bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic Characterization of DFNB16-associated Hearing Loss
Authors: Back Daniela , Shehata-Dieler Wafaa , Vona Barbara , Hofrichter Michaela A. H. , Schroeder Joerg , Haaf Thomas , Rahne Torsten , Hagen Rudolf , Schraven Sebastian P.
Published: December 2018

Hypothesis:

We hypothesized that patients with DFNB16 caused hearing loss show characteristical audiological findings depending on genetic results.

Background:

Hearing loss belongs to the most frequent congenital diseases. In 50–70% of individuals, hearing loss is caused by genetic defects. DFNB1 (deafness, neurosensory, autosomal-recessive) is the most frequently affected locus. Despite its great genetic heterogeneity, comprehensive analysis of genes like STRC, encoding stereocilin (DFNB16) is possible. The genetic architecture of the DFNB16 locus is challenging and requires a unique molecular genetic testing assay. The aim of the study is a systematic characterization of the audiological phenotype in DFNB16-positive patients.

Methods:

Since 2011, 290 patients with suspicion of inherited hearing loss received a human genetic exploration. Eighty two DFNB1-negative patients advanced to further testing in the DFNB16 locus. STRC-positive patients obtained complete audiological diagnostic workup. Additionally, epidemiological data was collected.

Results:

Nine of 82 (11%) of the examined patients (mean age 5 yr) showed mutations in the STRC (3 homozygous, 6 compound heterozygous). Aside from a moderate hearing loss in the pure tone audiogram, auditory brainstem response thresholds were 40–50 dB nHL. Otoacoustic emissions were detectable in only one patient.

Conclusions:

Examination of the DFNB16-locus should be a standard diagnostic test after negative DFNB1-gene screening result. Notably, DFNB16-associated hearing loss can be audiologically characterized as moderate sensorineural hearing loss in the main speech field with absent otoacoustic emissions. Our study is the first to correlate audiological findings with genetic results in patients with hearing loss due to STRC.
Symptom Care at Home
Authors: Mooney Kathi , Whisenant Meagan S. , Beck Susan L.
Published: December 2018

Introduction:

There is growing recognition that systematically obtaining the patient’s perspective on their health experience, using patient-reported outcomes (PRO), can be used to improve patient care in real time. Few PRO systems are designed to monitor and provide symptom management support between visits. Patients are instructed to contact providers between visits with their concerns, but they rarely do, leaving patients to cope with symptoms alone at home. We developed and tested an automated system, Symptom Care at Home (SCH), to address this gap in tracking and responding to PRO data in-between clinic visits. The purpose of this paper is to describe SCH as an example of a comprehensive PRO system that addresses unmet need for symptom support outside the clinic.

Methods for PRO Score Interpretation:

SCH uses pragmatic, single-item measures for assessing symptoms, which are commonly used and readily interpretable for both patients and providers. We established alerting values for PRO symptom data, which was particularly important for conserving oncology providers’ time in responding to daily PRO data.

Methods for Developing Recommendations for Acting on PRO Results:

The SCH system provides automated, just-in-time self-management coaching tailored to the specific symptom pattern and severity levels reported in the daily call. In addition, the SCH system includes a provider decision support system for follow-up symptom assessment and intervention strategies.

Discussion:

SCH provides PRO monitoring, tailored automated self-management coaching, and alerts the oncology team of poorly controlled symptoms with a provider dashboard that includes evidence-based decision support for follow-up to improve individual patients’ symptom care. We particularly emphasize our process for PRO selection, rationale for determining alerting thresholds, and the design of the provider dashboard and decision support. Currently, we are in the process of updating the SCH system, developing both web-based and app versions in addition to interactive voice response phone access and integrating the SCH system in the electronic health record.
Pseudomyxoma Peritonei After a Total Pancreatectomy for Intraductal Papillary Mucinous Neoplasm With Colloid Carcinoma in Lynch Syndrome
Authors: Hackeng Wenzel M. , de Guerre Livia E. V. M. , Kuypers Karel C. , Snoek Alexander M. , Morsink Folkert H. , Offerhaus G. Johan A. , Brosens Lodewijk A. A.
Published: December 2018

We report a case of pseudomyxoma peritonei (PMP) arising in a 62-year-old male patient with Lynch syndrome (LS). The patient's medical history included an adenocarcinoma of the colon for which a right hemicolectomy was performed and a pancreatectomy due to an intraductal papillary mucinous neoplasm (IPMN) with invasive colloid carcinoma. It was considered that the PMP could be a metastasis of the earlier colonic or pancreatic carcinoma. The pancreatic carcinoma, colon carcinoma, and PMP tissues were examined, and immunohistochemical and molecular analyses were performed to determine the PMP origin. Histopathologic examination revealed morphological similarities with the pancreatic colloid carcinoma, and further immunohistochemical and molecular analyses, including a shared GNAS mutation, confirmed the pancreatic origin of the PMP. In conclusion, this is a unique case of a patient with LS presenting with PMP originating from an IPMN with invasive colloid carcinoma, several years after pancreatectomy. The present case has important diagnostic implications. The IPMN should be considered as a rare extracolonic manifestation of LS, and pancreatic carcinoma origin should be considered in patients presenting with PMP. This case report highlights the added value of molecular diagnostics in daily pathology practice.
The Frequency of Lysosomal Acid Lipase Deficiency in Children With Unexplained Liver Disease
Authors: Kuloglu Zarife , Kansu Aydan , Selbuz Suna , Kalaycı Ayhan G. , Şahin Gülseren , Kirsaclioglu Ceyda Tuna , Demirören Kaan , Dalgıç Buket , Kasırga Erhun , Önal Zerrin , İşlek Ali ,   National LAL‐D Study Group
Published: December 2018

