bluuebunny/crossref_metadata_2025 huggingface dataset:
Transforming Veterans Health Administration Mental Health Clinician Education and Practices: 20 Years of Educational Initiatives by a Center of Excellence
Authors: Bryan Jennifer L. , Kauth Michael R. , Asghar-Ali Ali A.
Published: May 2019

Twenty years ago, the US Congress articulated a need to decrease the time it takes clinical best practices to move from the literature to daily clinical practice. The Veterans Affairs South Central Mental Illness Research, Education, and Clinical Center was one of several centers of excellence established to address this need. It is also unique in that it focuses on rural and underserved veterans. This article summarizes the education accomplishments of the South Central Mental Illness Research, Education, and Clinical Center thus far in providing educational resources and trainings to frontline Veterans Affairs mental health staff with the goal of bringing best practices to routine clinical care, thus improving mental health services. We describe the use of implementation science to support dissemination of information, such as the monthly mental health grand rounds, especially for rural staff to receive continuing education, and the adoption of evidence-based psychotherapy trainings. The Clinical Educator Grants program allows clinicians to share their clinical expertise through development of practical tools for practice gaps they identify. We describe some future directions to meet the evolving needs of Veterans Affairs and community clinicians to provide the best possible care to Veterans. Take-away messages are that, for trainings to be successful, an implementation plan is critical and that an effective educational program requires funding and leadership commitment.
Personal Commitment Statements: Encouraging the Clinical Application of Continuing Professional Development Events for Health Practitioners in Low- and Middle-Income Countries
Authors: Bornman Juan , Louw Brenda
Published: May 2019

Introduction:

Statements of commitment to change are commonly used to evaluate continuing medical education. However, this approach is new to evaluating the continuing professional development (CPD) of other health care practitioners such as audiology, speech-language therapy, occupational therapy, and physiotherapy in low- and middle-income countries. This study explored the use of Personal Commitment (to change) Statements (PCSs) as an evaluation tool of continuing education for health professionals in low- and middle-income countries, and its impact on the integration of new knowledge and skills with previous knowledge and clinical practice.

Methods:

PCSs were used in a case study conducted at a 1-day interprofessional CPD event held for health practitioners in South Africa. A qualitative thematic analysis was made of these PCSs, and results were synthesized into main themes.

Results:

Thirty-two participants turned in a PCS at the end of the CPD event with a total of 71 text statements. Three main domains were identified: (1) applying new knowledge in practice (61.97%); (2) increasing training-related content knowledge (21.12%); and (3) sharing information, skill, and resources (16.9%).

Discussion:

This study demonstrated that personal commitment statements can be used to describe the outcomes of CPD events for audiologists, speech-language, occupational, and physiotherapists. Participants engaged in reflection generated by the personal commitment statement, which contained no guiding statements, yet elicited responses showing that participants were more aware of the assessment tools and how they could use them in practice. Further study is warranted into the process and the role of follow-up regarding health practitioners' commitment to change in clinical practice.
Alignment of American Association of Colleges of Nursing Graduate-Level Nursing Informatics Competencies With American Medical Informatics Association Health Informatics Core Competencies
Authors: Monsen Karen A. , Bush Ruth A. , Jones Josette , Manos E. LaVerne , Skiba Diane J. , Johnson Stephen B.
Published: May 2019

This study yielded a map of the alignment of American Association of Colleges of Nursing Graduate-Level Nursing Informatics Competencies with American Medical Informatics Association Health Informatics Core Competencies in an effort to understand graduate-level accreditation and certification opportunities in nursing informatics. Nursing Informatics Program Directors from the American Medical Informatics Association and a health informatics expert independently mapped the American Association of Colleges of Nursing competencies to the American Medical Informatics Association Health Informatics knowledge, skills, and attitudes. The Nursing Informatics Program Directors' map connected an average of 4.0 American Medical Informatics Association Core Competencies per American Association of Colleges of Nursing competency, whereas the health informatics expert's map connected an average of 5.0 American Medical Informatics Association Core Competencies per American Association of Colleges of Nursing competency. Agreement across the two maps ranged from 14% to 60% per American Association of Colleges of Nursing competency, revealing alignment between the two groups' competencies according to knowledge, skills, and attitudes. These findings suggest that graduates of master's degree programs in nursing, especially those specializing in nursing informatics, will likely be prepared to sit for the proposed Advanced Health Informatics Certification in addition to the American Nurses Credentialing Center bachelor's-level Informatics Nursing Certification. This preliminary map sets the stage for further in-depth mapping of nursing informatics curricula with American Medical Informatics Association Core Competencies and will enable interprofessional conversations around nursing informatics specialty program accreditation, nursing workforce preparation, and nursing informatics advanced certification. Nursing informaticists should examine their need for credentials as key contributors who will address critical health informatics needs.
Shared Reading Practices and Early Literacy Promotion in the First Year of Life
Authors: Sinclair Elizabeth M. , McCleery Ellen J. , Koepsell Lorraine , Zuckerman Katharine E. , Stevenson Ellen B.
Published: May 2019

Limited research exists on family reading practices, the impact of counseling, and book distribution in the first 6 months of life, despite recommendations from the American Academy of Pediatrics and Reach Out and Read promoting shared reading from birth.

