bluuebunny/crossref_metadata_2025 huggingface dataset:
Umbilical artery thrombosis
Authors: Li Huanxi , Qufeng Wu , Wei Wei , Lin Xueyan , Zhang Xueqin
Published: November 2019

Rationale:

The umbilical cord is the way to exchange gas, supply nutrients, excrete metabolized. Thrombosis of the umbilical cord leads to fetal hypoxia, which jeopardizes fetal health and can cause fetal death. Umbilical vessel thrombosis, which is rarely reported, is difficult to detect prenatally.

Patient concerns:

Both pregnant women had an unremarkable pregnancy course until a routine ultrasound scan in the third trimester showed a single umbilical artery. However, one umbilical vein and 2 umbilical arteries were seen during an ultrasound examination at 32 weeks. Case 2 had a better pregnancy outcome because of the timely discovery of this complication.

Diagnosis:

Both cases were diagnosed as umbilical artery thrombosis.

Interventions:

The first patient received no interventions until they reported decreased fetal movements and gradually disappear. The second patient underwent an emergency cesarean section.

Outcomes:

In Case 1, an emergency ultrasound examination showed intrauterine fetal death, and the patient vaginally delivered a stillborn child weighing 3300 g in a day. In Case 2, a female neonate weighing 2860 g was delivered by cesarean section, and exhibited Apgar scores of 10 and 10 at 1 and 5 minutes.

Conclusion:

In the late-term abortions, obstetricians should be vigilant if ultrasound imaging shows suspected umbilical vascular thrombosis or shows 1 umbilical artery when there had previously been 2. The fetus should be closely monitored and interventions implemented as early as possible to improve the prenatal detection rate of umbilical vessel thrombosis and avoid adverse pregnancy outcomes.
Spontaneous rupture of unscarred uterus in the third trimester after in vitro fertilization-embryo transfer because of bilateral salpingectomy
Authors: Sun Yan , Huang Jing , Kong Hong-Fang
Published: November 2019

Rationale:

Rupture of an unscarred uterus after in vitro fertilization–embryo transfer (IVF-ET) in a primiparous woman is rare. Assisted reproductive technology (ART)-induced rupture of an unscarred uterus is usually attributable to increased dizygotic twinning rates. Salpingectomy can result in cornual scarring and increase the risk of uterine rupture as well as the mortality rate in a subsequent ectopic pregnancy. Here, we present the first reported case of a spontaneous, third-trimester, uterine rupture in a primiparous woman after IVF-ET due to a history of bilateral salpingectomy because of bilateral oviduct and ovarian cysts; the patient did not have an ectopic pregnancy or any cornual or other uterine scarring during this pregnancy after IVF-ET.

Patient concerns:

A 24-year-old woman with a history of IVF-ET and bilateral salpingectomy was admitted to our hospital with unexplained acute upper abdominal pain during the third trimester.

Diagnosis:

The fetal heart rate was abnormal. Abdominal ultrasonography was negative. Computed tomography revealed a small amount of abdominal and pericardial effusion. Laboratory tests revealed increased white blood cells. A diagnosis of pregnancy complicated by acute abdomen was considered. Emergent exploratory laparotomy revealed a uterine rupture at the right fundus adjacent to the right cornual area.

Interventions:

The patient was successfully managed with simultaneous exploratory laparotomy and lower-segment cesarean section. The rupture site was repaired.

Outcomes:

Two live infants were uneventfully delivered. Follow-up assessments of the mother and the female baby on the 42nd postpartum day yielded normal results. The male infant was diagnosed with left hydronephrosis and required an operation.

Lessons:

We conclude that the ART-associated increase in dizygotic twinning rates may be a neglected risk factor for spontaneous rupture of the unscarred uterus, especially in patients who have undergone salpingectomy. Uterine rupture should be considered in a patient with multiple pregnancy following IVF-ET who presents with acute abdominal pain and abnormal fetal heart rate. Timely exploratory laparotomy is the key to a good prognosis.
The expression and prognostic significance of Drp1 in lung cancer
Authors: Yu Lingling , Xiao Zuke , Tu Hongying , Tong Bo , Chen Shengsong
Published: November 2019

Background:

Dynamin-related protein 1 (Drp1) plays important roles in tumorigenesis, including lung cancer. However, the effect of Drp1 in lung cancer remains unclear. The present study was aimed to investigate the clinical significance and effect of Drp1 on prognosis of lung cancer.

Methods:

Oncomine and The Cancer Genome Atlas (TCGA) databases were selected to predict the differential expression levels of Drp1 in lung cancer. Then, 70 cases of lung cancer and normal tissues were collected and immunohistochemistry was used to detect the expression of Drp1. In addition, Kaplan–Meier Plotter database and TCGA database were used to verify the correlation between Drp1 expression and the clinical prognosis in lung cancer patients.

