predominantly pollinated by one bee species across its range. We measured heritability and evolvability of floral traits, using genome-wide molecular relatedness in a large wild population, and combined this with estimates of selection on the same individuals. We found evidence for both stabilizing selection and low trait heritability as explanations for stasis in flowers. The area of the standard petal is under stabilizing selection, but the variability observed in the wild is not heritable. A separate trait, floral weight, in turn presents high heritability, but is not currently under selection. We show how a stable environment can lead to a lack of evolutionary change, yet maintain heritable variation to respond to future selection pressures.
Identification and classification of hubs in miRNA target gene networks in human neural stem/progenitor cells following Japanese encephalitis virus infection
Authors: Mukherjee Sriparna , Akbar Irshad , Bhagat Reshma , Hazra Bibhabasu , Bhattacharyya Arindam , Seth Pankaj , Roy Dipanjan , Basu Anirban
Published: March 2019

Micro RNA dysregulation is observed in many viral diseases. RNA viruses modulate host miRNA machinery for their own benefit. JEV, a neurotropic RNA virus has been reported to manipulate several miRNAs in neuron or microglia. However, no report indicates a complete sketch of the miRNA profile of NSPCs contributing to viral persistence; hence being focused in our current study. We performed a miRNA array of 84 miRNAs in human neuronal progenitor cell line and primary neural precursor cells isolated from aborted foetus. Several fold down-regulation of hsa-miR-9-5p, hsa-miR-22-3p, hsa-miR-124-3p and hsa-miR-132-3p were found in both of the cells. Subsequently, we screened for the target genes of these miRNAs and looked for the important biological pathways the genes significantly regulate. Then we sorted out the target genes which are involved in two or more than two pathways. We constructed a protein-protein interaction (PPI) network of the miRNA target genes based on their interaction patterns. A binary adjacency matrix for each gene network was prepared. Different modules or communities were identified in those networks using community detection algorithms. Mathematically, we identified the hub genes by analyzing their degree centrality and participation co-efficient in the network. The hub genes were classified either as provincial (P<0.4) or connector hubs (P>0.4). We validated the expression of hub genes in both cell line and primary cells through qRT-PCR post JEV infection and respective miR-mimic transfection. Taken together, our findings highlight the importance of specific target gene networks of miRNAs affected by JEV infection in NSPCs.

Importance

JEV damages the neural stem/progenitor cell population of mammalian brain. However, JEV induced alteration in miRNA expression pattern of the cell population remains an open question, hence warrants our present study. In this study, we specifically address the down-regulation of four miRNAs and we prepared a protein-protein interaction network of miRNA target genes. We identified two types of hub genes in the PPI network namely connector hubs and provincial hubs. These two types of miRNA target hub genes critically influence the participation strength in the networks and thereby significantly influence up and down regulation in several key biological pathways. Computational analysis of the PPI networks identifies key protein interactions and hubs in those modules which opens up the possibility of precise identification and classification of host factors for viral infection in NSPCs and how RNA viruses modulate host miRNA machinery for their own benefit post JEV infection to the cells.
Effect of Antimicrobial Stewardship with Rapid MALDI-TOF Identification and Vitek 2 Antimicrobial Susceptibility Testing on Hospitalization Outcome
Authors: Cavalieri Stephen J , Kwon Seunghyug , Vivekanandan Renuga , Ased Sumaya , Carroll Cassara , Anthone Jennifer , Schmidt David , Baysden Maddy , Destache Christopher J
Published: March 2019

Introduction

Rapid organism identification (ID) and antimicrobial susceptibility testing (AST) along with antibiotic stewardship (ASP) are critical to appropriate treatment. We sought to capture time for bacterial culture and initiation of appropriate therapy for patients, from 2017 (without MALDI-TOF/Vitek 2 and ASP) and 2018 (with MALDI-TOF/Vitek 2 and ASP).

Methods

Eligible patients admitted to our hospital with a positive sputum, blood, or urine culture. Sequential patients were retrospectively obtained from March 1 to May 31, 2017. Seventy-seven patients from 2017 were compared to 77 patients from 2018. A time-in-motion study was performed to compare time to identification (ID), AST results, and ASP team intervention for the two periods. Data were entered into SPSS (ver 25) for analysis. Results are reported as mean (± SD) or percentage.