Objective:

To describe infant home reading trajectories and environments in the first year and to assess whether receiving books starting in the newborn period, compared with starting at 6 months, alters these trajectories.

Methods:

Two study groups were enrolled in a quasi-experimental sequential cohort study; both groups received shared reading counseling starting in the newborn period and completed surveys throughout the first year. The Standard group received books starting at 6 months, whereas the Early Books group received books starting at 2 weeks. Reading trajectories were assessed both overall and between the study groups.

Results:

At the 2-week visit, less than half of families in each group had started shared reading with their infant, which rose to >97% by 12 months. Approximately two-thirds of families owned >10 children's books at 2 weeks, which increased to >80% at 12 months. Incorporating shared reading into bedtime routines also increased during the first year. Early versus standard book distribution did not alter these trajectories.

Conclusion:

Over the first year of life, families almost universally initiated shared reading and increased the number of books in the home. Reading habits established during this time were maintained in both groups. Literacy promotion beginning at the earliest well-child visits may help establish routines that will persist throughout childhood.
Residual hepatitis C virus in peripheral blood mononuclear cell as a risk factor for hepatocellular carcinoma after achieving a sustained virological response: a dogma or fiction
Authors: Hanafy Amr S. , Seleem Waseem M. , Basha Mohammad A.A. , Marei Ayman M.
Published: May 2019

Background

Clinical worsening after achieving a sustained virological response (SVR) needs to be clarified and explained. Persistence of hepatitis C virus (HCV) core antigen interacts with the host proteins to interfere with signaling pathways and increases the susceptibility to hepatic carcinogenesis.

Objective

This study aimed to investigate the risk factors that increase the progression of liver disease and hepatocellular carcinoma in a subgroup of HCV patients who achieved a SVR.

Patients and methods

Eighty-nine HCV patients with hepatic decompensation were selected 8.2 ± 1.8 months after achieving SVR24. HCV core antigen and HCV RNA were detected in peripheral blood mononuclear cells. Matched control (n = 100) and training (n = 200) groups were recruited.

Results

Eighty-five patients showed a progression of Child–Turcotte–Pugh and model for end-stage liver disease scores, with positive RNA in peripheral blood mononuclear cell (357.4 ± 42.1 IU/million cell) and positive hepatitis C virus core antigen (n = 73); four patients were excluded. Susceptibility to decompensation and hepatocellular carcinoma after direct-acting antiviral drugs increased with age [odds ratio (OD) = 1.87], and was associated with male sex (OD = 1.65), diabetes (OD = 3.68), thrombocytopenia (OD = 2.44), pretreatment Alfa-fetoprotein (OD = 3.41), and occult HCV (OD = 4.1).

Conclusion

Clinical deterioration after SVR could be explained by occult HCV mainly in older male patients with diabetes and thrombocytopenia.
Determination of Serum Infliximab Concentration by Point‐of‐care Devices in Children With Inflammatory Bowel Disease
Authors: Curci Debora , Lucafò Marianna , Cifù Adriana , Bramuzzo Matteo , Martelossi Stefano , Favretto Diego , De Pellegrin Francesca , Fabris Martina , Vascotto Fulvia , Naviglio Samuele , Ventura Alessandro , Stocco Gabriele , Decorti Giuliana
Published: May 2019

Objectives:

Therapeutic drug monitoring is becoming increasingly important in clinical decision‐making in children with inflammatory bowel disease (IBD). However, enzyme‐linked immunosorbent assay (ELISA) assays do not allow results to be provided in real‐time. We sought to compare 2 point‐of‐care (POC) devices for quantification of serum infliximab concentration with 2 validated ELISA assays in children with IBD.

Methods:

We studied 32 serum samples from 19 children with IBD treated with infliximab. Serum samples were collected immediately before drug infusion (trough level). Infliximab was measured using 2 POC infliximab assays, Quantum Blue (POC IFX/QB) and Rida Quick (POC IFX/RQ), and 2 ELISA assays: Lisa‐Tracker (used as primary reference), and Promonitor (used as second control). Intraclass correlation coefficient (ICC) was assessed for quantitative comparison. Qualitative analysis was also performed to evaluate whether POC assays would correctly classify infliximab serum according to a target window (between 3 and 7 μg/mL).

Results:

ICC was 0.82 and 0.87 for POC IFX/QB and POC IFX/RQ with the primary reference ELISA assay, respectively; ICC between the 2 ELISA assays was 0.87. Classification of results according to therapeutic intervals showed good agreement between pairs of assays, with kappa of 0.67 and 0.80 for POC IFX/QB and POC IFX/RQ, respectively, with reference ELISA, and 0.81 between the 2 ELISAs. Accuracy of POC assays was better for drug levels <3 μg/mL.