Objectives:

Evidence suggests that lysosomal acid lipase deficiency (LAL‐D) is often underdiagnosed because symptoms may be nonspecific. We aimed to investigate the prevalence of LAL‐D in children with unexplained liver disease and to identify demographic and clinical features with a prospective, multicenter, cross‐sectional study.

Methods:

Patients (aged 3 months–18 years) who had unexplained transaminase elevation, unexplained hepatomegaly or hepatosplenomegaly, obesity‐unrelated liver steatosis, biopsy‐proven cryptogenic fibrosis and cirrhosis, or liver transplantation for cryptogenic cirrhosis were enrolled. A Web‐based electronic data collection system was used. LAL activity (nmol/punch/h) was measured using the dried blood spot method and classified as LAL‐D (<0.02), intermediate (0.02–0.37) or normal (> 0.37). A second dried blood spot sample was obtained from patients with intermediate LAL activity for confirmation of the result.

Results:

A total of 810 children (median age 5.6 years) from 795 families were enrolled. The reasons for enrollment were unexplained transaminase elevation (62%), unexplained organomegaly (45%), obesity‐unrelated liver steatosis (26%), cryptogenic fibrosis and cirrhosis (6%), and liver transplantation for cryptogenic cirrhosis (<1%). LAL activity was normal in 634 (78%) and intermediate in 174 (21%) patients. LAL‐D was identified in 2 siblings aged 15 and 6 years born to unrelated parents. Dyslipidemia, liver steatosis, and mild increase in aminotransferases were common features in these patients. Moreover, the 15‐year‐old patient showed growth failure and microvesicular steatosis, portal inflammation, and bridging fibrosis in the liver biopsy. Based on 795 families, 2 siblings in the same family were identified as LAL‐D cases, making the prevalence of LAL‐D in this study population, 0.1% (0.125%–0.606%). In the repeated measurement (76/174), LAL activity remained at the intermediate level in 38 patients.

Conclusions:

Overall, the frequency of LAL‐D patients in this study (0.1%) suggests that LAL‐D seems to be rare even in the selected high‐risk population.
Social Stress Affects Colonic Inflammation, the Gut Microbiome, and Short‐chain Fatty Acid Levels and Receptors
Authors: Maltz Ross M. , Keirsey Jeremy , Kim Sandra C. , Mackos Amy R. , Gharaibeh Raad Z. , Moore Cathy C. , Xu Jinyu , Somogyi Arpad , Bailey Michael T.
Published: December 2018

Objectives:

Gastrointestinal disorders, such as inflammatory bowel diseases (IBDs) and functional gastrointestinal disorders (FGIDs), involve disrupted homeostatic interactions between the microbiota and the host. Both disorders are worsened during stress, and in laboratory mice, stress exposure has been shown to change the composition of the gut microbiome. Stress‐induced changes to the microbiome exacerbate intestinal inflammation and alter intestinal motility in mice. It is, however, not yet known whether microbiota‐derived short‐chain fatty acids (butyrate, propionate, and acetate) and their receptors contribute to this effect.

Methods:

Mice were exposed to a social disruption stress, or left undisturbed as a control. After the first stress exposure, mice were orally challenged with Citrobacter rodentium or with vehicle. The levels of short‐chain fatty acids (SCFAs) were measured using gas chromatography‐mass spectrometry. SCFA receptors were measured via real‐time polymerase chain reaction. Microbial community composition was assessed using 16S rRNA gene sequencing.

Results:

Stress exposure reduced colonic SCFA levels. Stress exposure and C rodentium, however, significantly increased SCFA levels and changed the expression of SCFA receptors. The levels of SCFAs did not correlate with the severity of colonic inflammation, but the colonic expression of the SCFA receptor GPR41 was positively associated with inflammatory cytokines and colonic histopathology scores. The relative abundances of several taxa of colonic bacteria were significantly changed by stress exposure, including SCFA producers.