Results

Time to organism ID was significantly faster in 2018 (2018 24.9 ± 14.4, 2017 33.8 ± 17 h, p=0.001). Time to AST results was also significantly faster for patients in 2018 compared to 2017 (18.2 ± 14 compared to 28.5 ± 14.9 h, p<0.001). ASP team recommended significantly more adjustments to empiric antimicrobial therapy in 2018 (28% of 2018 vs. 2% in 2017, p< 0.001). Length of hospital stay was significantly shorter in 2018 compared to 2017 (2018 10.7 ± 11.1 days and 2017 15.5 ± 18.1 days, p=0.05).

Conclusions

Use of MALDI-TOF/Vitek 2 leads to an average 21.5 h faster ID and AST results that can be acted upon by ASP for appropriate antimicrobial recommendations.
Protein Structural Information and Evolutionary Landscape by In Vitro Evolution
Authors: Fantini Marco , Lisi Simonetta , De Los Rios Paolo , Cattaneo Antonino , Pastore Annalisa
Published: March 2019

Protein structure is tightly inter-twined with function according to the laws of evolution. Understanding how structure determines function has been the aim of structural biology for decades. Here, we have wondered instead whether it is possible to exploit the function for which a protein was evolutionary selected to gain information on protein structure and on the landscape explored during the early stages of molecular and natural evolution. To answer to this question, we developed a new methodology, which we named CAMELS (Coupling Analysis by Molecular Evolution Library Sequencing), that is able to obtain the in vitro evolution of a protein from an artificial selection based on function. We were able to observe with CAMELS many features of the TEM-1 beta lactamase local fold exclusively by generating and sequencing large libraries of mutational variants. We demonstrated that we can, whenever a functional phenotypic selection of a protein is available, sketch the structural and evolutionary landscape of a protein without utilizing purified proteins, collecting physical measurements or relying on the pool of natural protein variants.
The Zymoseptoria tritici ORFeome: a functional genomics community resource
Authors: Chaudhari Yogesh , Cairns Timothy C. , Sidhu Yaadwinder , Attah Victoria , Thomas Graham , Csukai Michael , Talbot Nicholas J. , Studholme David J. , Haynes Ken
Published: March 2019

Libraries of protein-encoding sequences can be generated by identification of open reading frames (ORFs) from a genome of choice that are then assembled into collections of plasmids termed ORFeome libraries. These represent powerful resources to facilitate functional genomic characterization of genes and their encoded products. Here, we report the generation of an ORFeome for Zymoseptoria tritici, which causes the most serious disease of wheat in temperate regions of the world. We screened the genome of strain IP0323 for high confidence gene models, identifying 4075 candidates from 10,933 predicted genes. These were amplified from genomic DNA, cloned into the Gateway® Entry Vector pDONR207, and sequenced, providing a total of 3022 quality-controlled plasmids. The ORFeome includes genes predicted to encode effectors (n = 410) and secondary metabolite biosynthetic proteins (n = 171), in addition to genes residing at dispensable chromosomes (n= 122), or those that are preferentially expressed during plant infection (n = 527). The ORFeome plasmid library is compatible with our previously developed suite of Gateway® Destination vectors, which have various combinations of promoters, selection markers, and epitope tags. The Z. tritici ORFeome constitutes a powerful resource for functional genomics, and offers unparalleled opportunities to understand the biology of Z. tritici.
Synonymous SNP: Rare versus frequent codon can cause Phenotypic changes in the human genome
Authors: Srivastav Ashu
Published: March 2019

Since the initial sequencing of the human genome, many projects are underway to understand the effects of genetic variation and phenotypic changes between individuals. Single nucleotide polymorphisms (SNPs) are an increasingly important tool for genetic and biomedical research. Synonymous Single Nucleotide Polymorphisms (sSNP) is an important source of human genome variability. It does not produce altered coding sequences therefore expected not to change the function of protein in which they occur. Examination of synonymous SNPs that change a rarely used codon into a frequently used one or vice versa may help in predicting their phenotypic effect on the individual carrying the change. Detail information of Human Synonymous Single-nucleotide-polymorphism may accelerate the research of personalized medicine since it has the crucial impact in the field of non-synonymous SNP.
Deletion of the creatine transporter gene in neonatal, but not adult, mice lead to cognitive deficits
Authors: Udobi Kenea C. , Delcimmuto Nicholas , Kokenge Amanda N. , Abdulla Zuhair I. , Perna Marla K. , Skelton Matthew R.
Published: March 2019

