bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting human epidermal growth factor receptor 2 (HER2) in gynecologic malignancies
Authors: Erickson Britt K. , Zeybek Burak , Santin Alessandro D. , Fader Amanda N.
Published: December 2019

Purpose of review

The purpose of this review is to describe the role of the human epidermal growth factor receptor 2 (HER2) as a biomarker and potential target in gynecologic malignancies and to describe contemporary updates in the use of anti-HER2 treatments for these cancers.

Recent findings

Approximately 25–30% of all patients with uterine serous carcinoma overexpress tumoral HER2. The anti-HER2 antibody trastuzumab represents an effective, targeted therapy with significant efficacy in the treatment of HER2-positive breast and gastric cancer. Recently, trastuzumab efficacy has also been demonstrated in a randomized controlled trial of women with advanced or recurrent uterine serous carcinoma. Additionally, trastuzumab may be effective in women with HER2-positive uterine carcinosarcoma. The role of anti-HER2 therapy is unclear in women with other gynecologic malignancies but is being evaluated.

HER2 amplification/overexpression is an effective therapeutic target in select gynecologic malignancies, and especially in the rare endometrial cancer subtype, uterine serous carcinoma. As anti-HER2-targeted therapies become increasingly available, more treatment options may become available for women with HER2-positive disease.
Immunotherapy for Gynecologic Cancer: Current Applications and Future Directions
Authors: LYNAM SARAH , LUGADE AMIT A. , ODUNSI KUNLE
Published: December 2019

The role of the immune system in the development of cancer has been a subject of ongoing clinical investigation in recent years. Emerging data demonstrate that tumorigenesis resulting in ovarian, uterine, and cervical cancers is a consequence of impaired host immune responses to cancerous cells. Leveraging the immune system through the use of immune checkpoint inhibitors, therapeutic vaccine therapy, and adoptive cell transfer presents a profound opportunity to revolutionize cancer treatment. This review will encompass the role of the immune system in development of gynecologic cancers and highlight recent data regarding immunotherapy applications in ovarian, uterine, and cervical cancers.
Speckle tracking echocardiography: imaging insights into the aorta
Authors: Rong Lisa Q. , Kim Jiwon , Gregory Alexander J.
Published: December 2019

Purpose of review

Pathophysiologic changes of aortic tissue may not always manifest as aneurysms, nor does the size of an aneurysm necessarily represent the severity of tissue abnormality – approximately 40% of patients who present with dissection have aortic diameters below criteria recommended for surgical resection. Noninvasive imaging-based quantification of aortic biomechanics has the potential to improve our knowledge of the pathophysiology of aortic disease, including patient-specific risk-stratification and intraoperative surgical decision-making.

Recent findings

We summarize the current state of clinical utilization of two-dimensional speckle tracking echocardiography (2D-STE) aortic strain to better understand the pathophysiology, clinical implications, and risk stratification of aortic disease.

2D-STE has demonstrated promising early results as an imaging modality to determine clinically relevant measures of aortic tissue mechanical properties. Further large multinational, multiethnic, age-stratified, and sex-stratified measures of normal aortic strain measurements, as well as comparison studies with alternative imaging techniques, will be needed to properly elucidate the role echocardiography will play in the clinical management of aortic disease.
Choosing the best antithrombotic regimen in patients with ventricular assist devices
Authors: Bader Feras , Mallah Saad , Atallah Bassam
Published: December 2019

Purpose of review

Two major complications compromise the outcomes and quality of life for left ventricular assist device (LVAD) patients. This review aims to discuss the mechanisms of thrombosis and bleeding, recent literature on the optimal approaches for antithrombotic therapy, and novel approaches to prevent bleeding.

Recent findings

Recent studies with the newly designed LVAD, the fully magnetically levitated rotor, show lower thrombotic risk but sustain similar bleeding risk. Small studies present options for less intense antithrombotic regimens with the newer devices. Bridging anticoagulation when needed in this patient population might require modified regimens and close monitoring to avoid anticoagulation overlap during the bridged periods. The necessity to add an antiplatelet to anticoagulation is particularly being challenged with the recent data. Antiplatelet responsiveness testing is an intriguing approach to customize regimens. In addition, novel approaches that target activation of the angiotensin II receptors and inflammatory responses might offer further protection against bleeding in implanted patients.

Close monitoring, novel, and patient-tailored approaches may offer the best antithrombotic strategies for LVAD patients. More clinical and long-term data are needed to establish the potential for less intense regimens particularly with the newly designed devices.
End-of-life care in patients with advanced heart failure
Authors: Diamant Michael J. , Keshmiri Hesam , Toma Mustafa
Published: December 2019

Purpose of review

With an aging population with heart failure, there is a growing need for end-of-life care in this population, including a focus on symptom management and quality-of-life considerations.

Recent findings

Targeted therapies focusing on symptom control and improving quality of life is the cornerstone of providing care in patients with heart failure near the end of life. Such therapies, including the use of inotropes for palliative purposes, have been shown to improve symptoms without an increase in mortality. In addition, recent evidence shows that implementing certain strategies in planning for end of life, including advance care planning and palliative care involvement, can significantly improve symptoms and quality of life, reduce hospitalizations, and ensure care respects patient values and preferences.