Conclusions:

Social stress can have a significant effect on infection‐induced colonic inflammation, and stress‐induced changes in microbial‐produced metabolites and their receptors may be involved.
The effect of task-oriented electromyography-triggered electrical stimulation of the paretic wrist extensors on upper limb motor function early after stroke: a pilot randomized controlled trial
Authors: Kirac-Unal Zeynep , Gencay-Can Asli , Karaca-Umay Ebru , Cakci Fatma A.
Published: December 2018

The combined effect of task-oriented motor training and electromyography (EMG)-triggered electrical stimulation (ES) has been examined in chronic stroke, but there are no published reports in patients with early stroke. Therefore, the purpose of this study was to determine the short-term and long-term effects of task-oriented EMG-triggered ES on upper limb motor function in acute/subacute stroke. Twenty-seven patients with stroke within the first 3 months after stroke onset were randomly allocated to an experimental group and a control group. Twenty-three patients (12 patients in the experimental group and 11 patients in the control group) completed the study. The control group received a conventional physical therapy for 20 sessions, and the experimental group received task-oriented EMG-triggered ES therapy for the wrist/finger extensors in addition to conventional physical therapy for 5 sessions a week for 4 weeks. Primary outcome measures were the Action Research Arm Test, the Brunnstrom stages of the hand/upper extremity, and the motor Functional Independence Measure. All patients were evaluated before the treatment, after the treatment, and at 3 months. The parametric and nonparametric statistics at the 5% level of significance (α=0.05) was used for testing the differences between the two groups at each main end point. At the end of the treatment, the experimental group showed significantly greater improvements in Brunnstrom stages and ARAT grasp/grip/pinch scores, but not motor Functional Independence Measure scores, when compared with the control group. The differences between the 3-months and postintervention evaluations were not significant between the two groups suggesting retention of the postintervention gains. Our results indicate that task-oriented EMG-triggered ES training may result in improvements in the paretic upper limb function in patients with acute/subacute stroke that are superior to the conventional treatment.
Using Theory to Inform and Guide Perinatal Bereavement Care
Authors: Hutti Marianne H. , Limbo Rana
Published: December 2018

Providing nursing care to perinatally bereaved women and their families is difficult, emotionally demanding, and complicated. Here we demonstrate how, through understanding the theoretical underpinnings of Guided Participation and perinatal grief intensity, nurses can significantly expand their competence and confidence in their ability to provide highly individualized, supportive, relationship-based perinatal bereavement care. The way that parents respond to a perinatal loss may range from little response to highly intense, long-lasting grief. Grief after such losses may be intensified when the loss experience is highly incongruent with a parent's expectations, and the parent is unable to act to reduce this incongruence. The Hutti Perinatal Grief Intensity theoretical framework and the Perinatal Grief Intensity Scale may be used to help identify parents who are likely to experience highly intense grief and need for professional follow-up after perinatal loss. However, many parents who experience intense grief have little experience in coping with such feelings. Guided Participation is a middle-range theory of teaching and learning. It is used in the context of perinatal bereavement to help bereaved parents navigate the feelings and numerous grief-related issues that occur as a consequence of the loss, with the nurse serving as the expert guide. This combined theoretical approach to care assists nurses to assess grief intensity and to provide highly effective, relationship-driven care.
Retroposition of the Globe After Le Fort III Midfacial Distraction
Authors: Resnick Cory M. , Salcines Alfonso , Hughes Christopher D. , Padwa Bonnie L. , Mulliken John B.
Published: December 2018

Background:

Patients with syndromic craniosynostosis exhibit exorbitism due to supraorbital and midfacial retrusion. This study documented the change in sagittal orbital-globe relationship following Le Fort III midfacial advancement.

Methods:

This retrospective case series comprised patients with syndromic craniosynostosis who underwent midfacial distraction from 1997 to 2016. Changes in sagittal globe position in relation to the orbital rims were measured by pre- and postoperative direct anthropometry, computed tomographic scans, or both methods. Descriptive statistics were calculated; significance was set at P < 0.05.

Results:

Anthropometry showed a significant increase from superior orbital rim-to-corneal apex (os-acor) (4.1 ± 4.0 mm, P < 0.001) and from inferior orbital rim-to-corneal apex (oi-acor) (4.5 ± 5.3 mm, P < 0.001). The lateral orbital rim to the corneal apex (ol-acor) dimension did not change significantly. Computed tomography measurements confirmed retropositioned globes relative to the anterior border of the orbital cavity (2.5 ± 6.4 mm, P = 0.036). The 2 analytic methods yielded statistically similar results.

Conclusion:

The globes move posteriorly a mean of 2.5 to 4.5 mm following Le Fort III midfacial distraction in patients with syndromic craniosynostosis. This finding is useful in attaining euophthalmos when planning and executing this procedure.
Innovation to Pediatric Cranioplasty
Authors: Konofaos Petros , Wallace Robert D.
Published: December 2018

Pediatric cranioplasty poses a reconstructive challenge because of children's developing anatomy and dynamic growth. Although several studies have advocated the use of autologous bone over synthetic material in pediatric population, the full coverage of the cranioplasty defect can be not fulfilled in the majority of the cases due to the size of the defect and the limited bone stock. There is an ongoing research for the development of alloplastic bone substitutes that avoid rigid fixation and promote graft transformation into viable tissue to improve outcomes in alloplastic pediatric cranioplasty. The aim of this study is to offer a detailed review on evolution, evaluation, planning, materials, and outcomes of cranioplasty in pediatric patients.
En-Bloc Excision of the High-ligated Inferior Mesenteric Vein Pedicle With the Specimen in Patients Undergoing Minimally Invasive and Open Sphincter Saving Rectal Resections for Cancer
Authors: Bilgin Ismail Ahmet , Aytaç Erman , Baca Bilgi , Benlice Çigdem , Aghayeva Afag , Esen Eren , Göksel Süha , Tayfun Karahasanoğlu , Hamzaoglu Ismail
Published: December 2018