Creatine (Cr) is a guanidino compound that provides readily-available phosphate pools for the regeneration of spent ATP. The lack of brain Cr causes moderate to severe intellectual disability, language impairment, and epilepsy. The most prevalent cause of Cr deficiency are mutations in the X-linkedSLC6A8(Creatine transporter; CrT) gene, known as CrT deficiency (CTD). There are no current treatments for CTD and the mechanisms that underlie the cognitive deficits are poorly understood. One of the most critical areas that need to be addressed is if Cr is necessary for brain development. To address this concern, theSlc6a8gene was knocked out in either neonatal (postnatal day (P)5) or adult (P60) mice. The P5 knockout mice showed deficits in the Morris water maze and novel object recognition, while there were no deficits in P60 knockout mice. Interestingly, the P5 knockout mice showed hyperactivity during the dark phase; however, when examining control mice, the effect was due to the administration of tamoxifen from P5-10. Taken together, the results of this study show that Cr is necessary during periods of brain development involved in spatial and object learning. This study also highlights the continued importance of using proper control groups for behavioral testing.

Take-home message

The learning and memory deficits seen in Slc6a8-deficient mice are likely due to the developmental loss of Cr.
Intrinsic Disorder and Degeneracy in Molecular Scale Organization of Biological Membrane
Authors: Iyer Sahithya S. , Srivastava Anand
Published: March 2019

The scale-rich spatiotemporal organization in biological membrane dictates the “molecular encounter” and in turn the larger scale biological processes such as molecular transport, trafficking and cellular signalling. In this work, we explore the degeneracy in lateral organization in lipid bilayer systems from the perspective of energy landscape theory. Our analysis on molecular trajectories show that bilayers with lipids havingin-vivocharacteristics have a highly frustrated energy landscape as opposed to a funnel-like energy landscape inin-vitrosystems. Lattice evolution simulations, with Hamiltonian trained from atomistic trajectories using lipids topology and non-affine displacement measures to characterize the extent of order-disorder in the bilayer, show that the inherent frustration inin-vivolike systems renders them with the ability to access a wide range of nanoscale patterns with equivalent energy penalty. We posit that this structural degeneracy could provide for a larger repository to functionally important molecular organization inin-vivosettings.
Characterizing neuronal synaptic transmission using stochastic hybrid systems
Authors: vahdat Zahra , Xu Zikai , Singh Abhyudai
Published: March 2019

Action potential-triggered release of neurotransmitters at chemical synapses forms the key basis of communication between two neurons. To quantify the stochastic dynamics of the number of neurotransmitters released, we investigate a model where neurotransmitter-filled vesicles attach to a finite number of docking sites in the axon terminal, and are subsequently released when the action potential arrives. We formulate the model as a Stochastic Hybrid System (SHS) that combines three key noise mechanisms: random arrival of action potentials, stochastic refilling of docking sites, and probabilistic release of docked vesicles. This SHS representation is used to derive exact analytical formulas for the mean and noise (as quantified by Fano factor) in the number of vesicles released per action potential. Interestingly, results show that in relevant parameter regimes, noise in the number of vesicles released is sub-Poissonian at low frequencies, super-Poissonian at intermediate frequencies, and approaches a Poisson limit at high frequencies. In contrast, noise in the number of neurotransmitters in the synaptic cleft is always super-Poissonian, but is lowest at intermediate frequencies. We further investigate changes in these noise properties for non-Poissonian arrival of action potentials, and when the probability of release is frequency dependent. In summary, these results provide the first glimpse into synaptic parameters not only determining the mean synaptic strength, but also shaping its stochastic dynamics that is critical for information transfer between neurons.
Dissecting the cognitive phenotype of post-stroke fatigue using drift diffusion modeling of sustained attention
Authors: Ulrichsen Kristine M. , Alnæs Dag , Kolskår Knut K. , Richard Geneviève , Sanders Anne-Marthe , Dørum Erlend S. , Ihle-Hansen Hege , Pedersen Mads L. , Tornås Sveinung , Nordvik Jan E. , Westlye Lars T.
Published: March 2019

