bluuebunny/crossref_metadata_2025 huggingface dataset:
Study for Cephalometrics of Facial Bone by Computerized Tomography Images
Authors: Yi Chang Ryul , Choi Young Woong
Published: October 2019

Authors tried to investigate the maxillomandibular morphology of Korean nationality with computerized tomography images and establish a series of cephalometric values which should be considered in orthognathic plastic surgery in Korea.

The computerized tomography images of 200 patients were retrospectively reviewed with the computer workstation in Sanggye Paik Hospital, Inje University College of Medicine from 2016 to 2017.

The mean distance between nasion to point A (NA) line and the maxillary central incisor was 5.07 cm. The mean distance from nasion to point B (NB) line to the mandibular central incisor was 7.11 cm. The mean angle between NA line and the long axis of the maxillary central incisor was 20.58 degree. The mean angle between NB line and the long axis of the mandibular central incisor was 26.47 degree. The mean angle between SN (sella to nasion) line and NA line was 83.18 degree. The mean angle between SN line and NB line was 78.83 degree. The mean angle between NA line and NB line was 4.35 degree. There were no any statistically significant differences between age groups. But there were statistically significant difference in the mean of angle between NB line and the long axis of the mandibular central incisor (P = 0.025, between sex groups) and in the mean of angle between NA line and the long axis of the maxillary central incisor between sex groups in the 51 to 60 age group (P = 0.045).

The maxillomandibular profile of Korean adults was established which can be applied for orthognathic surgery of Korean patients.
Learning Impacts of Pretraining Video-Assisted Debriefing With Simulated Errors or Trainees' Errors in Medical Students in Basic Life Support Training
Authors: Li Qi , Lin Jing , Fang Li-Qun , Ma Er-Li , Liang Peng , Shi Ting-Wei , Xiao Hong , Liu Jin
Published: October 2019

Background

Previous studies demonstrated that pretraining video-assisted debriefing (VAD) with trainees' errors (TE) videotaped in a skills pretest improved skill learning of basic life support (BLS). However, conducting a pretest and preparing TE video examples is resource intensive. Exposing individual trainee's errors to peers might be a threat to learners' psychological safety. We hypothesized pretraining VAD with simulated errors (SE, performed by actors) might have the same beneficial effect on skills learning as pretraining VAD with TE, but avoid drawbacks of TE.

Methods

Three hundred twenty-two third-year medical students were randomized into 3 groups (the control [C], TE, SE). A videotaped BLS skills pretest was conducted in 3 groups. Then, group C received traditional training with concurrent feedback. Video-assisted debriefing with TE in the pretest or SE was delivered in groups TE or SE, respectively, followed by BLS training without any feedback. Basic life support skills were retested 1 week later (posttest). Students completed a survey to express their preference to TE or SE for VAD in the future.

Results

Higher BLS skills scores were observed in groups TE (85.7 ± 7.0) and SE (86.8 ± 7.5) in the posttest, compared with group C (68.7 ± 13.3, P < 0.001). No skills difference was observed between group TE and SE in the posttest. More trainees (65.8%) preferred SE for VAD.

Conclusions

Pretraining VAD with SE had an equivalent beneficial effect as VAD with TE on BLS skills learning in medical students. More trainees preferred SE for VAD with regard to psychological safety.
Cognitive and Physical Factors Affecting High-Speed Driving Ability in Older Adults
Authors: Shih Huei-Yu , Chu I-Hua , Wang Chih-Chung , Liaw Lih-Jiun , Hsu Hsiu-Tao , Wu Wen-Lan
Published: October 2019

Background and Purpose:

The ability to drive is important for the elderly to maintain their mobility and independence. Therefore, to investigate age-related changes in driving-related functions and their relation to the braking ability of drivers driving at high speeds, subjects were organized by age into study groups (younger, middle-aged, and older).

Methods:

For a correlational comparative study, 36 male participants were recruited and instructed to complete the Assessment of Driving-Related Skills (ADReS), lower limbs muscle test, and driving tasks on a driving simulator under 3 speed conditions. For the driving tasks, 3 event phases were analyzed: perception-reaction time (PRT), brake-movement time, and fast pressing time.

Results:

Older drivers demonstrated a significant decline in certain driving-related cognitive and motor abilities, as well as hip flexion and knee extension muscle strength, and exhibited a significantly longer PRT under moderate- and high-speed conditions compared with younger drivers. A longer PRT under moderate- and high-speed conditions was significantly associated with poor driving-related cognitive and motor abilities.

Conclusion:

The increased PRT for older drivers under moderate- and high-speed conditions might increase their risk of vehicular accidents on highways.
Effectiveness of Chair Yoga for Improving the Functional Fitness and Well-being of Female Community-Dwelling Older Adults With Low Physical Activities
Authors: Yao Ching-Teng , Tseng Chien-Hsing
Published: October 2019

Objective:

This study investigated the effect of a 12-week chair yoga program on functional fitness and well-being in community-dwelling older women with low physical activities.