Results:

Drp1 was significantly overexpressed in lung cancer tissues based on Oncomine and TCGA databases (P < .05). Moreover, results from immunohistochemistry showed that Drp1 protein level in lung cancer was also significantly higher than that in the matched normal tissues (P < .05). Prognostic analysis from Kaplan–Meier Plotter database with the chosen probe IDs of 203105_s_at suggested that Drp1 was negatively correlated to overall survival (OS) of lung cancer patients (HR = 1.16, 95% CI: 1.02–1.31; P = .025), but not in the probe IDs of 226154_at (HR = 0.86, 95% CI: 0.73–1.01; P = .069). However, prognosis from TCGA database showed inconsistent results in which high expression of Drp1 was correlated with worse survival probability of all, male, female in lung adenocarcinoma (P < .05), but not in LUSC (P > .05).

Conclusion:

Drp1 was highly expressed in lung cancer based on bioinformatics analysis and tissue microarray, but there was a lot of inconsistency in prognosis depending on different levels of Drp1 from the bioinformatics analysis.
Optimizing Time to Antibiotic Administration in Children with Possible Febrile Neutropenia through Quality Improvement Methodologies
Authors: Burns Beech , Hartenstein Melinda , Lin Amber , Langley Denise , Burns Erin , Heilman James , Tanski Mary , Stork Linda , Ma O. John
Published: November 2019

Introduction:

Febrile neutropenia is a potentially life-threatening complication of chemotherapy in pediatric oncology patients. Prompt initiation of antibiotic therapy may minimize morbidity and mortality associated with this condition, and time to antibiotic (TTA) administration <60 minutes is used as a quality benchmark by many institutions. We implemented a quality improvement initiative to achieve TTA < 60 minutes in >80% of eligible patients in the pediatric emergency department.

Methods:

After collecting baseline data, we employed consecutive PDSA cycles to (i) reduce time to antibiotic order after patient arrival; (ii) expedite the preparation of antibiotic by pharmacy; and (iii) enable antibiotic ordering before patient arrival. Statistical process control methodologies were used for key outcome measures to compare pre-intervention, post-intervention, and maintenance periods.

Results:

Comparing pre-intervention and post-intervention years, mean TTA decreased from 64 to 53 minutes and the percentage of patients receiving antibiotics in <60 minutes increased from 59% to 84%. Improvements were sustained in the maintenance period of the project, with mean TTA administration of 44 minutes and 85% of patients receiving antibiotics within our stated goal.

Conclusion:

Through a series of PDSA cycles, we decreased TTA and increased the percentage of febrile neutropenia patients receiving antibiotics in <60 minutes.
Kidney Donor Profile Index Is a Reliable Alternative to Liver Donor Risk Index in Quantifying Graft Quality in Liver Transplantation
Authors: Scheuermann Uwe , Truong Tracy , Seyferth Elisabeth R. , Freischlag Kyle , Gao Qimeng , Yerxa John , Ezekian Brian , Davis Robert P. , Schroder Paul M. , Peskoe Sarah B. , Barbas Andrew S.
Published: November 2019

Background.

The most established metric for estimating graft survival from donor characteristics in liver transplantation is the liver donor risk index (LDRI). The LDRI is calculated from donor and transplant-related variables, including cold ischemic time. Because cold ischemic time is unknown at the time of organ offer, LDRI is not available for organ acceptance decisions. In contrast, the kidney donor profile index (KDPI) is derived purely from donor variables known at the time of offer and thus calculated for every deceased donor in the United States. The similarity in donor factors included in LDRI and KDPI led us to hypothesize that KDPI would reliably approximate LDRI in estimating graft survival in liver transplantation.

Methods.

The United Network of Organ Sharing registry was queried for adults who underwent deceased donor liver transplantation from 2002 to 2016. The cohort was divided into quintiles of KDPI and LDRI, and graft survival was calculated according to Kaplan Meier. Hazard ratios for LDRI and KDPI were estimated from Cox proportional hazards models, and Uno’s concordance statistic was compared.

Results.

In our analysis of 63 906 cases, KDPI closely approximated LDRI in estimating liver graft survival, with an equivalent concordance statistic of 0.56.

Conclusions.

We conclude that KDPI can serve as a reasonable alternative to LDRI in liver acceptance decisions.
Reserve in Alzheimer's disease: update on the concept, functional mechanisms and sex differences
Authors: Ewers Michael
Published: November 2019

Purpose of review

Epidemiological evidence suggests that higher reserve significantly delays the dementia onset in Alzheimer's disease. Yet, confusion in terminology of reserve and related concepts exists and the lack of quantitative measures and unclear neural substrates of reserve have hampered progress. We review here the latest advances in the concept, measures and functional brain mechanisms of reserve, as well as their moderating factors including sex and gender.

Recent findings

The definition of reserve has been revised towards a more simplified concept, and the development of quantitative measurements of a cognitive advantage in disease has been advanced. Functional MRI and FDG-PET studies have provided for the first time converging evidence for the involvement of the cognitive control and salience network and temporal pole in reserve. Women tend to show lower resilience than men at advanced stages of AD.