Post-stroke fatigue (PSF) is a prevalent symptom among stroke patients. Its symptom burden is pervasive, persistent and associated with poor rehabilitation outcomes, though its mechanisms are poorly understood. Many patients with PSF experience cognitive difficulties, but studies aiming to identify cognitive correlates of PSF have been largely inconclusive. In contrast to conventional neuropsychological assessment, computational modeling of behavioral data allows for a dissection of specific cognitive processes associated with group or individual differences in fatigue. With the aim to zero in on the cognitive phenotype of PSF, we fitted a hierarchical drift diffusion model (hDDM) to response time data from Attention Network Test (ANT) obtained from 53 chronic stroke patients. The computational model accurately reconstructed the individual level response time distributions in the different ANT conditions, and hDDM regressions identified an interaction between trial number and fatigue symptoms on non-decision time, intuitively indicating that the cognitive phenotype of fatigue entails an increased vulnerability to sustained attentional effort. These novel results demonstrate the significance of considering the sustained nature of cognitive effort when defining the cognitive phenotype of post-stroke fatigue, and suggest that the use of computational approaches offers a further characterization of the specific processes underlying observed behavioral differences.
Exclusion and genomic relatedness methods for assignment of parentage using genotyping-by-sequencing data
Authors: Dodds K. G. , McEwan J. C. , Brauning R. , van Stijn T. C. , Rowe S. J. , McEwan K. M. , Clarke S. M.
Published: March 2019

Genotypes are often used to assign parentage in agricultural and ecological settings. Sequencing can be used to obtain genotypes but does not provide unambiguous genotype calls, especially when sequencing depth is low in order to reduce costs. In that case, standard parentage analysis methods no longer apply. A strategy for using low-depth sequencing data for parentage assignment is developed here. It entails the use of relatedness estimates along with a metric termed excess mismatch rate which, for parent-offspring pairs or trios, is the difference between the observed mismatch rate and the rate expected under a model of inheritance and allele reads without error. When more than one putative parent has similar statistics, bootstrapping can provide a measure of the relatedness similarity. Putative parent-offspring trios can be further checked for consistency by comparing the offspring’s estimated inbreeding to half the parent relatedness. Suitable thresholds are required for each metric. These methods were applied to a deer breeding operation consisting of two herds of different breeds. Relatedness estimates were more in line with expectation when the herds were analysed separately than when combined, although this did not alter which parents were the best matches with each offspring. Parentage results were largely consistent with those based on a microsatellite parentage panel with three discordant parent assignments out of 1561. Two models are investigated to allow the parentage metrics to be calculated with non-random selection of alleles. The tools and strategies given here allow parentage to be assigned from low-depth sequencing data.
Cross-transmission is not the source of newMycobacterium abscessusinfections in a multi-centre cohort of cystic fibrosis patients
Authors: Doyle Ronan M. , Rubio Marc , Dixon Garth , Hartley John , Klein Nigel , Coll Pere , Harris Kathryn A.
Published: March 2019

Background

Mycobacterium abscessusis an extensively drug resistant pathogen that causes pulmonary disease particularly in cystic fibrosis (CF) patients. Identifying direct patient-to-patient transmission ofM. abscessusis critically important in directing infection control policy for the management of risk in CF patients. A variety of clinical labs have used molecular epidemiology to investigate transmission. However there is still conflicting evidence as to howM. abscessusis acquired and whether cross-transmission occurs. Recently labs have applied whole-genome sequencing (WGS) to investigate this further and in this study we investigate whether WGS can reliably identify cross-transmission inM. abscessus.

Methods

We retrospectively sequenced the whole genomes of 145M. abscessusisolates from 62 patients seen at four hospitals in two countries over 16 years.

Results

We have shown that a comparison of a fixed number of core single nucleotide variants (SNVs) alone cannot be used to infer cross-transmission inM. abscessusbut does provide enough information to replace multiple existing molecular assays. We detected one episode of possible direct patient-to-patient transmission in a sibling pair. We found that patients acquired uniqueM. abscessusstrains even after spending considerable time on the same wards with otherM. abscessuspositive patients.