Shifting focus from prolonging life to enhancing quality of life in heart failure patients approaching the end of life can be achieved by recognizing and managing end-stage heart failure-related symptoms, advanced care planning, and a multidisciplinary care approach.
Valve sparing root replacement: an update
Authors: De Paulis Ruggero , Scaffa Raffaele , Chirichilli Ilaria
Published: December 2019

Purpose of review

Until the year 2000, the publications concerning aortic valve sparing (AVS) did not exceed 20 articles; in the following years almost 300 publications have appeared. Over 35 years from the introduction of valve sparing techniques and 500 years after the death of Leonardo da Vinci, this review highlights the significant steps in modern imaging techniques and the excellent clinical results in the field of reconstructive aortic root surgery.

Recent findings

AVS operations underwent significant modifications over the last few years making it reproducible with satisfactory outcomes. The extraordinary potential of imaging opens new boundless horizons in the perspective of an increasingly patient-tailored surgical planning. The basic surgical concepts include the preservation and resuspension of the aortic valve in a near-normal environment (with the creation of functionally suited neo-aortic sinuses) and the re-establishment of a normal relationship of the aortic root components.

Today is possible to perform a reimplantation procedure with the creation of neo-sinuses or a remodeling procedure with the addition of annular support. Both procedures can now guarantee an anatomical root reconstruction and an increased long-term durability. AVS operations have become established alternatives to Bentall procedures for patients with aortic root pathology, especially in young patients.
EFFECT OF INVERTED INTERNAL LIMITING MEMBRANE FLAP ON CLOSURE RATE, POSTOPERATIVE VISUAL ACUITY, AND RESTORATION OF OUTER RETINAL LAYERS IN PRIMARY IDIOPATHIC MACULAR HOLE SURGERY
Authors: Baumann Carmen , Kaye Stephen , Iannetta Danilo , Sultan Ziyaad , Dwivedi Rahul , Pearce Ian
Published: December 2019

Purpose:

To investigate the role of an internal limiting membrane (ILM) flap in macular hole (MH) surgery on closure rate, visual acuity, and integrity of the outer retinal layers.

Methods:

Retrospective, nonrandomized interventional analysis in which 117 eyes of 117 patients were included who had undergone pars-plana vitrectomy (PPV) and gas tamponade for primary idiopathic MH >400 µm with either conventional ILM peeling or with inverted ILM flap technique at The Royal Liverpool University Hospital between January 2016 and April 2018. Main outcome measures were closure of MH, best-corrected visual acuity (BCVA) at 3, 6, and 12 months, and restoration of external limiting membrane and ellipsoid zone (EZ) using optical coherence tomography.

Results:

Macular hole closure rate was significantly higher in patients with an ILM flap (67/68; 98.53%) than in those with conventional ILM peeling (43/49; 87.76%) (P = 0.02). Both groups showed significant improvements in their preoperative to postoperative BCVA at 3 months from 1.07 (0.43) logarithm of the minimum angle of resolution (logMAR) (20/235 Snellen) to 0.71 (0.34) logMAR (20/103 Snellen) (P <0.001), but there was no significant difference between the two groups (P = 0.45, P = 0.71). We found significant associations between postoperative BCVA and preoperative BCVA (P < 0.01) and the integrity of the EZ (P < 0.01). In 35 patients who had follow-up to 12 months, there was a significant improvement in BCVA between 3, 6, and 12 months from 0.73 (0.45) logMAR (20/107 Snellen) to 0.53 (0.24) logMAR (20/68 Snellen) and to 0.35 (0.18) logMAR (20/45 Snellen), respectively (P < 0.01). There was no significant difference at these time periods between the two groups (P = 0.62, P = 0.21, P = 0.31). The integrity of the EZ also improved significantly between 3, 6, and 12 months (P = 0.01), irrespective of the presence of an ILM flap (P = 0.58), but with a trend toward delay in restoration in those patients with an ILM flap. The improvement in BCVA at 12 months, taking into account the age of the patient, size and duration of the MH, presence of an ILM flap, and preoperative BCVA was dependent on the state of the EZ (P = 0.01).

Conclusion:

In patients undergoing primary pars-plana vitrectomy for MH >400 µm, the presence of an inverted ILM flap was associated with a significantly higher closure rate than a conventional ILM peeling. Best-corrected visual acuity showed a strong correlation with the integrity of the EZ and both improved significantly between 3, 6, and 12 months, irrespective of the presence of an ILM flap.
AUTOMATED RETINAL LAYER SEGMENTATION AND THEIR THICKNESS PROFILES IN HEALTHY SUBJECTS
Authors: Giannakaki-Zimmermann Helena , Munk Marion R. , Ebneter Andreas , Wolf Sebastian , Zinkernagel Martin
Published: December 2019

Purpose:

To assess whether retinal thickness measurements with a standard 30° spectral domain optical coherence tomography (SD-OCT) are comparable with wide-field 55° SD-OCT.

Methods:

Thirty-three healthy individuals were scanned using 55° as well as 30° SD-OCT according to a standardized protocol. Automated retinal layer segmentation of standard and wide-field SD-OCTs was assessed using customized software.

Results:

Both lenses showed a high correlation when analyzing total retinal thickness within the central, the inner, and the outer retinal ring (r = > 0.9). Automated thickness measurements with the 55° system were marginally higher compared with the 30° lens. The thickness of each separate retinal layer using automated segmentation showed excellent correlations within the inner and outer rings (range: r = 0.6—r = 0.9 for the inner ring and range: r = 0.9—r = 1.0 for the outer ring).