Methods:

A total of 31 community-dwelling older women with low physical activity participated in this quasi-experimental study. Two communities of the elderly were allocated to 2 groups through lot drawing. Subjects were randomly assigned to control or intervention groups by community to avoid contamination—the experimental group of 16 people and the control group of 15 people. The participants in the experimental group trained chair yoga exercise for 12 weeks with 2 sessions per week, 110 minutes per session, whereas the control group maintained its regular daily activities. Data collection from multiple variables was conducted using questionnaire (well-being) and examination on functional fitness (handgrip strength, lower limb muscle strength, upper limb muscle strength, static balance, agility and dynamic balance, lower limb flexibility, upper limb flexibility).

Results:

The results showed a significant improvement for the experimental group in the handgrip strength (P = .001), upper limb muscle strength (P = .047), lower limb muscle strength (P = .007), static balance (P = .016), agility and dynamic balance (P = .009), and in the well-being (P = .003) after the intervention. The control group reveals deteriorated result in upper limb muscle strength (P = .016). Among other functional fitness and well-being variables, there is no significant difference.

Conclusion:

The chair yoga training provides a simple and inexpensive exercise program that improves the functional fitness and well-being effectively.
Combining Multifactorial Assessment Tools and Dimensionality Reduction Analysis for Fall Risk Classification in Community-Dwelling Older Adults
Authors: Lin I-Ching , Yang Chia-Chi , Lai Yi-Horng , Guo Lan-Yuen
Published: October 2019

Background and Purpose:

Optimal approaches in fall risk assessment involve interdisciplinary collaboration of assessment. This current work aimed at screening the fall risk characteristics from the objective balance and mobility tests between older fallers and nonfallers and further assessing the feasibility of 2 statistical dimensionality reduction models, Linear Discriminant Analysis (LDA) and Generalized Discriminant Analysis (GDA) for discriminating older nonspecific fallers. We hypothesized that the high-dimensionality objective sensor-based parameters, followed by a feature selection and dimensionality reduction process, would be able to discriminate older nonspecific fallers.

Methods:

Thirty-one community-living older individuals who were older than 60 years (faller: n = 15; nonfaller: n = 16) were recruited. The measurements include gait, balance, and ankle proprioception performances. LDA and GDA were further applied to obtain more discriminative feature space. Receiver-operating characteristic (ROC) curves were constructed to compare the classification quality in all the features.

Results:

Although some features in single objective measure reached statistical significance, the original features still resulted in high within-class and low between-class variances in the feature space. By further applying LDA and GDA on the original features, the performance of LDA in the feature space was improved. The area under the curve of ROC was GDA dimensionality reduction feature (1), LDA dimensionality reduction feature (0.99), proprioception (0.752), inertial measurement unit (0.745), and center of pressure (0.72), respectively.

Conclusions:

Experimental results showed the GDA feature has the best classification quality and the additional advantage in combination of interdisciplinary multifactorial fall risk assessment.
Spinal Cord Ischemia in Pancreas Transplantation: The UK Experience
Authors: Phillips Benedict L. , Papadakis Georgios , Bell Rachel , Sinha Sanjay , Callaghan Chris J. , Akyol Murat , Watson Christopher J.E. , Drage Martin
Published: October 2019

Background.

Spinal cord ischemia (SCI) is a rare but devastating condition that can occur in the perioperative period resulting in paraplegia. Although diabetes mellitus is a risk factor for SCI in other types of major surgery, SCI is not widely recognized in transplantation. The aim of this study was to quantify the risk of SCI in pancreatic transplantation.

Methods.

All UK pancreas transplant units were surveyed between 2017 and 2018. The risk of SCI in pancreas transplantation was estimated using the number of radiologically confirmed cases relative to the number of pancreatic transplants from UK registry data during the same time period.

Results.

There have been 6 cases of SCI during pancreas transplantation since 2002. No aortic clamping occurred in any recipient. During or after surgery, all patients experienced episodes of hypotension (systolic blood pressure ≤ 90 mm Hg) before the onset of neurological symptoms. Epoprostenol, epidural anesthesia, and postoperative hemodialysis may have contributed to systemic hypotension. The mainstay of early treatment for SCI for all cases was blood pressure control.

Conclusions.

Based on these findings, there is approximately a 1:440 risk of SCI in pancreas transplantation. Hypotension appears to be a prominent risk factor. Strategies for mitigating the risk of SCI are discussed, drawing on evidence from thoraco-abdominal aortic aneurysm surgery. The risk of long-term neurological deficit should be discussed with prospective pancreas recipients given the potential impact on posttransplant quality of life.
DSA Are Associated With More Graft Injury, More Fibrosis, and Upregulation of Rejection-associated Transcripts in Subclinical Rejection
Authors: Höfer Anne , Jonigk Danny , Hartleben Björn , Verboom Murielle , Hallensleben Michael , Hübscher Stefan G. , Manns Michael P. , Jaeckel Elmar , Taubert Richard
Published: October 2019

Background.

Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation.

Methods.

To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance, and immune regulation was analyzed in 77 biopsies with “no histologic rejection” (NHR; n = 25), “clinical TCMR” (cTMCR; n = 16), and subTCMR (n = 36). In addition, all available subTCMR biopsies (n = 71) were tested for DSA with bead assays.

Results.

SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR. DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR-associated transcripts. In nonsupervised analysis, DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR.

Conclusions.

T cell-mediated rejection seems to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR-associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection-associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
Atorvastatin attenuates spinal cord injury by chronic fluorosis in rats
Authors: Shen Qingfeng , Cao Yangjing , Xia Yingpeng
Published: October 2019

The aim of the study was to explore the effect of atorvastatin on improvement of the function of the spinal cord in rats with chronic fluorosis. Sixty 3-month-old Wistar rats were separated randomly into three groups: normal group (N group), control group (C group) and atorvastatin group (A group). The Basso Beattie and Bresnahan scale and oblique board test showed that the rats in A group got higher score and better hind-limb motor function than C group. Immunohistochemistry and western blotting revealed that compared with N group, matrix metalloproteinase 9 (MMP-9) and p53 were highly expressed and myelin basic protein (MBP) was low expressed in spinal cord of C group. Meanwhile, MMP-9 and p53 expression were decreased and MBP was upregulated by atorvastatin compared with C group. In conclusion, the improvement of the function of the spinal cord in rats can be found when they were treated with atorvastatin.
The Financial Impact of Living in Canada With an Ostomy
Authors: LeBlanc Kimberly , Heerschap Corey , Martins Lina , Butt Britney , Wiesenfeld Samantha , Woo Kevin
Published: October 2019

PURPOSE:

The aim of this study was to explore how living with an ostomy financially impacts Canadians.

METHODS:

A descriptive, pan-Canadian, cross-sectional online and paper-based survey was conducted using a convenience sample.

RESULTS:

Surveys were completed by 467 individuals. Seventy-six percent (n = 355) reported spending more than $1000 annually on ostomy supplies, with 58% (n = 271) paying partially out of pocket. Atlantic regions relied primarily on insurance (n = 81), and the central, prairies, and western regions used a combination of funding (provincial government funding and/or insurance) (n = 385) with no significant out-of-pocket funding differences between regions (χ2 = 18.267, P = .079). Fifteen percent (n = 70) reported frequent peristomal skin problems, and 19% (n = 89) indicated that having an ostomy negatively affected their ability to work. When experiencing ostomy-related problems, 60% (n = 280) sought assistance from a nurse specialized in wound, ostomy, and continence (NSWOC) and spent significantly less on ostomy supplies (χ2 = 231.267, P < .001).

CONCLUSION:

This study demonstrated that living with an ostomy may result in financial burden and that Canadian regional variations in funding and access to an NSWOC should be explored.
Functional MRI connectivity accurately distinguishes cases with psychotic disorders from healthy controls, based on cortical features associated with neurodevelopment
Authors: Morgan Sarah E , Young Jonathan , Patel Ameera X , Whitaker Kirstie J , Scarpazza Cristina , van Amelsvoort Therese , Marcelis Machteld , van Os Jim , Donohoe Gary , Mothersill David , Corvin Aiden , Arango Celso , Mechelli Andrea , van den Heuvel Martijn , Kahn René S , McGuire Philip , Brammer Michael , Bullmore Edward T
Published: October 2019

Background

Machine learning (ML) can distinguish cases with psychotic disorder from healthy controls based on magnetic resonance imaging (MRI) data, with reported accuracy in the range 60-100%. It is not yet clear which MRI metrics are the most informative for case-control ML.

Methods

We analysed multi-modal MRI data from two independent case-control studies of patients with psychotic disorders (cases, N = 65, 28; controls, N = 59, 80) and compared ML accuracy across 5 MRI metrics. Cortical thickness, mean diffusivity and fractional anisotropy were estimated at each of 308 cortical regions, as well as functional and structural connectivity between each pair of regions. Functional connectivity data were also used to classify non-psychotic siblings of cases (N=64) and to distinguish cases from controls in a third independent study (cases, N=67; controls, N = 81).

Results

In both principal studies, the most diagnostic metric was fMRI connectivity: the areas under the receiver operating characteristic curve were 92% and 77%, respectively. The cortical map of diagnostic connectivity features was replicable between studies (r = 0.31, P < 0.001); correlated with replicable case-control differences in fMRI degree centrality, and with prior cortical maps of aerobic glycolysis and adolescent development of functional connectivity; predicted intermediate probabilities of psychosis in siblings; and replicated in the third case-control study.