Conclusions

This novel analysis has demonstrated that the majority of patients in this study have not acquiredM. abscessusthrough direct patient-patient transmission or a common reservoir. Tracking transmission using WGS will only realise its full potential with proper environmental screening as well as patient sampling.

Key points

Whole genome sequencing should replace current molecular typing used routinely in clinical microbiology laboratories.

Patient-to-patient spread ofM. abscessusis not common.

Environmental screening may provide a better understanding acquisition ofM. abscessusinfections.
Non-medical prescribing policy in the United Kingdom National Health Service: systematic review and narrative synthesis
Authors: Graham-Clarke Emma , Rushton Alison , Noblet Timothy , Marriott John
Published: March 2019

Non-medical prescribing was introduced into the United Kingdom (UK) to improve patient care, through extending healthcare professionals’ roles. More recent government health service policy focuses on the increased demand and the need for efficiency. This systematic review aimed to describe any changes in government policy position and the role that non-medical prescribing plays in healthcare provision.

The systematic review and narrative analysis included policy and consultation documents that describe independent non-medical prescribing. A pre-defined protocol was registered with PROSPERO (CRD42015019786). Professional body websites, other relevant websites and the following databases were searched to identify relevant papers: HMIC, Lexis Nexis, UK Government Web Archive, UKOP, UK Parliamentary Papers and Web of Science. Papers published between 2006 and February 2018 were included.

Following exclusions, 45 papers were selected for review; 23 relating to policy or strategy and 22 to consultations. Of the former, 13/23 were published 2006-2010 and the remainder since 2013. Two main themes are identified: chronological aspects and healthcare provision. The impact of government change and associated major healthcare service reorganisation resulted in the publication gap for policy documents. The role of non-medical prescribing has evolved to support efficient service delivery, and cost reduction. For many professions, prescribing appears embedded into practice; however, pharmacy continues to produce policy documents, suggesting that prescribing is not yet perceived as normal practice.

Prescribing appears to be more easily adopted into practice where it can form part of the overall care of the patient. Where new roles are required to be established, then prescribing takes longer to be universally adopted. While this research concerns policy and practice in the UK, this aspect of role adoption has wider potential implications.
Rehabilitation promotes the recovery of structural and functional features of healthy neuronal networks after stroke
Authors: Allegra Mascaro Anna Letizia , Conti Emilia , Lai Stefano , Giovanna Antonino Paolo Di , Spalletti Cristina , Alia Claudia , Panarese Alessandro , Scaglione Alessandro , Sacconi Leonardo , Micera Silvestro , Caleo Matteo , Pavone Francesco Saverio
Published: March 2019

Rehabilitation is the most effective treatment for promoting the recovery of motor deficits after stroke. One of the most challenging experimental goals is to unambiguously link brain rewiring to motor recovery prompted by rehabilitative therapy. Here, we investigated which aspects of cortical remodeling are induced by rehabilitation by combining optical imaging and manipulation tools in a mouse model of stroke. We revealed that the stabilization of peri-infarct synaptic contacts fostered by rehabilitation goes along with increased vascular density induced by angiogenesis. Furthermore, we showed the progressive formation of a new motor representation in the peri-infarct area where temporal and spatial features of cortical activation recovered towards pre-stroke condition. In the same animals we observed the reinforcement of inter-hemispheric connectivity after rehabilitation. The present work provides the first evidences that rehabilitation promotes the combined recovery of structural and functional features distinctive of healthy neuronal networks.
Neuronal histone methyltransferase EZH2 regulates neuronal morphogenesis, synaptic plasticity, and cognitive behavior of mice
Authors: Zhang Mei , Zhang Yong , Xu Qian , Crawford Joshua , Qian Cheng , Wang Guo-Hua , Lewis Eastman , Hall Philip , Dolen Gül , Huganir Richard L. , Qian Jiang , Dong Xin-Zhong , Pletnikov Mikhail V. , Liu Chang-Mei , Zhou Feng-Quan
Published: March 2019