Conclusion:

Fifty-five degree wide-field SD-OCT provides a good overview of the posterior pole and presents similar quantitative values as a standard 30° OCT lens. Therefore, thickness values are comparable when switching between these two lenses.
Antegrade Continence Enema
Authors: Holder Monica , Desjarlais Marie , Harrington Anne , Kern Patricia
Published: December 2019

The broad term “ACE” refers to an antegrade continence enema that allows you to flush or empty the colon starting from the beginning of the colon (cecum) and flushing to the end (rectum) for patients with true fecal incontinence or constipation with the inability to empty the bowel with oral therapy. The terms “cecostomy,” “MACE,” “ACE,” and “Malone” have often been used interchangeably; however, they do have technical differences. The purpose of this article is to describe and compare specifically Malone/appendicostomy, neo-Malone/neo-appendicostomy, and cecostomy. The contents of this publication are compiled of both expert opinions and literature review.
Influences of Two-Year Professional Education Delivered in English on Japanese Undergraduate Physiotherapy Students’ English Vocabulary and International Perspectives: A Retrospective Cohort Study
Authors: Mine Koya , Girdwood Michael , Toyoda Hiroko , Nakayama Takashi
Published: December 2019

Introduction.

Low levels of English proficiency among Japanese physiotherapists pose serious barriers to implement evidence-based practice and think about their careers in global terms. This retrospective cohort study aimed to investigate the influences of a series of lectures regarding various physiotherapy topics conducted in English, on Japanese undergraduate physiotherapy students’ English vocabulary and international perspectives.

Methods.

Twelve students from Tokyo University of Technology participated in a total of 60 lectures throughout 2 years. On a weekly basis, 90-minute physiotherapy lectures were conducted in English. Another 12 students who did not participate in lectures were randomly chosen and served as a control group. English vocabulary regarding physiotherapy was assessed through a word translation test. Furthermore, students’ subjective interests in learning English, studying and working abroad, awareness toward the importance of learning English and physiotherapy from foreign countries, and the level of physiotherapy in Japan compared with that in other countries were also evaluated using 11-point numerical rating scale.

Results.

English vocabulary scores were significantly higher in the experimental group (P < .01). The effect size was large (3.09). Interest levels in learning English, and studying and working abroad were significantly higher in the experimental group (P < .01). Effect sizes were large (1.89 and 1.11, respectively). However, levels of awareness toward the importance of learning English and physiotherapy from other countries and the level of physiotherapy in Japan were not significantly different between the two groups.

Discussion and Conclusions.

Two-year professional education in English may lead to benefits in English vocabulary related to physiotherapy and motivating students to think about their careers in global perspectives. Based on these findings, educational staff in Japanese physiotherapy schools are encouraged to consider to introduce professional education using English for undergraduate students.
A Systematic Review of Interventions for Balance Dysfunction in Patients With Vestibular Schwannoma
Authors: Ojha Shilpa , Clamp Philip J.
Published: December 2019

Objective:

Dizziness is a major contributing factor to poor quality of life for patients with vestibular schwannoma (acoustic neuroma). We wished to review the literature on interventions for balance dysfunction in these patients.

Data Sources:

A systematic literature review was performed identifying studies that measured balance function before and after treatment for vestibular schwannoma. Data sources include Medline (1950–present), EMBASE (1974–present), Cochrane Library (issue 3, 2008), NHS Centre of reviews and dissemination, Clinical Evidence, Cochrane central register of controlled trial, and CINAHL.

Study Selection:

A minimum follow-up of 6 months was required, to estimate long-term balance function. Eight articles were identified, including five studies with surgical intervention, two studies with stereotactic radiotherapy, and one comparing the two. Study design was generally poor with a high risk of bias. These studies all utilized the Dizziness Handicap Inventory (DHI) as a measure of pre- and postintervention balance function.

Data Extraction:

Results showed that overall DHI scores are not statistically affected by intervention irrespective of modality (surgery or stereotactic radiotherapy). Patients selected with severe dizziness, who undergo surgery, improved postoperatively. No other studies for severe dizziness were noted for comparison.

Conclusions:

Age, sex, and tumor size have no statistically significant effect on DHI outcomes, and no evidence to suggest which treatment modality has better dizziness related outcomes.

No specific treatment modality was superior in terms of long-term balance function. Patients with severe dizziness may benefit from surgery, although no comparator studies were identified.
A nitric oxide synthase inhibitor, L-NAME, prevents L-arginine-induced downregulation of the rat cortical somatostatinergic system
Authors: Ocaña-Fuentes Aurelio , Puebla-Jiménez Lilian , Burgos-Ramos Emma , Muñoz-Acedo Gema , Boyano-Adánez María del Carmen , Barrios Vicente , Arilla-Ferreiro Eduardo
Published: December 2019