Conclusions:

POC infliximab assays showed good agreement with traditional ELISA assays. POC devices may represent a viable option for real‐time therapeutic drug monitoring in children treated with infliximab.
Structural Differences in Meibum From Teenagers Without and With Dry Eye and Allogeneic Hematologic Stem Cell Transplantations
Authors: Ramasubramanian Aparna , Borchman Douglas
Published: May 2019

Although dry eye occurs mostly in adults, dry eye may be induced in teens receiving allogeneic hematologic stem cell transplantations (AHSCT). Changes in meibum composition and structure has been associated with dry eye. The structure of meibum from teens with dye eye or teens with dry eye and AHSCT has not been studied, so in this study, we compared the structure of meibum from teens receiving AHSCT that had a dry eye with meibum from teens without AHSCT and without dry eye symptoms.
Identifying predictors of HPV-related head and neck squamous cell carcinoma progression and survival through patient-derived models
Authors: Facompre ND , Rajagopalan P , Sahu V , Pearson AT , Montone KT , James CD , Gleber-Netto FO , Weinstein GS , Jalaly J , Lin A , Rustgi AK , Nakagawa H , Califano JA , Pickering CR , White EA , Windle B , Morgan IM , Cohen RB , Gimotty PA , Basu D
Published: May 2019

Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate biomarkers and preclinical models. This study addressed both limitations using the largest panel of HPV+ HNSCC patient-derived xenografts (PDXs) and organoids described to date. Whole exome profiles of the PDXs were compared to those of HPV+ human tumors and cell lines, and genetic features of the models were analyzed relative to their growth properties and outcomes of their patients of origin. PDX engraftment enriched for negatively prognostic NOTCH1 mutations while preserving multiple features lost in existing cell lines, includingPIK3CAmutations,TRAF3deletion, and absence ofEGFRamplification. Observation of more mutations in faster-growing models facilitated identification of an association between mutational burden and local progression in both HPV+ and HPV-HNSCCs. Reduced E7 and p16INK4Alevels found in a PDX from a lethal case led to detection of a similar profile among recurrent HPV+ HNSCCs in two patient cohorts, where low E2F target gene expression downstream of E7 predicted recurrence and mortality. Our findings bridge a critical gap in preclinical models for HPV+ HNSCCs and simultaneously reveal novel applications for mutational burden and E2F target dysregulation in biomarker development.
Evidence of a Causal Association Between Cancer and Alzheimer’s Disease: a Mendelian Randomization Analysis
Authors: Seddighi Sahba , Houck Alexander L , Rowe James B , Pharoah Paul DP
Published: May 2019

Objectives

To determine whether cancer confers protection against Alzheimer’s disease and to evaluate the relationship in the context of smoking-related cancers versus non-smoking related cancers

Design

Mendelian randomization analysis using cancer-associated genetic variants as instrumental variables

Setting

International Genomics of Alzheimer’s Project

Participants

17,008 Alzheimer’s disease cases and 37,154 controls

Main outcome measures

Odds ratio of Alzheimer’s disease per 1-unit higher log odds of genetically predicted cancer

Results

We found that genetically predicted lung cancer (OR 0.91, 95% CI 0.84-0.99, p=0.019), leukemia (OR 0.98, 95% CI 0.96-0.995, p=0.012), and breast cancer (OR 0.94, 95% CI 0.89-0.99, p=0.028) were associated with 9.0%, 2.4%, and 5.9% lower odds of Alzheimer’s disease, respectively, per 1-unit higher log odds of cancer. When genetic predictors of all cancers were pooled, cancer was associated with 2.5% lower odds of Alzheimer’s disease (OR 0.98, 95% CI 0.96-0.988, p=0.00027) per 1-unit higher log odds of cancer. Finally, genetically predicted smoking-related cancers showed a more robust inverse association with Alzheimer’s disease than non-smoking related cancers (5.2% lower odds, OR 0.95, 95% CI 0.92-0.98, p=0.0026, vs. 1.9% lower odds, OR 0.98, 95% CI 0.97-0.995, p=0.0091).

Conclusions

Genetically predicted lung cancer, leukemia, breast cancer, and all cancers in aggregate are associated with lower odds of incident Alzheimer’s disease. Furthermore, the risk of Alzheimer’s disease was lower in smoking-related versus non-smoking related cancers. These results add to the substantial epidemiological evidence of an inverse association between history of cancer and lower odds of Alzheimer’s disease, by suggesting a causal basis for this relationship.
Repurposing a macromolecular machine: Architecture and evolution of the F7 chemosensory system
Authors: Ortega Davi R. , Subramanian Poorna , Mann Petra , Kjær Andreas , Chen Songye , Watts Kylie J. , Pirbadian Sahand , Collins David A. , Kooger Romain , Kalyuzhnaya Marina G. , Ringgaard Simon , Briegel Ariane , Jensen Grant J.
Published: May 2019

How complex, multi-component macromolecular machines evolved remains poorly understood. Here we reveal the evolutionary origins of the chemosensory machinery that controls flagellar motility inEscherichia coli. We first identified ancestral forms still present inVibrio cholerae, Pseudomonas aeruginosa, Shewanella oneidensisandMethylomicrobium alcaliphilum, characterizing their structures by electron cryotomography and finding evidence that they function in a stress response pathway. Using bioinformatics, we then traced the evolution of the system through γ-Proteobacteria, pinpointing key evolutionary events that led to the machine now seen inE. coli.Our results suggest that two ancient chemosensory systems with different inputs and outputs (F6 and F7) existed contemporaneously, with one (F7) ultimately taking over the inputs and outputs of the other (F6), which was subsequently lost.
Genomic diversity affects the accuracy of bacterial SNP calling pipelines
Authors: Bush Stephen J. , Foster Dona , Eyre David W. , Clark Emily L. , De Maio Nicola , Shaw Liam P. , Stoesser Nicole , Peto Tim E. A. , Crook Derrick W. , Walker A. Sarah
Published: May 2019