Conclusions

ML most accurately distinguished cases from controls by a replicable pattern of fMRI connectivity features, highlighting abnormal hubness of cortical nodes in an anatomical pattern consistent with the concept of psychosis as a disorder of network development.
Evaluation of the General Practice Pharmacist (GPP) intervention to optimise prescribing in Irish primary care: a non-randomised pilot study
Authors: Cardwell Karen , Smith Susan M , Clyne Barbara , McCullagh Laura , Wallace Emma , Kirke Ciara , Fahey Tom , Moriarty Frank
Published: October 2019

Objective

Limited evidence suggests integration of pharmacists into the general practice team could improve medicines management for patients, particularly those with multimorbidity and polypharmacy. This study aimed to develop and assess the feasibility of an intervention involving pharmacists, working within general practices, to optimise prescribing in Ireland.

Design

Non-randomised pilot study

Setting

Primary care in Ireland

Participants

Four general practices, purposively sampled and recruited to reflect a range of practice sizes and demographic profiles.

Intervention

A pharmacist joined the practice team for six months (10 hours/week) and undertook medication reviews (face-to-face or chart-based) for adult patients, provided prescribing advice, supported clinical audits, and facilitated practice-based education.

Outcome measures

Anonymised practice-level medication (e.g. medication changes) and cost data were collected. Patient-Reported Outcome Measure (PROM) data were collected on a subset of older adults (aged ≥65 years) with polypharmacy using patient questionnaires, before and six weeks after medication review by the pharmacist.

Results

Across four practices, 787 patients were identified as having 1,521 prescribing issues by the pharmacists. Issues relating to potentially inappropriate or high-risk prescribing were addressed most often by the prescriber (51.8%), compared to cost-related issues (7.5%). Medication changes made during the study equated to approximately €57,000 in cost savings assuming they persisted for 12 months. Ninety-six patients aged ≥65 years with polypharmacy were recruited from the four practices for PROM data collection and 64 (66.7%) were followed up. There were no changes in patients’ treatment burden or attitudes to deprescribing following medication review, and there were conflicting changes in patients’ self-reported quality of life.

Conclusions

This non-randomised pilot study demonstrated that an intervention involving pharmacists, working within general practices is feasible to implement and has potential to improve prescribing quality. This study provides rationale to conduct a randomised controlled trial to evaluate the clinical and cost-effectiveness of this intervention.

Article summary

Strengths and limitations of this study

This is the first study examining the role of general practice-based pharmacists in Ireland and the feasibility of evaluating this role.

Integration of pharmacists was limited to four general practices, although these were diverse in terms of practice characteristics.

A range of medication and patient-reported outcome measures data were collected, although because this was a pilot study there was no control group to compare these to.
DeepProg: an ensemble of deep-learning and machine-learning models for prognosis prediction using multi-omics data
Authors: Poirion Olivier , Jing Zheng , Chaudhary Kumardeep , Huang Sijia , Garmire Lana X.
Published: October 2019

Multi-omics data are good resources for prognosis and survival prediction, however, these are difficult to integrate computationally. We introduce DeepProg, a novel ensemble framework of deep-learning and machine-learning approaches that robustly predicts patient survival subtypes using multi-omics data. It identifies two optimal survival subtypes in most cancers and yields significantly better risk-stratification than other multi-omics integration methods. DeepProg is highly predictive, exemplified by two liver cancer (C-index 0.73-0.80) and five breast cancer datasets (C-index 0.68-0.73). Pan-cancer analysis associates common genomic signatures in poor survival subtypes with extracellular matrix modeling, immune deregulation, and mitosis processes. DeepProg is freely available at https://github.com/lanagarmire/DeepProg
An iterative and automated computational pipeline for untargeted strain-level identification using MS/MS spectra from pathogenic samples
Authors: Kuhring Mathias , Doellinger Joerg , Nitsche Andreas , Muth Thilo , Renard Bernhard Y.
Published: October 2019

Untargeted accurate strain-level classification of a priori unidentified organisms using tandem mass spectrometry is a challenging task. Reference databases often lack taxonomic depth, limiting peptide assignments to the species level. However, the extension with detailed strain information increases runtime and decreases statistical power. In addition, larger databases contain a higher number of similar proteomes.

We present TaxIt, an iterative workflow to address the increasing search space required for MS/MS-based strain-level classification of samples with unknown taxonomic origin. TaxIt first applies reference sequence data for initial identification of species candidates, followed by automated acquisition of relevant strain sequences for low level classification. Furthermore, proteome similarities resulting in ambiguous taxonomic assignments are addressed with an abundance weighting strategy to improve candidate confidence.