Activation of NMDA receptors leads to nitric oxide (NO) synthesis by NO synthase (NOS) from L-arginine. Neuronal NOS colocalizes with somatostatinergic (SRIF) neurons and there is growing evidence of an interaction between NO and the cerebral SRIFergic system in several neurological diseases. Our aim was to study the effect of L-arginine on the regulation of the SRIFergic system in the frontoparietal cortex of male Sprague–Dawley rats. Intraperitoneal administration of L-arginine (150 mg/Kg), twice-daily during eight days, induced a decrease in SRIF receptor density, which was accompanied by a reduction in the capacity of SRIF to stimulate inositol-1,4,5-triphosphate (IP3) accumulation and SRIF-like immunoreactivity (SRIF-LI) levels. To determine if these changes were related to L-arginine-derived NO synthesis, a NOS inhibitor, Nω-nitro-L-arginine methyl ester was coadministered with L-arginine. Its coadministration prevented the reduction in the SRIF receptor density, accumulation of IP3 and SRIF-LI content. These findings indicate that L-arginine induces a deleterious effect on the cortical somatostatinergic system and that the inhibition of NOS could be helpful in some neurological disorders where this neurotransmitter system is affected.
ParB spreading on DNA requires cytidine triphosphatein vitro
Authors: Jalal Adam S. B. , Tran Ngat T. , Le Tung B. K.
Published: December 2019

In all living organisms, it is essential to transmit genetic information faithfully to the next generation. The SMC-ParAB-parSsystem is widely employed for chromosome segregation in bacteria. A DNA-binding protein ParB nucleates onparSsites and must associate with neighboring DNA, a process known as spreading, to enable efficient chromosome segregation. Despite its importance, how the initial few ParB molecules nucleating atparSsites recruit hundreds of further ParB to spread is not fully understood. Here, we reconstitute aparS-dependent ParB spreading event using purified proteins fromCaulobacter crescentusand show that CTP is required for spreading. We further show that ParB spreading requires a closed DNA substrate, and a DNA-binding transcriptional regulator can act as a roadblock to attenuate spreading unidirectionallyin vitro. Our biochemical reconstitutions recapitulate many observedin vivoproperties of ParB and opens up avenues to investigate the interactions between ParB-parSwith ParA and SMC.
Bayesian inference associates rareKDRvariants with specific phenotypes in pulmonary arterial hypertension
Authors: Swietlik Emilia M. , Greene Daniel , Zhu Na , Megy Karyn , Cogliano Marcella , Rajaram Smitha , Pandya Divya , Tilly Tobias , Lutz Katie A. , Welch Carrie C. L. , Pauciulo Michael W. , Southgate Laura , Martin Jennifer M. , Treacy Carmen M. , Penkett Christopher J. , Stephens Jonathan C. , Bogaard Harm J. , Church Colin , Coghlan Gerry , Coleman Anna W. , Condliffe Robin , Eyries Mélanie , Gall Henning , Ghio Stefano , Girerd Barbara , Holden Simon , Howard Luke , Humbert Marc , Kiely David G. , Kovacs Gabor , Lordan Jim , Machado Rajiv D. , Ross Robert V. MacKenzie , McCabe Colm , Moledina Shahin , Montani David , Olschewski Horst , Pepke-Zaba Joanna , Price Laura , Rhodes Christopher J. , Seeger Werner , Soubrier Florent , Suntharalingam Jay , Toshner Mark R. , Noordegraaf Anton Vonk , Wharton John , Wild Jim , Wort Stephen John ,   NIHR BioResource for Translational Research - Rare Diseases,   National Cohort Study of Idiopathic and Heritable PAH,   PAH Biobank Enrolling Centers’ Investigators, Lawrie Allan , Wilkins Martin R. , Trembath Richard C. , Shen Yufeng , Chung Wendy K. , Swift Andrew J. , Nichols William C. , Morrell Nicholas W. , Gräf Stefan
Published: December 2019

Background

Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics.

Methods

We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed.

Results

Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsenseKDRvariant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants inKDR. Four additional PAH cases with rare likely loss-of-function variants inKDRwere independently identified in the US PAH Biobank cohort with similar phenotypic characteristics.

Conclusions

The Bayesian inference approach allowed us to independently validateKDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence forKDRbeing a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.
Chr21 protein-protein interactions: enrichment in products involved in intellectual disabilities, autism and Late Onset Alzheimer Disease
Authors: Viard Julia , Loe-Mie Yann , Daudin Rachel , Khelfaoui Malik , Plancon Christine , Boland Anne , Tejedor Francisco , Huganir Richard L. , Kim Eunjoon , Kinoshita Makoto , Liu Guofa , Haucke Volker , Moncion Thomas , Yu Eugene , Hindie Valérie , Bléhaut Henri , Mircher Clotilde , Herault Yann , Deleuze Jean-François , Rain Jean-Christophe , Simonneau Michel , Lepagnol-Bestel Aude-Marie
Published: December 2019