Although high-ligated pedicle of the inferior mesenteric artery is usually kept in the resected specimens, the value of preserving high-ligated pedicle of the inferior mesenteric vein within the resected specimens of the sphincter saving rectal resections for cancer is not well defined. In the current study, patients undergoing open, laparoscopic, and robotic sphincter saving rectal resection for cancer were prospectively included. Lymph node invasion and presence of lymph nodes along the IMV pedicles were analyzed. In total 100 patients were included. There were lymph nodes in 63 patients at the IMV and 71 patients at the IMA pedicles. En-bloc removal of the high-ligated IMV pedicle with the resected specimen significantly increased the number of harvested lymph nodes(P<0.001) regardless of surgical modality (P=0.36). Although it increases the number of harvested lymph nodes with acceptable operative morbidity, no oncological benefits were found related to preservation of high-ligated pedicle of the inferior mesenteric vein within the resected specimen of the rectum.
A Multi-Scale Modelling Framework of the Whole Human Body Based on Multi-Objective Functions
Authors: Khaksar Masood , Cluett Will , Mahadevan Radhakrishnan
Published: December 2018

Constraint-based multi-scale metabolic models are powerful tools to study complex biological systems like the human body, and to develop new treatment strategies for human diseases. They capture different scales of the system under study and provide the opportunity of understanding the interaction between multiple scales. In this paper, we have used our previously developed multi-scale whole body metabolism framework to establish a new approach to include multiple objectives of the human cells in computational analysis. The model has 3555 ordinary differential equations (ODEs) integrated with a genome-scale model of the hepatocyte, including 1826 biochemical reactions. The model has been solved for 74 objective functions simultaneously. Simulation results show that the integration algorithm has promise with respect to convergence, computational efficiency and response to perturbation. The results suggest that this method holds significant potential for the simulation of the range of metabolic phenotypes for mammalian cells where there are multiple objectives.
Combining heterogeneous data sources for neuroimaging based diagnosis: re-weighting and selecting what is important
Authors: Donini Michele , Monteiro Joao M. , Pontil Massimiliano , Hahn Tim , Fallgatter Andreas J. , Shawe-Taylor John , Mourao-Miranda Janaina
Published: December 2018

Combining neuroimaging and clinical information for diagnosis, as for example behavioral tasks and genetics characteristics, is potentially beneficial but presents challenges in terms of finding the best data representation for the different sources of information. Their simple combination usually does not provide an improvement if compared with using the best source alone. In this paper, we proposed a framework based on a recent multiple kernel learning algorithm called EasyMKL and we investigated the benefits of this approach for diagnosing two different mental health diseases. The well known Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset tackling the Alzheimer Disease (AD) patients versus healthy controls classification task, and a second dataset tackling the task of classifying an heterogeneous group of depressed patients versus healthy controls. We used EasyMKL to combine a huge amount of basic kernels alongside a feature selection methodology, pursuing an optimal and sparse solution to facilitate interpretability. Our results show that the proposed approach, called EasyMKLFS, outperforms baselines (e.g. SVM and SimpleMKL), state-of-the-art random forests (RF) and feature selection (FS) methods.
Genetic determination of stomatal patterning in winter wheat (Triticum aestivum L.)
Authors: Yates Steven Andrew , Bruun Andreas , Hodel Marius , Grieder Christoph , Hund Andreas , Walter Achim , Studer Bruno
Published: December 2018

Leaf stomata are microscopic pores mediating plant-environment interactions. Their role in carbon uptake and transpiration make them prime candidates for improving water use efficiency (WUE). Stomatal density (SD), the number of stomata per unit area, has been shown to be negatively correlated with WUE. However, little is known about the genetic basis of SD in wheat (Triticum aestivum L.), and to what extant genetic variation exists in contemporary wheat germplasm. Here, we evaluated stomatal patterning over two growing seasons in a set of 333 wheat lines, representing the European winter wheat germplasm. Stomatal patterning was mainly determined by two underlying traits, the distance between files of stomata and the distance between stomata within a file. By haplotype association mapping, quantitative trait loci for SD were consistently detected in both seasons on wheat chromosomes (CHR) 2A, 3A and 7B. The single nucleotide polymorphism markers most significantly associated with SD coincided with the genes INDUCER OF CBF EXPRESSION 1 (ICE1) and STOMATAL CYTOKINESIS-DEFECTIVE 1 (SCD1) on CHR 3A, and genes involved in ethylene and auxin signaling on CHR 2A and 7B, respectively. Our study unlocks the phenotypic and genotypic variation for stomatal patterning traits in contemporary wheat germplasm. It provides gene targets for functional validation and practical tools to manipulate SD using marker-assisted selection for crop improvement.
BRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors
Authors: Reisländer Timo , Lombardi Emilia Puig , Groelly Florian J. , Miar Ana , Porru Manuela , Wright Benjamin , Lockstone Helen , Biroccio Annamaria , Harris Adrian , Londono Arturo , Tarsounas Madalena
Published: December 2018