We apply our iterative workflow on several samples of bacterial and viral origin. In comparison to non-iterative approaches using unique peptides or advanced abundance correction, TaxIt identifies microbial strains correctly in all examples presented (with one tie), thereby demonstrating the potential for untargeted and deeper taxonomic classification. TaxIt makes extensive use of public, unrestricted and continuously growing sequence resources such as the NCBI databases and is available under open-source license at https://gitlab.com/rki_bioinformatics.
RNase 2/EDN cleaves the anticodon loops of tRNAs to produce immunostimulatory tRNA halves in asthma
Authors: Shigematsu Megumi , Kawamura Takuya , Shah Sushrut D. , Deshpande Deepak A. , Kirino Yohei
Published: October 2019

Asthma, the most prevalent chronic inflammatory airway disease, develops due to allergen-induced airway inflammation driven by various mediators, including proinflammatory cytokines. Our research shows that inhalation of house dust mite (HDM) in mice leads to a significant increase in the levels of tRNA half molecules in asthmatic lungs. Transcriptomic analyses of ribonucleases unequivocally identifiedEar11(RNase 2a/Edn) as the most responsive endoribonuclease to HDM exposure. Indeed, human EDN is taken up by lung epithelial cells and cleaves the anticodon loops of mature tRNAs to produce tRNA halves. These tRNA halves, abundantly generated by EDN, include immunostimulatory species that promote the production of proinflammatory cytokine by activating Toll-like receptor 7. Reconstitution of thein vitroEDN-mediated RNA cleavage system elucidated specific positional and nucleotide preferences within the tRNA anticodon loop, providing a molecular basis for the generation of specific tRNA halves. These findings represent a previously overlooked, yet potentially critical, factor in the induction of cytokines during the pathogenesis of asthma.
Combining metabarcoding and morphological approaches to identify phytoplankton taxa associated with harmful algal blooms
Authors: Esenkulova Svetlana , Sutherland Ben J.G. , Tabata Amy , Haigh Nicola , Pearce Christopher M. , Miller Kristina M.
Published: October 2019

Molecular techniques are expected to be highly useful in detecting taxa causing harmful algal blooms (HABs). This is the first report in Canada evaluating HABs-related species identification using a combination of morphological and molecular approaches. Microscopy, quantitative polymerase chain reaction (qPCR), and metabarcoding with multiple markers (i.e.16S, 18S-dinoflagellate and 18S-diatom, large subunit (28S) rDNA) were applied on samples (n=54) containing suspected harmful algae (e.g.Alexandriumspp.,Chattonellasp.,Chrysochromulinaspp.,Dictyochaspp.,Heterosigma akashiwo,Protoceratium reticulatum,Pseudochattonella verruculosa, Pseudo-nitzschiaspp.,Pseudopedinellasp.). Due to methodology limitations, qPCR result interpretation was limited, although good detectability occurred using previously published assays forAlexandrium tamarense,H. akashiwo, andP. verruculosa. Overall, the multiple-marker metabarcoding results were superior to the morphology-based methods, with the exception of taxa from the silicoflagellate group. The combined results using both 18S markers and the 28S marker together closely corresponded with morphological identification of targeted species, providing the best overall taxonomic coverage and resolution. The most numerous unique taxa were identified using the 18S-dinoflagellate amplicon, and the best resolution to the species level occurred using the 28S amplicon. Molecular techniques are therefore highly useful for HABs taxa detection, but currently depend on deploying multiple markers for metabarcoding.
Constitutive Expression of the Progesterone Receptor Isoforms Promotes Hormone-Dependent Development of Ovarian Neoplasms
Authors: Wetendorf Margeaux , Li Rong , Wu San-Pin , Liu Jian , Creighton Chad J. , Wang Tianyuan , Janardhan Kyathanahalli S. , Willson Cynthia J. , Lanz Rainer B. , Murphy Bruce D. , Lydon John P. , DeMayo Francesco J.
Published: October 2019

Abnormal expression of the progesterone receptor (PGR) isoforms, PGRA and PGRB, is often observed in women with reproductive tract cancer. To assess the importance of the PGR isoform ratio in the maintenance of the healthy reproductive tract, mice with Cre recombinase- activated PGRA and PGRB transgenes were bred with the PGRCremouse model to generate strains expressing either PGRA or PGRB in PGR positive tissues. The PGRB mice developed ovarian neoplasms at 23 weeks of age derived from ovarian luteal cells, while the PGRA expressing mice displayed a reduced frequency of tumor development. Transcriptomic analyses of the ovarian tumors revealed an enhanced AKT pathway signature, which is in agreement with expression changes found in human ovarian adenocarcinoma. Effective treatment with the PGR antagonist RU486 reduced tumor growth and the expression of cell cycle genes. We concluded that tumor growth and proliferation is hormone and PGR isoform dependent. Further analysis of the PGRB cistrome identified binding events of critical mitotic phase entry genes. This work suggests an intriguing mechanism whereby the expression of the PGR isoforms determinesin vivoneoplasia through high-jacking of the cell cycle pathway.
A CTP-dependent gating mechanism enables ParB spreading on DNA
Authors: Jalal Adam S. B. , Tran Ngat T. , Stevenson Clare. E. M. , Chimthanawala Afroze , Badrinarayanan Anjana , Lawson David M. , Le Tung B. K.
Published: October 2019