Intellectual disability (ID) found in Down syndrome (DS), which is characterized by an extra copy of 234 genes on Chr21 is poorly understood. We first used two DS mouse models that either display an extra copy of theDyrk1Agene or of the mouse Chr16 syntenic region. Exome sequencing of transcripts deregulated in embryonic hippocampus uncovers enrichment in genes involved in chromatin and synapse respectively. Using large-scale yeast two-hybrid screen (154 distinct screens) of human brain library containing at least 107independent fragments, we identified 3,636 novel protein-protein interactions with an enrichment of direct interactors of both Chromosome 21(Hsa21) baits and rebounds in ID-related genes. Using proximity ligation assays, we identified that Hsa21-encoded proteins are located at the dendritic spine postsynaptic density in a protein network located at the dendritic spine post synapse. We located Hsa21 DYRK1A and DSCAM that confers a ∼ 20-fold increase in Autism Spectrum Disorders (ASDs), in this postsynaptic network. We found that a DSCAM intracellular domain binds either DYRK1A or DLGs that are multimeric scaffolds for the clustering of receptors, ion channels, and associated signaling proteins. The DYRK1A-DSCAM interaction is conserved from drosophila to humans. The identified postsynaptic.network is enriched in ARC-related synaptic plasticity, ASDs and Late-Onset Alzheimer Disease. Altogether, these results emphasize links between DS and brain diseases with complex genetics.
Bromodomain inhibition reveals FGF15/19 as a target of epigenetic regulation and metabolic control
Authors: Kozuka Chisayo , Sales Vicencia , Osataphan Soravis , Yuchi Yixing , Chimene-Weiss Jeremy , Mulla Christopher , Isganaitis Elvira , Desmond Jessica , Sanechika Suzuka , Kusuyama Joji , Goodyear Laurie , Shi Xu , Gerszten Robert E. , Wu Lei , Qi Jun , Patti Mary-Elizabeth
Published: December 2019

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we demonstrated that bromodomain-containing proteins (Brds), transcriptional regulators binding to acetylated histone, are potent modulators of glucose metabolism via the gut-liver farnesoid X receptor (FXR)-fibroblast growth factor 15/19 (FGF15/19) pathway. In vivo inhibition of Brd4 by the inhibitor JQ1 in mice strongly inhibited ileal expression of FGF15, resulting in decreased FGFR4-related signaling, increased glucose production in the liver and hyperglycemia. Adverse metabolic effects of BRD4 inhibition were reversed by overexpression of FGF19, with improvement in hyperglycemia. At a cellular level, we demonstrate that BRD4 binds to the promoter region of FGF19 in human intestinal cells; BRD inhibition by JQ1 reduces binding to the FGF19 promoter and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum, and a contributor to hepatic and systemic glucose metabolism.
SingleCellSignalR: Inference of intercellular networks from single-cell transcriptomics
Authors: Cabello-Aguilar Simon , Tack Fabien Kon Sun , Alame Mélissa , Fau Caroline , Lacroix Matthieu , Colinge Jacques
Published: December 2019

Single-cell transcriptomics offers unprecedented opportunities to infer the ligand-receptor interactions underlying cellular networks. We introduce a new, curated ligand-receptor database and a novel regularized score to perform such inferences. For the first time, we try to assess the confidence in predicted ligand-receptor interactions and show that our regularized score outperforms other scoring schemes while controlling false positives. SingleCellSignalR is implemented as an open-access R package accessible to entry-level users and available fromhttps://github.com/SCA-IRCM. Analysis results come in a variety of tabular and graphical formats. For instance, we provide a unique network view integrating all the intercellular interactions, and a function relating receptors to expressed intracellular pathways. A detailed comparison with related tools is conducted. Among various examples, we demonstrate SingleCellSignalR on mouse epidermis data and discover an oriented communication structure from external to basal layers.
Early life glucocorticoid exposure modulates immune function in zebrafish (Danio rerio) larvae
Authors: van den Bos Ruud , Cromwijk Suzanne , Tschigg Katharina , Althuizen Joep , Zethof Jan , Whelan Robert , Flik Gert , Schaaf Marcel
Published: December 2019

In this study we have assessed the effects of increased cortisol levels during early embryonic development on immune function in zebrafish (Danio rerio) larvae. Fertilized eggs were exposed to either a cortisol-containing, a dexamethasone-containing (to stimulate the glucocorticoid receptor selectively) or a control medium for 6 hours post-fertilisation (0-6 hpf). First, we measured baseline expression of a number of immune-related genes (socs3a,mpeg1.1,mpeg1.2andirg1l) 5 days post-fertilisation (dpf) in larvae of the AB and TL strain to assess the effectiveness of our exposure procedure and potential strain differences. Cortisol and dexamethasone strongly up-regulated baseline expression of these genes independent of strain. The next series of experiments were therefore carried out in larvae of the AB strain only. We measured neutrophil/macrophage recruitment following tail fin amputation (performed at 3 dpf) and phenotypical changes as well as survival following LPS-induced sepsis (150 μg/ml; 4-5 dpf). Dexamethasone, but not cortisol, exposure at 0-6 hpf enhanced neutrophil recruitment 4 hours post tail fin amputation. Cortisol and dexamethasone exposure at 0-6 hpf led to a milder phenotype (e.g. less tail fin damage) and enhanced survival following LPS challenge compared to control exposure. Gene-expression analysis showed accompanying differences in transcript abundance oftlr4bb, cxcr4a, myd88,il1β and il10. These data show that early-life exposure to cortisol, which may be considered to be a model or proxy of maternal stress, induces an adaptive response to immune challenges, which seems mediated via the glucocorticoid receptor.
Element content and distribution has limited, tolerance metric dependent, impact on salinity tolerance in cultivated sunflower (Helianthus annuus)
Authors: Temme A.A. , Burns V.A. , Donovan L.A.
Published: December 2019