Recent studies showed that in the nervous system histone methyltransferase EZH2-mediated trimethylation of histone H3 lysine 27 (H3K27me3) acts to regulate neural stem cell proliferation and fate specificity through silencing different gene sets. Here we explored the function of EZH2 in early post-mitotic excitatory neurons by generating a neuronal specific Ezh2 conditional knockout mouse line. The results showed that lack of neuronal EZH2 led to delayed neuronal migration, more complex dendritic arborization, and significantly increased dendritic spine density. RNA-sequencing (RNA-seq) experiments comparing control and Ezh2 knockout neurons revealed that neuronal EZH2 regulated genes related to neuronal morphogenesis. In particular, Pak3 was identified as a target gene suppressed by EZH2 and H3K27me3, and expression of dominant negative PAK3 reversed Ezh2 knockout-induced higher dendritic spine density. Lastly, lack of neuronal EZH2 resulted in impaired memory behaviors in adult mice. Our results demonstrated that neuronal EZH2 played important roles in controlling multiple steps of neuronal morphogenesis during development, which had long-lasting effects on cognitive function in adult mice.
Microfluidic Rapid and Autonomous Analytical Device (microRAAD) to Detect HIV from Whole Blood Samples
Authors: Phillips Elizabeth A. , Moehling Taylor J. , Ejendal Karin F.K. , Hoilett Orlando S. , Byers Kristin M. , Basing Laud Anthony , Jankowski Lauren A. , Bennett Jackson B. , Lin Li-Kai , Stanciu Lia A. , Linnes Jacqueline C.
Published: March 2019

Early Human Immunodeficiency Virus (HIV) testing is critical to preventing transmission and providing treatment to HIV-positive individuals, yet an estimated 30% of HIV-positive individuals do not know their status because of barriers to early diagnosis. Readily accessible, highly sensitive, and rapid diagnostic tests would enable patients’ prompt treatment with anti-retroviral therapies and reduce transmission. However, existing HIV diagnostic technologies either do not detect early stages of infection or require multiple days of laboratory processing, delaying notification of patients’ status.

Molecular techniques that amplify HIV RNA can detect the earliest stages of infection, within 8-10 days after transmission. However, most of these molecular assays require cold-chain storage of reagents, significant sample preparation, and extensive laboratory infrastructure. To achieve early detection, we developed a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay with a limit of detection of 10 HIV-1 RNA copies visualized by eye using a lateral flow immunoassay. To demonstrate automated sample-to-answer detection of HIV, we incorporate dried amplification reagents and wax valves in low-cost substrates with resistive heating elements and circuitry. By combining controlled heating with paper’s capillary flow, our assembled device automatically isolates viral particles from human blood samples, amplifies HIV-1 RNA, and transports products to a detection zone. We determine that as few as 105HIV-1 viral particles can be separated from whole blood, amplified, and visually detected within 90 minutes of sample addition into our Microfluidic Rapid and Autonomous Analysis Device (microRAAD). The low-cost and automated attributes of microRAAD demonstrate its utility as a point-of-care testing platform.
Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell cycle arrest
Authors: Cho Sangkyun , Vashisth Manasvita , Abbas Amal , Majkut Stephanie , Vogel Kenneth , Xia Yuntao , Ivanovska Irena L. , Irianto Jerome , Tewari Manorama , Zhu Kuangzheng , Tichy Elisia D. , Mourkioti Foteini , Tang Hsin-Yao , Greenberg Roger A. , Prosser Benjamin L. , Discher Dennis E.
Published: March 2019

Whether cell forces or extracellular matrix (ECM) can impact genome integrity is largely unclear. Here, acute perturbations (~1hr) to actomyosin stress or ECM elasticity cause rapid and reversible changes in lamin-A, DNA damage, and cell cycle. Embryonic hearts, differentiated iPS-cells, and various nonmuscle cell types all show that actomyosin-driven nuclear rupture causes cytoplasmic mis-localization of DNA repair factors and excess DNA damage. Binucleation and micronuclei increase as telomeres shorten, which all favor cell cycle arrest. Deficiencies in lamin-A and repair factors exacerbate these effects, but lamin-A-associated defects are rescued by repair factor overexpression and by contractility modulators in clinical trials. Contractile cells on stiff ECM normally exhibit low phosphorylation and slow degradation of lamin-A by matrix-metalloprotease-2 (MMP2), and inhibition of this lamin-A turnover and also actomyosin contractility is seen to minimize DNA damage. Lamin-A is thus stress-stabilized to mechano-protect the genome.
Assessing the role of long-noncoding RNA in nucleus accumbens in subjects with alcohol dependence
Authors: McMichael Gowon O. , Drake John , Vornholt Eric Sean , Cresswell Kellen , Williamson Vernell , Chatzinakos Chris , Mamdani Mohammed , Hariharan Siddharth , Kendler Kenneth S. , Miles Michael F. , Kalsi Gursharan , Riley Brien P. , Dozmorov Mikhail , Bacanu Silviu-Alin , Vladimirov Vladimir I.
Published: March 2019