Proper chromosome segregation is essential in all living organisms. The ParA-ParB-parS system is widely employed for chromosome segregation in bacteria. Previously, we showed that Caulobacter crescentus ParB requires cytidine triphosphate to escape the nucleation site parS and spread by sliding to the neighboring DNA 1. Here, we provide the structural basis for this transition from nucleation to spreading by solving co-crystal structures of a C-terminal domain truncated C. crescentus ParB with parS and with a CTP analog. Nucleating ParB is an open clamp, in which parS is captured at the DNA-binding domain (the DNA-gate). Upon binding CTP, the N-terminal domain (NTD) self-dimerizes to close the NTD-gate of the clamp. The DNA-gate also closes, thus driving parS into a compartment between the DNA-gate and the C-terminal domain. CTP hydrolysis and/or the release of hydrolytic products are likely associated with re-opening of the gates to release DNA and to recycle ParB. Overall, we suggest a CTP-operated gating mechanism that regulates ParB nucleation, spreading, and recycling.
A consensus phylogenomic approach highlights paleopolyploid and rapid radiation in the history of Ericales
Authors: Larson Drew A. , Walker Joseph F. , Vargas Oscar M. , Smith Stephen A.
Published: October 2019

Premise of study

Large genomic datasets offer the promise of resolving historically recalcitrant species relationships. However, different methodologies can yield conflicting results, especially when clades have experienced ancient, rapid diversification. Here, we analyzed the ancient radiation of Ericales and explored sources of uncertainty related to species tree inference, conflicting gene tree signal, and the inferred placement of gene and genome duplications.

Methods

We used a hierarchical clustering approach, with tree-based homology and orthology detection, to generate six filtered phylogenomic matrices consisting of data from 97 transcriptomes and genomes. Support for species relationships was inferred from multiple lines of evidence including shared gene duplications, gene tree conflict, gene-wise edge-based analyses, concatenation, and coalescent-based methods and is summarized in a consensus framework.

Key Results

Our consensus approach supported a topology largely concordant with previous studies, but suggests that the data are not capable of resolving several ancient relationships due to lack of informative characters, sensitivity to methodology, and extensive gene tree conflict correlated with paleopolyploidy. We found evidence of a whole genome duplication before the radiation of all or most ericalean families and demonstrate that tree topology and heterogeneous evolutionary rates impact the inferred placement of genome duplications.

Conclusions

Our approach provides a novel hypothesis regarding the history of Ericales and confidently resolves most nodes. We demonstrate that a series of ancient divergences are unresolvable with these data. Whether paleopolyploidy is a major source of the observed phylogenetic conflict warrants further investigation.
Dopamine buffering capacity imaging: A pharmacodynamic fMRI method for staging Parkinson disease
Authors: Black Kevin J. , Acevedo Haley K. , Koller Jonathan M.
Published: October 2019

We propose a novel brain imaging method for objectively quantifying disease severity in Parkinson disease (PD). Levodopa pharmacological fMRI (phMRI) hysteresis mapping is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled previously based on clinical effects, but clinical measurements are influenced by confounding factors such as patient fatigue. The new method proposes to measure the effect directly and objectively based on the timing of the known metabolic and blood flow response of several brain regions to exogenous levodopa. Such responses are robust and can be quantified without ionizing radiation using perfusion MRI.

Here we present simulation studies based on published clinical dose-response data and an intravenous levodopa infusion. Standard pharmacokinetic-pharmacodynamic methods were used to model the response. Then the effect site rate constant ke was estimated from simulated response data plus Gaussian noise.

Predicted time:effect curves sampled at times consistent with phMRI differ substantially based on clinical severity. Estimated ke from noisy input data was recovered with good accuracy.

These simulation results support the feasibility of levodopa phMRI hysteresis mapping to measure the severity of dopamine denervation objectively and simultaneously in several brain regions.
Correlating surface plasmon resonance microscopy of living and fixated cells with electron microscopy allows for investigation of potential preparation artifacts
Authors: Kreysing Eva , Seyock Silke , Hassani Hossein , Brauweiler-Reuters Elke , Neumann Elmar , Offenhäusser Andreas
Published: October 2019

Abstract

The investigation of the cell-substrate interface is of great importance for a broad spectrum of areas such as biomedical engineering, brain-chip interfacing and fundamental research. Due to its unique resolution and the prevalence of instruments, electron microscopy (EM) is used as one of the standard techniques for the analysis of the cell-substrate interface. However, possible artifacts that might be introduced by the required sample preparation have been the subject of speculation for decades. Due to recent advances in Surface plasmon resonance microscopy (SPRM), the technique now offers a label-free alternative for the interface characterization with nanometer resolution in axial direction. In contrast to EM, SPRM studies do not require fixation and can therefore be performed on living cells. Here, we present a workflow that allows us to quantify the impact of chemical fixation on the cell-substrate interface. These measurements confirmed that chemical fixation preserved the average cell-substrate distances in the majority of studied cells. Furthermore, we were able to correlate the SPRM measurements with EM images of the cell-substrate interface of the exact same cells allowing us to identify regions with good agreement between the two methods and reveal artifacts introduced during further sample preparation.
Meta-analysis of the General Coral Stress Response:Acroporacorals show opposing responses depending on stress intensity
Authors: Dixon Groves , Abbott Evelyn , Matz Mikhail
Published: October 2019