Disruption of ion homeostasis is a major component of salinity stress’s effect on crop yield. In cultivated sunflower prior work revealed a trade-off between vigor and salinity tolerance. Here we determined the association of elemental content/distribution traits with salinity tolerance, both with and without taking this trade-off into account. We grew seedlings of twelve Helianthus annuus genotypes in two treatments (0/100 mM NaCl). Plants were measured for biomass (+allocation), and element content (Na, P, K, Ca, Mg, S, Fe, B, Mn, Cu, Zn) in leaves (young and mature), stem, and roots. Genotype tolerance was determined by the proportional decline in biomass and as the deviation from the expected vigor/tolerance trade-off. Genotype rankings on these metrics were not the same. Elemental content and allocation/distribution were highly correlated both at the plant and organ level. Suggestive associations between tolerance and elemental traits were fewer and weaker than expected and differed by tolerance metric. Given the highly correlated nature of elemental content, it remains difficult to pinpoint specific traits underpinning tolerance. Results do show that taking vigor related trade-offs into account is important in determining traits related to tolerance and that the multivariate nature of associated traits should be considered.
A Registration and Deep Learning Approach to Automated Landmark Detection for Geometric Morphometrics
Authors: Devine Jay , Aponte Jose D. , Katz David C. , Liu Wei , Lo Vercio Lucas D. , Forkert Nils D. , Percival Christopher J. , Hallgrímsson Benedikt
Published: December 2019

Geometric morphometrics is the statistical analysis of landmark-based shape variation and its covariation with other variables. Over the past two decades, the gold standard of landmark data acquisition has been manual detection by a single observer. This approach has proven accurate and reliable in small-scale investigations. However, big data initiatives are increasingly common in biology and morphometrics. This requires fast, automated, and standardized data collection. Image registration, or the spatial alignment of images, is a fundamental technique in automatic image analysis that is well-poised for such purposes. Yet, in the few studies that have explored the utility of registration-based landmarks for geometric morphometrics, relatively high or catastrophic labelling errors around anatomical extrema are common. Such errors can result in misleading representations of the mean shape, an underestimation of biological signal, and altered variance-covariance patterns.

We combine image registration with a deep and domain-specific neural network to automate and optimize anatomical landmark detection for geometric morphometrics. Using micro-computed tomography images of genetically and morphologically variable mouse skulls, we test our landmarking approach under a variety of registration conditions, including different non-linear deformation frameworks (small vs. large) and atlas strategies (single vs. multi).

Compared to landmarks derived from conventional image registration workflows, our optimized landmark data show significant reductions in error at problematic locations (up to 0.63 mm), a 36.4% reduction in average landmark coordinate error, and up to a 45.1% reduction in total landmark distribution error. We achieve significant improvements in estimates of the sample mean shape and variance-covariance structure.

For biological imaging datasets and morphometric research questions, our method can eliminate the time and subjectivity of manual landmark detection whilst retaining the biological integrity of these expert annotations.
A receptor-like kinase mediated phosphorylation of Gα protein affects signaling during nodulation
Authors: Choudhury Swarup Roy , Pandey Sona
Published: December 2019

SUMMARY

Heterotrimeric G-proteins, comprised of Gα, Gβ and Gγ subunits regulate signaling in eukaryotes. In metazoans, G-proteins are activated by GPCR-mediated GDP to GTP exchange on Gα; however, the role of receptors in regulating plant G-protein signaling remains equivocal. Mounting evidence points to the involvement of receptor-like kinases (RLKs) in regulating plant G-protein signaling pathways, but their mechanistic details remain limited. We have previously shown that during soybean nodulation, the nod factor receptor 1 (NFR1) interacts with G-protein components and indirectly controls signaling.

We explored the direct regulation of G-protein signaling by RLKs using protein-protein interactions, receptor-mediated phosphorylation and the effects of such phosphorylations on soybean nodule formation.

Results presented in this study demonstrate a direct, phosphorylation-based regulation of Gα by symbiosis receptor kinase (SymRK). SymRKs interact with and phosphorylate Gα at multiple residues, including two in its active site, which abolishes GTP binding. In addition, phospho-mimetic Gα fails to interact with Gβγ, potentially allowing for constitutive signaling by the freed Gβγ.

These results uncover a novel mechanism of G-protein cycle regulation in plants where receptor-mediated phosphorylation of Gα not only affects its activity, but also influences the availability of its signaling partners, thereby exerting a two-pronged control on signaling.
The importance of Indigenous Peoples’ lands for the conservation of terrestrial vertebrates
Authors: O’Bryan Christopher J. , Garnett Stephen T. , Fa John E. , Leiper Ian , Rehbein Jose , Fernández-Llamazares Álvaro , Jackson Micha V. , Jonas Harry D. , Brondizio Eduardo S. , Burgess Neil D. , Robinson Catherine J. , Zander Kerstin K. , Venter Oscar , Watson James E.M.
Published: December 2019