Background

Accurately identifying SNPs from bacterial sequencing data is an essential requirement for using genomics to track transmission and predict important phenotypes such as antimicrobial resistance. However, most previous performance evaluations of SNP calling have been restricted to eukaryotic (human) data. Additionally, bacterial SNP calling requires choosing an appropriate reference genome to align reads to, which, together with the bioinformatic pipeline, affects the accuracy and completeness of a set of SNP calls obtained.

This study evaluates the performance of 41 SNP calling pipelines using simulated data from 254 strains of 10 clinically common bacteria and real data from environmentally-sourced and genomically diverse isolates within the genera Citrobacter, Enterobacter, Escherichia and Klebsiella.

Results

We evaluated the performance of 41 SNP calling pipelines, aligning reads to genomes of the same or a divergent strain. Irrespective of pipeline, a principal determinant of reliable SNP calling was reference genome selection. Across multiple taxa, there was a strong inverse relationship between pipeline sensitivity and precision, and the Mash distance (a proxy for average nucleotide divergence) between reads and reference genome. The effect was especially pronounced for diverse, recombinogenic, bacteria such as Escherichia coli, but less dominant for clonal species such as Mycobacterium tuberculosis.

Conclusions

The accuracy of SNP calling for a given species is compromised by increasing intra-species diversity. When reads were aligned to the same genome from which they were sequenced, among the highest performing pipelines was Novoalign/GATK. However, across the full range of (divergent) genomes, among the consistently highest-performing pipelines was Snippy.
Statistical learning attenuates visual activity only for attended stimuli
Authors: Richter David , de Lange Floris P.
Published: May 2019

Perception and behavior can be guided by predictions, which are often based on learned statistical regularities. Neural responses to expected stimuli are frequently found to be attenuated after statistical learning. However, whether this sensory attenuation following statistical learning occurs automatically or depends on attention remains unknown. In the present fMRI study, we exposed human volunteers to sequentially presented object stimuli, in which the first object predicted the identity of the second object. We observed a strong attenuation of neural activity for expected compared to unexpected stimuli in the ventral visual stream. Crucially, this sensory attenuation was only apparent when stimuli were attended, and vanished when attention was directed away from the predictable objects. These results put important constraints on neurocomputational theories that cast perception as a process of probabilistic integration of prior knowledge and sensory information.
Identification of new therapeutic targets inCRLF2-overexpressing B-ALL through discovery of TF-gene regulatory interactions
Authors: Badri Sana , Carella Beth , Lhoumaud Priscillia , Castro Dayanne M. , Gibbs Claudia Skok , Raviram Ramya , Narang Sonali , Evensen Nikki , Watters Aaron , Carroll William , Bonneau Richard , Skok Jane A.
Published: May 2019

Although genetic alterations are initial drivers of disease, aberrantly activated transcriptional regulatory programs are often responsible for the maintenance and progression of cancer.CRLF2-overexpression in B-ALL patients leads to activation of JAK-STAT, PI3K and ERK/MAPK signaling pathways and is associated with poor outcome. Although inhibitors of these pathways are available, there remains the issue of treatment-associated toxicities, thus it is important to identify new therapeutic targets. Using a network inference approach, we reconstructed a B-ALL specific transcriptional regulatory network to evaluate the impact ofCRLF2-overexpression on downstream regulatory interactions.

Comparing RNA-seq fromCRLF2-High and other B-ALL patients (CRLF2-Low), we defined aCRLF2-High gene signature. Patient-specific chromatin accessibility was interrogated to identify altered putative regulatory elements that could be linked to transcriptional changes. To delineate these regulatory interactions, a B-ALL cancer-specific regulatory network was inferred using 868 B-ALL patient samples from the NCI TARGET database coupled with priors generated from ATAC-seq peak TF-motif analysis. CRISPRi, siRNA knockdown and ChIP-seq of nine TFs involved in the inferred network were analyzed to validate predicted TF-gene regulatory interactions.

In this study, a B-ALL specific regulatory network was constructed using ATAC-seq derived priors. Inferred interactions were used to identify differential patient-specific transcription factor activities predicted to controlCRLF2-High deregulated genes, thereby enabling identification of new potential therapeutic targets.
The Crk adapter protein is essential forDrosophilaembryogenesis, where it regulates multiple actin-dependent morphogenic events
Authors: Spracklen Andrew J. , Thornton-Kolbe Emma M. , Bonner Alison N. , Florea Alexandru , Compton Peter J. , Fernandez-Gonzalez Rodrigo , Peifer Mark
Published: May 2019