Heterozygous germline mutations in BRCA2 predispose to breast and ovarian cancer. Contrary to non-cancerous cells, where BRCA2 deletion causes cell cycle arrest or cell death, BRCA2 inactivation in tumors is associated with uncontrolled cell proliferation. We set out to investigate this conundrum by exploring modalities of cell adaptation to loss of BRCA2 and focused on genome-wide transcriptome alterations. Human cells in which BRCA2 expression was inhibited using a doxycycline (DOX)-inducible shRNA for 4 or 28 days were subjected to RNA-seq analyses. Gene sets differentially expressed in BRCA2-deficient versus -proficient cells revealed a biphasic response to BRCA2 abrogation. The early, acute response consisted of downregulation of genes involved in cell cycle progression, DNA replication and repair and was associated with cell cycle arrest in G1. Surprisingly, the late, chronic response consisted predominantly of upregulation of innate immune response genes controlled by interferon. Activation of the cGAS-STING pathway detected in these cells further substantiated the concept that long-term BRCA2 abrogation triggers cell-intrinsic immune signaling. Importantly, we found that treatment with PARP inhibitors stimulated the interferon response in cells and tumors lacking BRCA2. We propose that PARP inhibitors may suppress growth of BRCA2-deficient cells and tumors, in part, by activating interferon signaling.
Combinations of slow translating codon clusters can increase mRNA half-life
Authors: Sharma Ajeet K. , O’Brien Edward P.
Published: December 2018

The introduction of a single, non-optimal codon cluster into a transcript was found to cause ribosomes to queue upstream of it and decrease the transcript’s half-life through the action of the dead box protein Dhh1p, which interacts with stalled ribosomes and promotes transcript degradation. Naturally occurring transcripts often contain multiple slow codon clusters, but the influence of these combinations of clusters on a transcript’s half-life is unknown. Using a kinetic model that describes translation and mRNA degradation, we find that the introduction of a second slow codon cluster into a transcript near the 5′-end can have the opposite effect than that of the first cluster by increasing the mRNA’s half-life. We experimentally validate this finding by showing that S. cerevisiae transcripts that only have a slow codon cluster towards the 3′-end of the coding sequence have shorter half-lives than transcripts with non-optimal clusters at both 3′ and 5′ -ends. The origin of this increase in half-life arises from the 5′-end cluster suppressing the formation of ribosome queues upstream of the second cluster, thereby decreasing the opportunities for translation-dependent degradation machinery, such as the Dhh1p protein, to interact with stalled ribosomes. We also find in the model that in the presence of two slow codon clusters the cluster closest to 5′-end is the primary determinant of mRNA half-life. These results identify two of the rules governing the influence of slow codon clusters on mRNA half-life, demonstrate that multiple slow codon clusters can have synergistic effects, and indicate that codon usage bias can play a more nuanced role in controlling cellular protein levels than previously thought.
Assignment of virus and antimicrobial resistance genes to microbial hosts in a complex microbial community by combined long-read assembly and proximity ligation
Authors: Bickhart Derek M. , Watson Mick , Koren Sergey , Panke-Buisse Kevin , Cersosimo Laura M. , Press Maximilian O. , Van Tassell Curtis P. , Van Kessel Jo Ann S. , Haley Bradd J. , Kim Seon Woo , Heiner Cheryl , Suen Garret , Bakshy Kiranmayee , Liachko Ivan , Sullivan Shawn T. , Ghurye Jay , Pop Mihai , Weimer Paul J. , Phillippy Adam M. , Smith Timothy P.L.
Published: December 2018

The characterization of microbial communities by metagenomic approaches has been enhanced by recent improvements in short-read sequencing efficiency and assembly algorithms. We describe the results of adding long-read sequencing to the mix of technologies used to assemble a highly complex cattle rumen microbial community, and compare the assembly to current short read-based methods applied to the same sample. Contigs in the long-read assembly were 7-fold longer on average, and contained 7-fold more complete open reading frames (ORF), than the short read assembly, despite having three-fold lower sequence depth. The linkages between long-read contigs, provided by proximity ligation data, supported identification of 188 novel viral-host associations in the rumen microbial community that suggest cross-species infectivity of specific viral strains. The improved contiguity of the long-read assembly also identified 94 antimicrobial resistance genes, compared to only seven alleles identified in the short-read assembly. Overall, we demonstrate a combination of experimental and computational methods that work synergistically to improve characterization of biological features in a highly complex rumen microbial community.
Transcriptomic biomarkers for prediction/classification of sample conditions in marine microeukaryotes (diatoms)
Authors: Ashworth Justin
Published: December 2018

Marine microeukaryotes express large and complex transcriptomes that often respond dynamically to environmental and physiological conditions. In parallel to developments in human disease research, the opportunity exists to employ transcriptomic features as "biomarkers" to understand and predict cellular and environmental states. Here, the prediction and classification of basic physiological and environmental states including light, growth phase and inorganic carbon status was explored for the model diatom T. pseudonana using publicly available data including 56 microarray and 316 mRNA-seq samples. Simple "machine learning" methods combined with integrative bootstrapped clustering were able to detect, recapitulate and expand biologically and environmentally relevant signals evident across hundreds of samples collected and processed independently by multiple laboratories. Agnostic, integrative and empirical "data-driven" approaches are likely applicable to modern questions in new environmental and experimental contexts.
Cryptic and extensive hybridization between ancient lineages of American crows
Authors: Slager David L. , Epperly Kevin L. , Ha Renee R. , Rohwer Sievert , Wood Chris , Van Hemert Caroline , Klicka John
Published: December 2018