Indigenous Peoples’ lands cover over one-quarter of the Earth’s surface, a significant proportion of which is still free from industrial-level human impacts. As a result, Indigenous Peoples’ lands are crucial for the long-term persistence of Earth’s biodiversity and ecosystem services. Yet, information on species composition within Indigenous Peoples’ lands globally remains unknown. Here, we provide the first comprehensive analysis of terrestrial vertebrate composition across mapped Indigenous lands by using distribution range data for 20,328 IUCN-assessed mammal, bird and amphibian species. We estimate that 12,521 species (62%) have ≥10% of their ranges in Indigenous Peoples’ lands, and 3,314 species (16%) have >half of their ranges within these lands. For threatened species assessed, 1,878 (41.5% of all threatened of all threatened mammals, birds and amphibians) occur in Indigenous Peoples’ lands. We also find that 3,989 species (of which 418 are threatened) have ≥10% of their range in Indigenous Peoples’ lands that have low human pressure. Our results are conservative because not all known Indigenous lands are mapped, and this analysis shows how important Indigenous Peoples’ lands are for the successful implementation of international conservation and sustainable development agendas.
Cerebral artery segmentation based on magnetization-prepared two rapid acquisition gradient echo multi-contrast images in 7 Tesla magnetic resonance imaging
Authors: Choi Uk-Su , Kawaguchi Hirokazu , Kida Ikuhiro
Published: December 2019

Cerebral artery segmentation plays an important role in the direct visualization of the human brain to obtain vascular system information. At ultra-high field magnetic resonance imaging, hyperintensity of the cerebral arteries in T1 weighted (T1w) images could be segmented from brain tissues such as gray and white matter. In this study, we propose an automated method to segment the cerebral arteries using multi-contrast images including T1w images of a magnetization-prepared two rapid acquisition gradient echoes (MP2RAGE) sequence at 7 T. The proposed method employed a seed-based region-growing strategy with the following procedures. (1) Two seed regions were defined by Frangi filtering applied to T1w images and by a simple calculation from multi-contrast images, (2) the two seed regions were combined, (3) the combined seed regions were expanded using a region growing algorithm to acquire the cerebral arteries. Time-of-flight (TOF) images were obtained as a reference to evaluate the proposed method. We successfully performed vessel segmentations from T1w MP2RAGE images, which mostly overlapped with the segmentations from the TOF images. As large arteries can affect the normalization of anatomical images to the standard coordinate space in functional and structural studies, we also investigated the effect of the cerebral arteries on spatial transformation using vessel segmentation by the proposed method. As a result, the T1w image removing the cerebral arteries showed better agreement with the standard atlas compared with the T1w image containing the arteries. Thus, because the proposed method using MP2RAGE images can obtain brain tissue anatomical information as well as cerebral artery information without need for additional acquisitions such as of the TOF sequence, it is useful and time saving for medical diagnosis and functional and structural studies.
Distinct microbial and immune niches of the human colon
Authors: James KR , Gomes T , Elmentaite R , Kumar N , Gulliver EL , King HW , Stares MD , Bareham BR , Ferdinand JR , Petrova VN , Polanski K , Forster SC , Jarvis LB , Suchanek O , Howlett S , James LK , Jones JL , Meyer KB , Clatworthy MR , Saeb-Parsy K , Lawley TD , Teichmann SA
Published: December 2019

Gastrointestinal microbiota and immune cells interact closely and display regional specificity, but little is known about how these communities differ with location. Here, we simultaneously assess microbiota and single immune cells across the healthy, adult human colon, with paired characterisation of immune cells in the mesenteric lymph nodes, to delineate colonic immune niches at steady-state. We describe distinct T helper cell activation and migration profiles along the colon and characterise the transcriptional adaptation trajectory of T regulatory cells between lymphoid tissue and colon. Finally, we show increasing B cell accumulation, clonal expansion and mutational frequency from caecum to sigmoid colon, and link this to the increasing number of reactive bacterial species.
The Arabidopsis condensin CAP-D subunits arrange interphase chromatin
Authors: Municio Celia , Antosz Wojciech , Grasser Klaus D. , Kornobis Etienne , Van Bel Michiel , Eguinoa Ignacio , Coppens Frederik , Bräutigam Andrea , Lermontova Inna , Bruckmann Astrid , Houben Andreas , Schubert Veit
Published: December 2019

Condensins are best known for their role in shaping chromosomes. However, other functions as organizing interphase chromatin and transcriptional control have been reported in yeasts and animals. Yeasts encode one condensin complex, while higher eukaryotes have two of them (condensin I and II). Both, condensin I and II, are conserved inArabidopsis thaliana, but so far little is known about their function. Here we show that theA. thalianaCAP-D2 (condensin I) and CAP-D3 (condensin II) subunits are highly expressed in mitotically active tissues.In silicoand pull-down experiments indicate that both CAP-D proteins interact with the other condensin I and II subunits. Our data suggest that the expression, localization and composition of the condensin complexes inA. thalianaare similar as in other higher eukaryotes. Previous experiments showed that the lack ofA. thalianaCAP-D3 leads to centromere association during interphase. To study the function of CAP-D3 in chromatin organization more in detail we compared the nuclear distribution of rDNA, of centromeric chromocenters and of different epigenetic marks, as well as the nuclear size between wild-type andcap-d3mutants. In these mutants an association of heterochromatic sequences occurs, but nuclear size and the general methylation and acetylation patterns remain unchanged. In addition, transcriptome analyses revealed a moderate influence of CAP-D3 on general transcription, but a stronger one on transcription of stress-related genes. We propose a model for the CAP-D3 function during interphase, where CAP-D3 localizes in euchromatin loops to stiff them, and consequently separates centromeric regions and 45S rDNA repeats.
Bagworm decorations are an anti-predatory structure
Authors: Khan Md Kawsar
Published: December 2019