Abstract

Small SH2/SH3 adapter proteins regulate cell fate and behavior by mediating interactions between cell surface receptors and downstream signaling effectors in many signal transduction pathways. The Crk family has tissue-specific roles in phagocytosis, cell migration and neuronal development, and mediates oncogenic signaling in pathways like that of Abelson kinase. However, redundancy among the two mammalian family members and the position of theDrosophilagene on the fourth chromosome precluded assessment of Crk’s full role in embryogenesis. We circumvented these limitations with shRNA and CRISPR technology to assess Crk’s function inDrosophilamorphogenesis. We found Crk is essential beginning in the first few hours of development, where it ensures accurate mitosis by regulating orchestrated dynamics of the actin cytoskeleton to keep mitotic spindles in syncytial embryos from colliding. In this role, it positively regulates levels of the Arp2/3 complex, its regulator SCAR, and F-actin in actin caps and pseudocleavage furrows. Crk loss leads to loss of nuclei and formation of multinucleate cells. We also found roles for Crk in embryonic wound healing and in axon patterning in the nervous system, where it localizes to the axons and midline glia. Thus, Crk regulates diverse events in embryogenesis that require orchestrated cytoskeletal dynamics.
Identification of 3’ UTR motifs required for mRNA localization to myelin sheaths in vivo
Authors: Yergert Katie M. , O’Rouke Rebecca , Hines Jacob H. , Appel Bruce
Published: May 2019

Myelin is a specialized membrane produced by oligodendrocytes that insulates and supports axons. Oligodendrocytes extend numerous cellular processes, as projections of the plasma membrane, and simultaneously wrap multiple layers of myelin membrane around target axons. Notably, myelin sheaths originating from the same oligodendrocyte are variable in size, suggesting local mechanisms regulate myelin sheath growth. Purified myelin contains ribosomes and hundreds of mRNAs, supporting a model that mRNA localization and local protein synthesis regulate sheath growth and maturation. However, the mechanisms by which mRNAs are selectively enriched in myelin sheaths are unclear. To investigate how mRNAs are targeted to myelin sheaths, we tested the hypothesis that transcripts are selected for myelin enrichment through consensus sequences in the 3’ untranslated region (3’ UTR). Using methods to visualize mRNA in living zebrafish larvae, we identified candidate 3’ UTRs that were sufficient to localize mRNA to sheaths and enriched near growth zones of nascent membrane. We bioinformatically identified motifs common in 3’ UTRs from three myelin-enriched transcripts and determined that these motifs are required for mRNA transport to myelin sheaths. Finally, we show that one motif is highly enriched in the myelin transcriptome, suggesting that this sequence is a global regulator of mRNA localization during developmental myelination.
Transparency, a better camouflage than crypsis in cryptically coloured moths
Authors: Arias Mónica , Elias Marianne , Andraud Christine , Berthier Serge , Gomez Doris
Published: May 2019

Predation is a ubiquitous and strong selective pressure on living organisms. Transparency is a predation defence widespread in water but rare on land. Some Lepidoptera display transparent patches combined with already cryptic opaque patches. While transparency has recently been shown to reduce detectability in conspicuous prey, we here test whether transparency decreases detectability in already cryptically-coloured terrestrial prey, by conducting field predation experiments with free avian predators and artificial moths. We monitored and compared survival of a fully opaque grey artificial form (cryptic), a form including transparent windows and a wingless artificial butterfly body. Survival of the transparent forms was similar to that of wingless bodies and higher than that of fully opaque forms, suggesting a reduction of detectability conferred by transparency. This is the first evidence that transparency decreases detectability in cryptic terrestrial prey. Future studies should explore the organisation of transparent and opaque patches on the animal body and their interplay on survival, as well as the costs and other potential benefits associated to transparency on land.
Doxorubicin-loaded human serum albumin nanoparticles overcome transporter-mediated drug resistance
Authors: Onafuye Hannah , Pieper Sebastian , Mulac Dennis , Cinatl Jindrich , Wass Mark N. , Langer Klaus , Michaelis Martin
Published: May 2019

Resistance to systemic drug therapies is a major reason for the failure of anti-cancer therapies. Here, we tested doxorubicin-loaded human serum albumin (HSA) nanoparticles in the neuroblastoma cell line UKF-NB-3 and its ABCB1-expressing sublines adapted to vincristine (UKF-NB-3rVCR1) and doxorubicin (UKF-NB-3rDOX20). Doxorubicin-loaded nanoparticles displayed increased anti-cancer activity in UKF-NB-3rVCR1and UKF-NB-3rDOX20cells relative to doxorubicin solution, but not in UKF-NB-3 cells. UKF-NB-3rVCR1cells were resensitised by nanoparticle-encapsulated doxorubicin to the level of UKF-NB-3 cells. UKF-NB-3rDOX20cells displayed a more pronounced resistance phenotype than UKF-NB-3rVCR1cells and were not re-sensitised by doxorubicin-loaded nanoparticles to the level of parental cells. ABCB1 inhibition using zosuquidar resulted in similar effects like nanoparticle incorporation, indicating that doxorubicin-loaded nanoparticles circumvent ABCB1-mediated drug efflux. The limited re-sensitisation of UKF-NB-3rDOX20cells to doxorubicin by circumvention of ABCB1-mediated efflux is probably due to the presence of multiple doxorubicin resistance mechanisms. So far, ABCB1 inhibitors have failed in clinical trials, probably because systemic ABCB1 inhibition results in a modified body distribution of its many substrates including drugs, xenobiotics, and other molecules. HSA nanoparticles may provide an alternative, more specific way to overcome transporter-mediated resistance.
Combinatorial prediction of marker panels from single-cell transcriptomic data
Authors: Delaney Conor , Schnell Alexandra , Cammarata Louis V. , Yao-Smith Aaron , Regev Aviv , Kuchroo Vijay K. , Singer Meromit
Published: May 2019