Most species and therefore most hybrid zones have historically been described using phenotypic characters. However, both speciation and hybridization can occur with negligible morphological differentiation. The Northwestern Crow (Corvus caurinus) and American Crow (Corvus brachyrhynchos) are sister taxonomic species with a continuous distribution that lack reliable traditional characters for identification. In this first population genomic study of Northwestern and American crows, we use genomic SNPs (nuDNA) and mtDNA to investigate whether these crows are genetically differentiated and the extent to which they may hybridize. We found that American and Northwestern crows have distinct evolutionary histories, supported by two nuDNA ancestry clusters and two 1.1%-divergent mtDNA clades dating to the late Pleistocene, when glacial advances may have isolated crow populations in separate refugia. We document extensive hybridization, with geographic overlap of mtDNA clades and admixture of nuDNA across >1,400 km of western Washington and western British Columbia. This broad hybrid zone consists of late-generation hybrids and backcrosses, not recent (e.g., F1) hybrids. Nuclear DNA and mtDNA clines were both centered in southwestern British Columbia, farther north than previously postulated. The mtDNA cline was narrower than the nuDNA cline, consistent with Haldane’s rule but not sex-biased dispersal. Overall, our results suggest a history of reticulate evolution in American and Northwestern crows, consistent with potentially recurring neutral expansion(s) from Pleistocene glacial refugia followed by lineage fusion(s). However, we do not rule out a contributing role for more recent potential drivers of hybridization, such as expansion into human-modified habitats.
Imaging mechanical properties of sub-micron ECM in live zebrafish using Brillouin microscopy
Authors: Bevilacqua Carlo , Sánchez Iranzo Héctor , Richter Dmitry , Diz-Muñoz Alba , Prevedel Robert
Published: December 2018

In this work, we quantify the mechanical properties of extra-cellular matrix (ECM) in live zebrafish using Brillouin microscopy. Optimization of the imaging conditions and parameters, combined with careful spectral analysis, allows us to resolve the thin ECM and distinguish its Brillouin frequency shift from the surrounding tissue. High-resolution mechanical mapping further enables to directly measure the thickness of the ECM label-free and in-vivo. We find the ECM to be ~400nm thick, in excellent agreement with electron microscopy quantification. Our results open the door for future studies that aim to investigate the role of ECM mechanics for zebrafish morphogenesis and axis elongation.
Optimizing adaptive cancer therapy: dynamic programming and evolutionary game theory
Authors: Gluzman Mark , Scott Jacob G. , Vladimirsky Alexander
Published: December 2018

Recent clinical trials have shown that the adaptive drug therapy can be more efficient than a standard MTD-based policy in treatment of cancer patients. The adaptive therapy paradigm is not based on a preset schedule; instead, the doses are administered based on the current state of tumor. But the adaptive treatment policies examined so far have been largely ad hoc. In this paper we propose a method for systematically optimizing the rules of adaptive policies based on an Evolutionary Game Theory model of cancer dynamics. Given a set of treatment objectives, we use the framework of dynamic programming to find the optimal treatment strategies. In particular, we optimize the total drug usage and time to recovery by solving a Hamilton-Jacobi-Bellman equation based on a mathematical model of tumor evolution. We compare adaptive/optimal treatment strategy with MTD-based treatment policy. We show that optimal treatment strategies can dramatically decrease the total amount of drugs prescribed as well as increase the fraction of initial tumour states from which the recovery is possible. We also examine the optimization trade-offs between the total administered drugs and recovery time. The adaptive therapy combined with optimal control theory is a promising concept in the cancer treatment and should be integrated into clinical trial design.
Quantitative relationships between SMAD dynamics and target gene activation kinetics in single live cells
Authors: Tidin Onur , Friman Elias T. , Naef Felix , Suter David M.
Published: December 2018

The transduction of extracellular signals through signaling pathways that culminate in a transcriptional response is central to many biological processes. However, quantitative relationships between activities of signaling pathway components and transcriptional output of target genes remain poorly explored. Here we developed a dual bioluminescence imaging strategy allowing simultaneous monitoring of nuclear translocation of the SMAD4 and SMAD2 transcriptional activators upon TGF-β stimulation, and the transcriptional response of the endogenous connective tissue growth factor (ctgf) gene. Using cell lines allowing to vary exogenous SMAD4/2 expression levels, we performed quantitative measurements of the temporal profiles of SMAD4/2 translocation and ctgf transcription kinetics in hundreds of individual cells at high temporal resolution. We found that while nuclear translocation efficiency had little impact on initial ctgf transcriptional activation, high total cellular SMAD4 but not SMAD2 levels increased the probability of cells to exhibit a sustained ctgf transcriptional response. The approach we present here allows time-resolved single cell quantification of transcription factor dynamics and transcriptional responses and thereby sheds light on the quantitative relationship between SMADs and target gene responses.
Exploration Of The Timeliness Of ICD Codes In Administrative Databases: A Nationwide Study
Authors: Simon Marie , Rance Bastien , Katsahian Sandrine , Bounebache Karim , Rey Gregoire , Chatellier Gilles , Neuraz Antoine , Burgun Anita , Looten Vincent
Published: December 2018