As climate change progresses, reef-building corals must contend more often with suboptimal conditions, motivating a need to understand coral stress response. Here we test the hypothesis that there is a stereotyped transcriptional response that corals enact under any stressful conditions, functionally characterized by downregulation of growth and activation of cell death, response to reactive oxygen species, immunity, and protein homeostasis. We analyze RNA-seq and Tag-Seq data from 14 previously published studies and supplement them with four new experiments involving different stressors, totaling over 600 gene expression profiles from the genusAcropora. Contrary to expectations, we found not one, but two distinct types of response. The type A response was observed under all kinds of high-intensity stress, showed strong correlations between independent projects, and was functionally consistent with the hypothesized stereotyped response. Higher similarity of type A responses irrespective of stress type supports its role as the General Coral Stress Response providing a blanket solution to severely stressful conditions. The distinct type B response was observed under lower intensity stress and was weaker and more variable among studies than type A. Unexpectedly, the type B response was broadly opposite the type A response: biological processes up-regulated under type A response tended to be down-regulated under type B response, and vice versa. Gene network analysis indicated that type B response does not involve specific co-regulated gene groups and is simply the opposite of type A response. We speculate that these paradoxically opposing responses may result from an inherent negative association between stress response and cell proliferation.
Multi-proxy analyses of a mid-15th century ‘Middle Iron Age’ Bantu-speaker palaeo-faecal specimen elucidates the configuration of the ‘ancestral’ sub-Saharan African intestinal microbiome
Authors: Rifkin Riaan F. , Vikram Surendra , Ramond Jean-Baptiste , Rey-Iglesia Alba , Brand Tina B. , Porraz Guillaume , Val Aurore , Hall Grant , Woodborne Stephan , Bailly Matthieu Le , Potgieter Marnie , Underdown Simon J. , Koopman Jessica E. , Cowan Don A. , Van de Peer Yves , Willerslev Eske , Hansen Anders J.
Published: October 2019

The archaeological incidence of ancient human faecal material provides a rare opportunity to explore the taxonomic composition and metabolic capacity of the ancestral human intestinal microbiome (IM). Following the recovery of a single desiccated palaeo-faecal specimen from Bushman Rock Shelter in Limpopo Province, South Africa, we applied a multi-proxy analytical protocol to the sample. Our results indicate that the distal IM of the Neolithic ‘Middle Iron Age’ (c. AD 1485) Bantu-speaking individual exhibits features indicative of a largely mixed forager-agro-pastoralist diet. Subsequent comparison with the IMs of the Tyrolean Iceman (Ötzi) and contemporary Hadza hunter-gatherers, Malawian agro-pastoralists and Italians, reveals that this IM precedes recent adaptation to ‘Western’ diets, including the consumption of coffee, tea, chocolate, citrus and soy, and the use of antibiotics, analgesics and also exposure to various toxic environmental pollutants. Our analyses reveal some of the causes and means by which current human IMs are likely to have responded to recent dietary changes, prescription medications and environmental pollutants, providing rare insight into human IM evolution following the advent of the Neolithic c. 12,000 years ago.
Evolution of CDK1 paralog specializations in a lineage with fast developing planktonic embryos
Authors: Ma Xiaofei , Øvrebø Jan Inge , Thompson Eric M
Published: October 2019

The active site of the essential, eukaryotic CDK1 kinase is generated by core structural elements, among which the PSTAIRE motif in the critical αC-helix, is universally conserved in metazoans. The CDK2 kinase, sharing the PSTAIRE, arose early in metazoan evolution and permitted subdivision of tasks along the S-M-phase axis. The marine chordate,Oikopleura dioica, is the only metazoan known to possess more than a single CDK1 ortholog, and all of its 5 paralogs show sequence divergences in the PSTAIRE. Through assessing CDK1 gene duplications in the appendicularian lineage, we show that the CDK1 activation loop substrate binding platform, ATP entrance site, hinge region, and main Cyclin binding interface, have all diversified under positive selection. Three of the 5 CDK1 paralogs are required for embryonic divisions and knockdown phenotypes illustrate further subdivision of functions along the S-M-phase axis. In parallel to CDK1 gene duplications, there has also been amplification in the Cyclin B complement. Among these, the CDK1d:Cyclin Ba pairing is required for oogenic meiosis and early embryogenesis and shows evidence of coevolution of an exclusive interaction. In an intriguing twist on the general rule that Cyclin B oscillations on a background of stable CDK1 levels regulate M-phase MPF activity, it is CDK1d protein levels that oscillate, rather than Cyclin Ba levels, to drive rapid, early embryonic cell cycles. Strikingly, the modified PSTAIRE of odCDK1d shows convergence over great evolutionary distance with plant CDKB, and in bothO. dioica, and plants, these variants exhibit increased specialization to M-phase.
Populations of genetic circuits are unable to find the fittest solution in a multilevel genotype-phenotype map
Authors: Catalán Pablo , Manrubia Susanna , Cuesta José A.
Published: October 2019