Single-cell transcriptomic studies are identifying novel cell populations with exciting functional roles in variousin vivocontexts, but identification of succinct gene-marker panels for such populations remains a challenge. In this work we introduce COMET, a computational framework for the identification of candidate marker panels consisting of one or more genes for cell populations of interest identified with single-cell RNA-seq data. We show that COMET outperforms other methods for the identification of single-gene panels, and enables, for the first time, prediction of multi-gene marker panels ranked by relevance. Staining by flow-cytometry assay confirmed the accuracy of COMET’s predictions in identifying marker-panels for cellular subtypes, at both the single- and multi-gene levels, validating COMET’s applicability and accuracy in predicting favorable marker-panels from transcriptomic input. COMET is a general non-parametric statistical framework and can be used as-is on various high-throughput datasets in addition to single-cell RNA-sequencing data. COMET is available for use via a web interface (http://www.cometsc.com) or a standalone software package (https://github.com/MSingerlab/COMETSC).
The onset time of balance control during walking is phase-independent, but the magnitude of the response is not
Authors: Reimann Hendrik , Fettrow Tyler , Grenet David , Thompson Elizabeth D. , Jeka John J.
Published: May 2019

The human body is mechanically unstable during walking. Maintaining upright stability requires constant regulation of muscle force by the central nervous system to push against the ground and move the body mass in the desired way. Activation of muscles in the lower body in response to sensory or mechanical perturbations during walking is usually highly phase-dependent, because the effect any specific muscle force has on the body movement depends upon the body configuration. Yet the resulting movement patterns of the upper body after the same perturbations are largely phase-independent. This is puzzling, because any change of upper-body movement must be generated by parts of the lower body pushing against the ground. How do phase-dependent muscle activation patterns along the lower body generate phase-independent movement patterns of the upper body? We hypothesize that in response to a perceived threat to balance, the nervous system generates a functional response by pushing against the ground in any way possible with the current body configuration. This predicts that the changes in the ground reaction force patterns following a balance perturbation should be phase-independent. Here we test this hypothesis by disturbing upright balance using Galvanic vestibular stimulation at three different points in the gait cycle. We measure the resulting changes in whole-body center of mass movement and the location of the center of pressure of the ground reaction force. We find that the whole-body balance response is not phase-independent as expected: balance responses are initiated faster and are smaller following a disturbance late in the gait cycle. Somewhat paradoxically, the initial center of pressure changes are larger for perturbations late in the gait cycle. The onset of the center of pressure changes however, does not depend on the phase of the perturbation. The results partially support our hypothesis of a phase-independent functional balance response underlying the phase-dependent recruitment of different balance mechanisms at different points of the gait cycle. We conclude that the central nervous system recruits any available mechanism to push against the ground to maintain balance as fast as possible in response to a perturbation, but the different mechanisms do not have equal strength.
Neuron Geometry Underlies Universal Network Features in Cortical Microcircuits
Authors: Gal Eyal , Perin Rodrigo , Markram Henry , London Michael , Segev Idan
Published: May 2019

Why do cortical microcircuits in a variety of brain regions express similar, highly nonrandom, network motifs? To what extent this structure is innate and how much of it is molded by plasticity and learning processes? To address these questions, we developed a general network science framework to quantify the contribution of neurons’ geometry and their embedding in cortical volume to the emergence of three-neuron network motifs. Applying this framework to a dense in silico reconstructed cortical microcircuits showed that the innate asymmetric neuron’s geometry underlies the universally recurring motif architecture. It also predicted the spatial alignment of cells composing the different triplets-motifs. These predictions were directly validated via in vitro 12-patch whole-cell recordings (7,309 triplets) from rat somatosensory cortex. We conclude that the local geometry of neurons imposes an innate, already structured, global network architecture, which serves as a skeleton upon which fine-grained structural and functional plasticity processes take place.
Dual Role of Jam3b in Early Hematopoietic and Vascular Development
Authors: Kobayashi Isao , Kobayashi-Sun Jingjing , Hirakawa Yuto , Ouchi Madoka , Yasuda Koyuki , Kamei Hiroyasu , Fukuhara Shigetomo , Yamaguchi Masaaki
Published: May 2019