INTRODUCTION: The ICD codes are ubiquitously available in hospital information systems and have been used in a number of areas such as epidemiology, phenotype-genotype association mining, surveillance of the use of drugs and medical devices and health care evaluation. We aimed to analyze the timeliness of the 3-character ICD-10 codes collected in the French national hospital discharge summary database between 2008 and 2017 and we classified the codes according to their evolution.
MATERIAL AND METHODS: We extracted all 3-character ICD-10 codes from all French hospital discharge summaries between 2008 and 2017. For each code and by the month, we computed a relative frequency; we also computed the overall amplitude of the study period. Temporal clustering, according to the SAX representation, was performed to classify the main evolution patterns.
RESULTS: We extracted 238,334,751 encounters corresponding to 56,621,773 distinct patients. 1,006 ICD codes presented a variation of the relative amplitude of frequencies lower than 50%, 510 codes between 50% and 100% and 521 greater than 100%. Out of the 2,037 codes included in the study, we kept the 1,758 for the temporal clustering. Four clusters were identified, including a global increase and a global decrease patterns.
DISCUSSION: The overall results showed a strong instability (i.e. large variation of frequency over time) of the use of ICD codes over time, with an important variation of the relative amplitude of the frequencies. We distinguished between external factors due to changes in billing, organization, policy or regulation and intrinsic factors due to epidemiological phenomenon. The detailed analysis of profiles show that the same cluster can contain profiles influenced by intrinsic epidemiological or external factors or both. Additional knowledge and sources are probably required to determine automatically the origin of the profile.
Cortical and thalamic connectivity of posterior parietal visual cortical areas PPc and PPr of the domestic ferret (Mustela putorius furo).
Authors: Dell Leigh-Anne , Innocenti Giorgio M , Hilgetag Claus C , Manger Paul R
Published: December 2018

The present study describes the ipsilateral and contralateral cortico-cortical and cortico-thalamic connectivity of the parietal visual areas PPc and PPr in the ferret using standard anatomical tract-tracing methods. The two divisions of posterior parietal cortex of the ferret are strongly interconnected, however area PPc shows stronger connectivity with the occipital and suprasylvian visual cortex, while area PPr shows stronger connectivity with the somatomotor cortex, reflecting the functional specificity of these two areas. This pattern of connectivity is mirrored in the contralateral callosal connections. In addition, PPc and PPr are connected with the visual and somatomotor nuclei of the dorsal thalamus. Numerous connectional similarities exist between the posterior parietal cortex of the ferret (PPc and PPr) and the cat (area 7 and 5), indicative of the homology of these areas within the Carnivora. These findings highlight the existence of a fronto-parietal network as a shared feature of the organization of parietal cortex across Euarchontoglires and Laurasiatherians, with the degree of expression varying in relation to the expansion and areal complexity of the posterior parietal cortex. This observation indicates that the ferret is a potentially valuable experimental model animal for understanding the evolution and function of the posterior parietal cortex and the fronto-parietal network across mammals. The data generated will also contribute to the Ferretome (www.ferretome.org) connectomics databank, to further cross-species analyses of connectomes and illuminate wiring principles of cortical connectivity across mammals.
Codon-dependent noise dictates cell-to-cell variability in nutrient poor environments
Authors: Balleza Enrique , Marshall Lisa F. , Mark Kim J. , Cluzel Philippe
Published: December 2018

Under nutrient-rich conditions, stochasticity of transcription drives protein expression noise. However, by shifting the environment to amino acid-limited conditions, we identified in E. coli a source of noise whose strength is dictated by translational processes. Specifically, we discovered that cell-to-cell variations in fluorescent protein expression depend on codon choice, with codons yielding lower mean expression after amino acid downshift also resulting in greater noise. We propose that ultra-sensitivity in the tRNA charging/discharging cycle shapes the strength of the observed noise by amplifying fluctuations in global intracellular parameters, such as the concentrations of amino acid, synthetase, and tRNA. We hypothesize that this codon-dependent noise may allow bacteria to selectively optimize cell-to-cell variability in poor environments without relying on low molecular numbers.
Parameter estimation and identifiability in a neural population model for electro-cortical activity
Authors: Hartoyo Agus , Cadusch Peter J. , Liley David T. J. , Hicks Damien G.
Published: December 2018

Electroencephalography (EEG) provides a non-invasive measure of brain electrical activity. Neural population models, where large numbers of interacting neurons are considered collectively as a macroscopic system, have long been used to understand features in EEG signals. By tuning dozens of input parameters describing the excitatory and inhibitory neuron populations, these models can reproduce prominent features of the EEG such as the alpha-rhythm. However, the inverse problem, of directly estimating the parameters from fits to EEG data, remains unsolved. Solving this multi-parameter non-linear fitting problem will potentially provide a real-time method for characterizing average neuronal properties in human subjects. Here we perform unbiased fits of a 22-parameter neural population model to EEG data from 82 individuals, using both particle swarm optimization and Markov chain Monte Carlo sampling. We estimate how much is learned about individual parameters by computing Kullback-Leibler divergences between posterior and prior distributions for each parameter. Results indicate that only a single parameter, that determining the dynamics of inhibition, is directly identifiable, while other parameters have large, though correlated, uncertainties. We show that the eigenvalues of the Fisher information matrix are roughly uniformly spaced over a log scale, indicating that the model is sloppy, like many of the regulatory network models in systems biology. These eigenvalues indicate that the system can be modeled with a low effective dimensionality, with inhibition being prominent in driving system behavior.