Many animals decorate their exterior with environmental materials and these decorations are predicted to increase their survival. The adaptive significance of these decorations, however, has seldomly been tested experimentally under field conditions. Here, I studied the anti-predatory functions of the decoration (bag) of a bagworm moth,Eumeta crameriagainst their natural predator,Oecophylla smaragdina, the Asian weaver ant. I experimentally tested if bag removal from caterpillars resulted in more predation than bagged caterpillar under field conditions, which would support the hypothesis that bags are selected to protect the caterpillars against their predators. In support of that, I showed that caterpillars without a bag were attacked, killed and taken to ants’ nest significantly more than bagged caterpillars. My study provides rare experimental evidence for anti-predatory functions of the decoration. My study suggests that decorating behaviour has evolved in animals as an anti-predatory defence mechanism.
Introgression across evolutionary scales suggests reticulation contributes to Amazonian tree diversity
Authors: Schley Rowan J. , Pennington R. Toby , Pérez-Escobar Oscar Alejandro , Helmstetter Andrew J. , de la Estrella Manuel , Larridon Isabel , Sabino Kikuchi Izai Alberto Bruno , Barraclough Timothy , Forest Félix , Klitgård Bente
Published: December 2019

Hybridization has the potential to generate or homogenize biodiversity and is a particularly common phenomenon in plants, with an estimated 25% of species undergoing inter-specific gene flow. However, hybridization in Amazonia’s megadiverse tree flora was assumed to be extremely rare despite extensive sympatry between closely related species, and its role in diversification remains enigmatic because it has not yet been examined empirically. Using members of a dominant Amazonian tree family (Brownea, Fabaceae) as a model to address this knowledge gap, our study recovered extensive evidence of hybridization among multiple lineages across phylogenetic scales. More specifically, our results uncovered several historical introgression events betweenBrownealineages and indicated that gene tree incongruence inBrowneais best explained by introgression, rather than solely by incomplete lineage sorting. Furthermore, investigation of recent hybridization using ∼19,000 ddRAD loci recovered a high degree of shared variation between twoBrowneaspecies which co-occur in the Ecuadorian Amazon. Our analyses also showed that these sympatric lineages exhibit homogeneous rates of introgression among loci relative to the genome-wide average, implying a lack of selection against hybrid genotypes and a persistence of hybridization over time. Our results demonstrate that gene flow between multiple Amazonian tree species has occurred across temporal scales, and contrasts with the prevailing view of hybridization’s rarity in Amazonia. Overall, our results provide novel evidence that reticulate evolution influenced diversification in part of the Amazonian tree flora, which is the most diverse on Earth.
Mitigating Local Over-fitting During Single Particle Reconstruction with SIDESPLITTER
Authors: Ramlaul Kailash , Palmer Colin M. , Aylett Christopher H. S.
Published: December 2019

Single particle analysis of cryo-EM images enables macromolecular structure determination at resolutions approaching the atomic scale. Experimental images are extremely noisy, however, and during iterative refinement it is possible to stably incorporate noise into the reconstructed density. Such “over-fitting” can lead to misinterpretation of the structure, and thereby flawed biological results. Several strategies are routinely used to prevent the spurious incorporation of noise within reconstructed volumes, the most common being independent refinement of two sides of a split dataset.

In this study, we show that over-fitting remains an issue within regions of low local signal-to-noise in reconstructed volumes refined using the half-set strategy. We propose a modified filtering process during refinement through the application of a local signal-to-noise filter, SIDESPLITTER, which we show to be capable of reducing over-fitting in both idealised and experimental settings, while maintaining independence between the two sides of a split refinement. SIDESPLITTER can also improve the final resolution in refinements of structures prone to severe over-fitting, such as membrane proteins in detergent micelles.
The effects of arbuscular mycorrhizal fungi (AMF) and Rhizophagus irregularis on soil microorganisms assessed by metatranscriptomics and metaproteomics
Authors: Lammel D.R. , Meierhofer D. , Johnston P. , Mbedi S. , Rillig M.C.
Published: December 2019

Arbuscular mycorrhizal fungi (AMF) form symbioses with approximately 80% of plant species and potentially benefit their hosts (e.g. nutrient acquisition) and the soil environment (e.g. soil aggregation). AMF also affect soil microbiota and soil multifunctionality. We manipulated AMF presence (via inoculation of non-sterile soil with Rhizophagus irregularis and using a hyphal compartment design) and used RNA-seq and metaproteomics to assess AMF roles in soil. The results indicated that AMF drove an active soil microbial community expressing transcripts and proteins related to nine metabolic functions, including the metabolism of C and N. We suggest two possible mechanisms: 1) the AMF hyphae produce exudates that select a beneficial community, or, 2) the hyphae compete with other soil microbes for available nutrients and consequently induce the community to mineralize nutrients from soil organic matter. We also identified candidate proteins that are potentially related to soil aggregation, such as Lpt and HSP60. Our results bridge microbial ecology and ecosystem functioning. We show that the AMF hyphosphere contains an active community related to soil respiration and nutrient cycling, thus potentially improving nutrient mineralization from soil organic matter and nutrient supply to the plants.