In order to efficiently derive hematopoietic stem cells (HSCs) from pluripotent precursors, it is crucial to understand how mesodermal cells acquire hematopoietic or endothelial identity due to their close developmental connection. Although Npas4 has been recently identified as a conserved master regulator of hemato-vascular development, the molecular mechanisms underlying the cell fate divergence between hematopoietic and vascular endothelial cells are still unclear. Here, we show in zebrafish that the divergence of hematopoietic and vascular endothelial cells in mesodermal cells is regulated by Junctional adhesion molecule 3b (Jam3b) via two independent signaling pathways. Mutation ofjam3bled to the reduction ofnpas4lexpression in the posterior lateral plate mesoderm and defect of both hematopoietic and vascular development. Mechanistically, we uncover that Jam3b promotes endothelial specification by regulatingnpas4lexpression through the repression of the Rap1a-Erk signaling cascade. Jam3b subsequently promotes hematopoietic development including HSCs by regulatinglrrc15expression in endothelial precursors through the activation of an integrin-dependent signaling cascade. Our data provide insight into the divergent mechanisms for instructing hematopoietic or vascular fates from mesodermal cells.
Parallel accumulation – serial fragmentation combined with data-independent acquisition (diaPASEF): Bottom-up proteomics with near optimal ion usage
Authors: Meier Florian , Brunner Andreas-David , Frank Max , Ha Annie , Bludau Isabell , Voytik Eugenia , Kaspar-Schoenefeld Stephanie , Lubeck Markus , Raether Oliver , Aebersold Ruedi , Collins Ben C. , Röst Hannes L. , Mann Matthias
Published: May 2019

Data independent acquisition (DIA) modes isolate and concurrently fragment populations of different precursors by cycling through segments of a predefined precursor m/z range. Although these selection windows collectively cover the entire m/z range, overall only a few percent of all incoming ions are sampled. Making use of the correlation of molecular weight and ion mobility in a trapped ion mobility device (timsTOF Pro), we here devise a novel scan mode that samples up to 100% of the peptide precursor ion current. We extend an established targeted data extraction workflow by including the ion mobility dimension for both signal extraction and scoring, thereby increasing the specificity for precursor identification. Data acquired from whole proteome digests and mixed organism samples demonstrate deep proteome coverage and a very high degree of reproducibility as well as quantitative accuracy, even from 10 ng sample amounts.
Identification of lumbrokinase by fibrin-plate method, fibrin-zymography and liquid chromatography mass spectrometry
Authors: Ke’ Bingbing , Xian Ruiqing , Jiang Hong , Guo Jianghong
Published: May 2019

Lumbrokinase, extracted from the cultured earthworm ofEisenia fetida, has been widely used as biochemical medicine in China to prevent or treat thrombosis. In the present study, the mechanism of lumbrokinase was investigated using the fibrin plate method. The results revealed that lumbrokinase contained both fibrinolytic and kinase components. The method of fibrin-zymography was used to show the existence and activity of lumbrokinase, and we proved that the fibrin-zymogram gel could be adopted as the identification method of earthworm. Subsequently, the components were identified by mass spectrometry. According to the results, fibrinolytic related components existed in the drug. These proteins were further compared with other serine proteins. The result showed that the identified proteins were similar to human trypsin and bovine trypsin. Besides, some also exhibited similar characteristics with human plasminogen activators. The mentioned results demonstrated that lumbrokinase products contained two major groups of protein components, suggesting two different functions.
The Dps4 fromNostoc punctiformeATCC 29133 is a member of His-type FOC containing Dps protein class that can be broadly found among cyanobacteria
Authors: Howe Christoph , Moparthi Vamsi K. , Ho Felix M. , Persson Karina , Stensjö Karin
Published: May 2019

Dps proteins (DNA-binding proteins from starved cells) have been found to detoxify H2O2. At their catalytic centers, the ferroxidase center (FOC), Dps proteins utilize Fe2+to reduce H2O2and therefore play an essential role in the protection against oxidative stress and maintaining iron homeostasis. Whereas most bacteria accommodate one or two Dps, there are five different Dps proteins inNostoc punctiforme, a phototrophic and filamentous cyanobacterium. This uncommonly high number of Dps proteins implies a sophisticated machinery for maintaining complex iron homeostasis and for protection against oxidative stress. Functional analyses and structural information on cyanobacterial Dps proteins are rare, but essential for understanding the function of each of the NpDps proteins. In this study, we present the crystal structure of NpDps4 in its metal-free, iron- and zinc-bound forms. The FOC coordinates either two iron atoms or one zinc atom. Spectroscopic analyses revealed that NpDps4 could oxidize Fe2+utilizing O2, but no evidence for its use of the oxidant H2O2could be found. We identified Zn2+to be an effective inhibitor of the O2-mediated Fe2+oxidation in NpDps4. NpDps4 exhibits a FOC that is very different from canonical Dps, but structurally similar to the atypical one from DpsA ofThermosynechococcus elongatus. Sequence comparisons among Dps protein homologs to NpDps4 within the cyanobacterial phylum led us to classify a novel FOC class: the His-type FOC. The features of this special FOC have not been identified in Dps proteins from other bacterial phyla and it might be unique to cyanobacterial Dps proteins.
Precession electron diffraction tomography on twinned crystals: application to CaTiO3thin films
Authors: Steciuk Gwladys , David Adrian , Petříček Václav , Palatinus Lukáš , Mercey Bernard , Prellier Wilfrid , Pautrat Alain , Boullay Philippe
Published: May 2019