The evolution of gene regulatory networks (GRNs) is of great relevance for both evolutionary and synthetic biology. Understanding the relationship between GRN structure and its function can allow us to understand the selective pressures that have shaped a given circuit. This is especially relevant when considering spatiotemporal expression patterns, where GRN models have been shown to be extremely robust and evolvable. However, previous models that studied GRN evolution did not include the evolution of protein and genetic elements that underlie GRN architecture. Here we usetoyLIFE, a multilevel genotype-phenotype map, to show that not all GRNs are equally likely in genotype space and that evolution is biased to find the most common GRNs.toyLIFE rules create Boolean GRNs that, embedded in a one-dimensional tissue, develop a variety of spatiotemporal gene expression patterns. Populations oftoyLIFE organisms choose the most common GRN out of a set of equally fit alternatives and, most importantly, fail to find a target pattern when it is very rare in genotype space. Indeed, we show that the probability of finding the fittest phenotype increases dramatically with its abundance in genotype space. This phenotypic bias represents a mechanism that can prevent the fixation in the population of the fittest phenotype, one that is inherent to the structure of genotype space and the genotype-phenotype map.
Modeling the Shape of Synaptic Spines by their Actin Dynamics
Authors: Bonilla-Quintana Mayte , Wörgötter Florentin , Tetzlaff Christian , Fauth Michael
Published: October 2019

Dendritic spines are the morphological basis of excitatory synapses in the cortex and their size and shape correlates with functional synaptic properties. Recent experiments show that spines exhibit large shape fluctuations that are not related to activity-dependent plasticity but nonetheless might influence memory storage at their synapses. To investigate the determinants of such spontaneous fluctuations, we propose a mathematical model for the dynamics of the spine shape and analyze it in 2D — related to experimental microscopic imagery — and in 3D. We show that the spine shape is governed by a local imbalance between membrane tension and the expansive force from actin bundles that originates from discrete actin polymerization foci. Experiments have shown that only few such polymerization foci co-exist at any time in a spine, each having limited life time. The model shows that the momentarily existing set of such foci pushes the membrane along certain directions until foci are replaced and other directions may now be affected. We explore these relations in depth and use our model to predict shape and temporal characteristics of spines from the different biophysical parameters involved in actin polymerization. Reducing the model further to a single recursive equation we finally demonstrate that the temporal evolution of the number of active foci is sufficient to predict the size of the model-spines. Thus, our model provides the first platform to study the relation between molecular and morphological properties of the spine with a high degree of biophysical detail.

Author summary

Synaptic spines are post-synaptic contact points for pre-synaptic signals in many cortical neurons and it has been shown that synaptic transmission is correlated with spine size. However, spine size and shape can vary quite strongly on short time scales and it is currently unknown how these shape variations emerge. In this study we present a biophysical model that links spine shape fluctuations to the dynamics of the spine’s actin-based cytoskeleton. We show that shape fluctuations arise from the fact that fast actin polymerization in a spine is a discrete process happening at only few polymerization foci. Life and death of these foci determine from moment to moment how the membrane bulges or retracts. We provide an in-depth analysis of this effect for a large set of biophysical parameters and quantify the spatial-temporal structure of the spines. Our model, thus, provides a quantitative characterization of the link between spine morphology and the underlying molecular processes, which forms an essential step towards a better understanding of synaptic transmission during steady state but also during synaptic plasticity.
Effect of feedback regulation on stem cell fractions in tissues and tumors: understanding chemo-resistance in bladder cancer
Authors: Weiss Lora D. , van den Driessche P. , Lowengrub John S. , Wodarz Dominik , Komarova Natalia L.
Published: October 2019

While resistance mutations are often implicated in the failure of cancer therapy, lack of response also occurs without such mutants. In bladder cancer mouse xenografts, repeated chemotherapy cycles have resulted in cancer stem cell (CSC) enrichment, and consequent loss of therapy response due to the reduced susceptibility of CSCs to drugs. A particular feedback loop present in the xenografts has been shown to promote CSC enrichment in this system. Yet, many other regulatory loops might also be operational and might promote CSC enrichment. Their identification is central to improving therapy response. Here, we perform a comprehensive mathematical analysis to define what types of regulatory feedback loops can and cannot contribute to CSC enrichment, providing guidance to the experimental identification of feedback molecules. We derive a formula that reveals whether or not the cell population experiences CSC enrichment over time, based on the properties of the feedback. We find that negative feedback on the CSC division rate or positive feedback on differentiated cell death rate can lead to CSC enrichment. Further, the feedback mediators that achieve CSC enrichment can be secreted by either CSCs or by more differentiated cells. The extent of enrichment is determined by the CSC death rate, the CSC self-renewal probability, and by feedback strength. Defining these general characteristics of feedback loops can guide the experimental screening for and identification of feedback mediators that can promote CSC enrichment in bladder cancer and potentially other tumors. This can help understand and overcome the phenomenon of CSC-based therapy resistance.