Author summary

Electroencephalography (EEG), where electrodes are used to measure electric potential on the outside of the scalp, provides a simple, non-invasive way to study brain activity. Physiological interpretation of features in EEG signals has often involved use of collective models of neural populations. These neural population models have dozens of input parameters to describe the properties of inhibitory and excitatory neurons. Being able to estimate these parameters by direct fits to EEG data holds the promise of providing a real-time non-invasive method of inferring neuronal properties in different individuals. However, it has long been impossible to fit these nonlinear, multi-parameter models effectively. Here we describe fits of a 22-parameter neural population model to EEG spectra from 82 different subjects, all exhibiting alpha-oscillations. We show how only one parameter, that describing inhibitory dynamics, is constrained by the data, although all parameters are correlated. These results indicate that inhibition plays a central role in the generation and modulation of the alpha-rhythm in humans.
Membrane curvature sensing of the lipid-anchored K-Ras small GTPases
Authors: Liang Hong , Mu Huanwen , Jean-Francois Frantz , Lakshman Bindu , Sarkar-Banerjee Suparna , Zhuang Yinyin , Zeng Yongpeng , Gao Weibo , Nissley Dwight V , Gorfe Alemayehu A , Zhao Wenting , Zhou Yong
Published: December 2018

Cell morphologies, defined by plasma membrane (PM) local curvature, change during mitogen-dependent function and pathology, such as growth, division and proliferation. The lipid-anchored Ras small GTPases are essential upstream regulators of the mitogen-activated protein kinases (MAPKs) cascades and play key roles in many pathological conditions, especially cancer. Ras signaling is mostly compartmentalized to the cell PM through the formation of nanometer-sized domains, termed as nanoclusters, and undergo selective lipid sorting for efficient effector recruitment and activation. Thus, Ras function might be sensitive to changing PM curvature, potentially regulating mechanosensing of mitogen signaling. We employed nanofabrication and super-resolution imaging and found that Ras functions respond to PM curvature modulations in an isoform specific manner: nanoclustering and signaling of the most oncogenically prevalent isoform K-Ras favor less curved PM, while those of another isoform H-Ras favor more curved PM. We then examined whether Ras membrane curvature sensing is mediated by lipid sorting. We found that anionic phospholipids sense changing PM curvature in distinct manners: phosphatidylserine (PS) localization shows preference for less curved membrane but phosphoinositol 4,5-bisphosphate (PIP2) localization favors more curved PM. Depletion of endogenous PS abolishes K-Ras PM curvature sensing. Exogenous PS addback and synthetic bilayer binding assays further show that only mixed-chain PS species, but not other PS species, mediate K-Ras curvature sensing. Taken together, the Ras proteolipid nano-assemblies on the PM act as relay stations to convert mechanical stimulations to mitogenic signaling circuits, thus a novel mechanism for cancer cell mechanotransduction.
REACTION-DIFFUSION MECHANISMS UNDERLYING HIRSCHPRUNG'S DISEASE AND THEIR PRACTICAL IMPICATIONS
Authors: Tozzi Arturo
Published: December 2018

The erratic extent of aganglionic and hypoganglionic segments in Hirschsprung's disease (HD) makes it difficult to predict the amount of the intestine to remove in order to restore the proper functional motility. Our aim was to assess whether the embryonic rostro-caudal intestinal colonization by neuroblasts from the neural crest follows a predictable pattern in HD. In touch with Turing's reaction diffusion model (RD), which describes biological patterns (such as leopard spots and lung branching morphogenesis) in terms of interactions/competitions between activating and inhibiting factors, we hypothesized that intestinal neural density could be triggered by local gut factors that counteract the proximal-distal embryonic progression of neural progenitors. While the neuronal number is approximately the same throughout the whole intestine in healthy subjects, in HD neural density decreases rostro-caudally towards the rectal region, due to an augmented activity and concentration of distal local inhibitors. In order to prove our hypothesis of HD's nervous rostro-caudal adjustments driven by Turing-like processes, we compared the neuronal density patterns achieved through RD models' simulations with the neuronal numbers detected in different colonic regions from affected children. We showed that the virtual and the real plots display fully overlapping and matching features. The fact that neuronal decreases in impaired colons match Turing equations's previsions points towards the human intestine (both healthy and sick) as colonized through a diffusive proximal-distal neural pattern that is predictable, allowing us to straightforwardly calculate the length of the gut to resect during surgical procedures for HD.