Strain engineering via epitaxial thin-film synthesis is an efficient way to modify the crystal structure of a material in order to induce new features or improve existing properties. One of the challenges in this approach is to quantify structural changes occurring in these films. While X-ray diffraction is the most widely used technique for obtaining accurate structural information from bulk materials, severe limitations appear in the case of epitaxial thin films. This past decade, precession electron diffraction tomography has emerged as a relevant technique for the structural characterization of nano-sized materials. While its usefulness has already been demonstrated for solving the unknown structure of materials deposited in the form of thin films, the frequent existence of orientation variants within the film introduces a severe bias in the structure refinement, even when using the dynamical diffraction theory to calculate diffracted intensities. This is illustrated here using CaTiO3films deposited on SrTiO3substrates as a case study. By taking into account twinning in the structural analysis, it is shown that the structure of the CaTiO3films can be refined with an accuracy comparable to that obtained by dynamical refinement from non-twinned data. The introduction of the possibility to handle twin data sets is undoubtedly a valuable add-on and, notably, paves the way for a successful use of precession electron diffraction tomography for accurate structural analyses of thin films.
Bis(4-acetoxy-N,N-dimethyltryptammonium) fumarate: a new crystalline form of psilacetin, an alternative to psilocybin as a psilocin prodrug
Authors: Chadeayne Andrew R. , Golen James A. , Manke David R.
Published: May 2019

The title compound (systematic name: bis{2-[4-(acetyloxy)-1H-indol-3-yl]ethan-1-aminium} but-2-enedioate), 2C14H19N2O2
+·C4H2O4
2−, has a single protonated psilacetin cation and one half of a fumarate dianion in the asymmetric unit. There are N—H...O hydrogen bonds between the ammonium H atoms and the fumarate O atoms, as well as N—H...O hydrogen bonds between the indole H atoms and the fumarate O atoms. The hydrogen bonds hold the ions together in infinite one-dimensional chains along [111].
Institutional drivers of environmental management accounting adoption in public sector water organisations
Authors: Imtiaz Ferdous Mohammad , Adams Carol A. , Boyce Gordon
Published: May 2019

Purpose

The purpose of this paper is to examine the influences on the adoption of environmental management accounting (EMA) in corporatised water supply organisations, from an institutional theory perspective, drawing on the concepts of reflexive isomorphism and institutional logics.

Design/methodology/approach

The primary research involves case analysis of three companies in the Australian water supply industry, drawing on interviews, internal documents and publicly available documents, including annual reports.

Findings

Two key drivers for the adoption and emergence of EMA are: the emergence of a government regulator in the form of the Essential Services Commission (ESC) and community expectations with regard to environmental performance and disclosure. The water organisations were found to be reflexively isomorphic, while seeking to align their commercial logic to “sustainability” and “ensuring community expectations” logics to the legitimate adoption of EMA.

Originality/value

The paper contributes to the literature by providing case study evidence of the intentions and motivations of management in adopting EMA, and the nature of that adoption process over an extended period. Further, it provides empirical evidence of the applicability of reflexive isomorphism in the context of EMA and institutional logics.
Accounting and the enactment of power: municipal reform by Peter Leopold 1774–1775
Authors: Maran Laura , Funnell Warwick , Castellini Monia
Published: May 2019

Purpose

The purpose of this paper is to understand the enduring, fundamental contributions of accounting practices in the pursuit of decentralization by governments, with an examination of Peter Leopold’s reform of the municipalities in the late eighteenth century in Italy.

Design/methodology/approach

An extensive textual analysis of the very comprehensive collection of primary sources of the Grand Duchy of Tuscany during the de’ Medici and Hapsburg-Lorraine’s rule identified the reasons for Peter Leopold’s decision to decentralize his government’s authority and responsibilities. A systemic comparison of the 1765–1766 and 1775–1776 financial reports of the Municipality of Castrocaro and Terra del Sole disclosed the importance of the micro-practices of accounting and reporting for the reform.

Findings

In the context of the eighteenth century enlightenment, Peter Leopold legitimized his reform by the introduction of a modern style of government based on the rationalization of the municipal administrative system and decentralization of central authority and responsibility. The reform was made feasible by the substitution of a birth right principle with an economic discourse which linked tax payments to property ownership. This had the unintended consequence of increased taxes, higher municipal expenditures and possible inequalities between municipalities.

Research limitations/implications

The findings of the study are dependent on the resources which have survived and are now preserved in the official archives of Galeata and Florence. This work contributes to the extant literature on administrative reforms in a crucial period for the redefinition of sovereignty by the ruling classes, with the rise of the modern State. It extends historical understanding of the public sector with a focus on local government in the eighteenth century in a non-Anglo-Saxon context.

Practical implications

The examination of the reform of Peter Leopold contributes to an enhanced understanding of present-day decentralization by governments in the context of the new public management (NPM). It provides to NPM advocates a broader temporal and contextual understanding of the impact of current decentralization reforms.

Originality/value

Few accounting studies have considered the micro-aspects of decentralization reforms at the municipal level and tried to identify their impact on the wealth of the population. Moreover, Peter Leopold’s reform is considered one of the most innovative and enlightened of the eighteenth century, while the remainder of Europe was still overwhelmingly committed to the centralization of administrative apparatuses. Finally, this study relates to the multi-disciplinary debate about the recognition, qualification and accountization of the impact of decentralization of responsibility for the delivery of government services.