Recently, long noncoding RNA (lncRNA) were implicated in the etiology of alcohol dependence (AD). As lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step towards understanding lncRNA functions in AD. To that end, we profiled the expression of lncRNA and protein coding genes (PCG) in nucleus accumbens (NAc) from 41 subjects with AD and 41 controls. At false discovery rate (FDR) of 5%, we identified 69 and 309 differentially expressed lncRNA and PCG genes, respectively. Using co-expression network analyses, we identified three lncRNA and five PCG modules significantly correlated with AD at Bonferroni adj. p≤0.05. To better understand lncRNA functions, we integrated the lncRNA and PCG hubs from the significant AD modules; at FDR of 5%, we identified 3 151 positive and 2 255 negative correlations supporting the functional role of lncRNA in the development of AD. Gene enrichment analysis revealed that PCG significantly correlated with lncRNA are, among others, enriched for neuronal and immune related processes. To highlight the mechanisms, by which genetic variants contribute to AD, we integrated lncRNA and PCG hubs with genome-wide SNP data. At FDR≤0.3, we identified 276 expression quantitative trait loci (eQTL), affecting the expression of 20 and 256 lncRNA and PCG hubs, respectively. Our study is the first to profile lncRNA expression in nucleus accumbens in a large postmortem alcohol brain sample and our results may provide novel insights into the regulation of the brain transcriptome across disease.
Neutrophil-derived extracellular vesicles: proinflammatory trails and anti-inflammatory microvesicles
Authors: Youn Young-Jin , Shrestha Sanjeeb , Kim Jun-Kyu , Lee Yu-Bin , Lee Jee Hyun , Hur Keun , Mali Nanda Maya , Nam Sung-Wook , Kim Sun-Hwa , Song Dong-Keun , Jin Hee Kyung , Bae Jae-sung , Hong Chang-Won
Published: March 2019

Extracellular vesicles (EVs) are membrane-derived vesicles that mediate intercellular communications. Neutrophils produce different subtypes of EVs during inflammatory responses. Neutrophil-derived trails (NDTRs) are generated by neutrophils migrating toward inflammatory foci, whereas neutrophil-derived microvesicles (NDMVs) are thought to be generated by neutrophils that have arrived at the inflammatory foci. However, the physical and functional characteristics of neutrophil-derived EVs are incompletely understood. In this study, we investigated the similarities and differences between neutrophil-derived EV subtypes. Neutrophil-derived EVs shared similar characteristics regarding stimulators, generation mechanisms, and surface marker expression. Both neutrophil-derived EV subtypes exhibited similar functions, such as direct bactericidal activity and induction of monocyte chemotaxis via MCP-1. However, NDTR generation was dependent on the integrin signaling, while NDMV generation was dependent on the PI3K pathway. The CD16 expression level differentiated the neutrophil-derived EV subtypes. Interestingly, both subtypes showed different patterns of miRNA expression and were easily phagocytosed by monocytes. NDTRs induced M1 macrophage polarization, whereas NDMVs induced M2 macrophage polarization. Moreover, NDTRs but not NDMVs exerted protective effects against sepsis-induced lethality in a murine sepsis model and pathological changes in a murine chronic colitis model. These results suggest a new insight into neutrophil-derived EV subtypes: proinflammatory NDTRs and anti-inflammatory NDMVs.

Key points

Neutrophil-derived trails are proinflammatory extracellular vesicles that induce M1 macrophage polarization and protect against inflammation

Neutrophil-derived microvesicles are anti-inflammatory extracellular vesicles that induce M2 macrophage polarization