Neuroimaging studies have provided substantial evidence for putative brain mechanisms supporting reserve in Alzheimer's disease. However, the findings are still somewhat disparate and call for the development of unifying and testable theory of functional and structural brain properties that subserve reserve. Sex differences emerged as a moderating factor of reserve in Alzheimer's disease and need to be made a major research focus in Alzheimer's disease.
Can computers understand words like humans do? Comparable semantic representation in neural and computer systems
Authors: Zhang Linmin , Wang Lingting , Yang Jinbiao , Qian Peng , Wang Xuefei , Qiu Xipeng , Zhang Zheng , Tian Xing
Published: November 2019

Semantic representation has been studied independently in neuroscience and computer science. A deep understanding of human neural computations and the revolution to strong artificial intelligence appeal for a joint force in the language domain. We investigated comparable representational formats of lexical semantics between these two complex systems with fine temporal resolution neural recordings. We found semantic representations generated from computational models significantly correlated with EEG responses at an early stage of a typical semantic processing time window in a two-word semantic priming paradigm. Moreover, three representative computational models differentially predicted EEG responses along the dynamics of word processing. Our study provided a finer-grained understanding of the neural dynamics underlying semantic processing and developed an objective biomarker for assessing human-like computation in computational models. Our novel framework trailblazed a promising way to bridge across disciplines in the investigation of higher-order cognitive functions in human and artificial intelligence.
Standardizing Human Brain Parcellations
Authors: Lawrence Ross M. , Bridgeford Eric W. , Myers Patrick E. , Arvapalli Ganesh C. , Ramachandran Sandhya C. , Pisner Derek A. , Frank Paige F. , Lemmer Allison D. , Nikolaidis Aki , Vogelstein Joshua T.
Published: November 2019

Using brain atlases to localize regions of interest is a requirement for making neuroscientifically valid statistical inferences. These atlases, represented in volumetric or surface coordinate spaces, can describe brain topology from a variety of perspectives. Although many human brain atlases have circulated the field over the past fifty years, limited effort has been devoted to their standardization. Standardization can facilitate consistency and transparency with respect to orientation, resolution, labeling scheme, file storage format, and coordinate space designation. Our group has worked to consolidate an extensive selection of popular human brain atlases into a single, curated, open-source library, where they are stored following a standardized protocol with accompanying metadata, which can serve as the basis for future atlases. The repository containing the atlases, the specification, as well as relevant transformation functions is available at https://github.com/neurodata/neuroparc.
Messinian vegetation and climate of the intermontane Florina-Ptolemais-Servia Basin, NW Greece inferred from palaeobotanical data: How well do plant fossils reflect past environments?
Authors: Bouchal Johannes M. , Güner Tuncay H. , Velitzelos Dimitrios , Velitzelos Evangelos , Denk Thomas
Published: November 2019

The late Miocene is marked by pronounced environmental changes and the appearance of strong temperature and precipitation seasonality. Although environmental heterogeneity is to be expected during this time, it is challenging to reconstruct palaeoenvironments using plant fossils. We investigated leaves and dispersed spores/pollen from 6.4–6 Ma strata in the intermontane Florina-Ptolemais-Servia Basin (FPS) of northwestern Greece. To assess how well plant fossils reflect the actual vegetation of the FPS, we assigned fossil-taxa to biomes providing a measure for environmental heterogeneity. Additionally, the palynological assemblage was compared to pollen spectra from modern lake sediments to assess biases in spore/pollen representation in the pollen record. We found a close match of the Vegora assemblage with modernFagus–Abiesforests of Turkey. Using taxonomic affinities of leaf fossils, we further established close similarities of the Vegora assemblage with modern laurophyllous oak forests of Afghanistan. Finally, using information from sedimentary environment and taphonomy, we distinguished local and distantly growing vegetation types. We then subjected the plant assemblage of Vegora to different methods of climate reconstruction and discussed their potentials and limitations. Leaf and spore/pollen records allow accurate reconstructions of palaeoenvironments in the FPS, whereas extra-regional vegetation from coastal lowlands is likely not captured.
Identification of miRNA signatures for kidney renal clear cell carcinoma using the tensor-decomposition method
Authors: Ng Ka-Lok , Taguchi Y-h
Published: November 2019

Cancer is a highly complex disease caused by multiple genetic factors. MicroRNA (miRNA) and mRNA expression profiles are useful for identifying prognostic biomarkers for cancer. Kidney renal clear cell carcinoma (KIRC), which accounts for more than 70% of all renal malignant tumour cases, was selected for our analysis.

Traditional methods of identifying cancer prognostic markers may not be accurate. Tensor decomposition (TD) is a useful method uncovering the underlying low-dimensional structures in the tensor. The TD-based unsupervised feature extraction method was applied to analyse mRNA and miRNA expression profiles. Biological annotations of the prognostic miRNAs and mRNAs were examined utilizing the pathway and oncogenic signature databases DIANA-miRPath and MSigDB.

TD identified the miRNA signatures and the associated genes. These genes were found to be involved in cancer-related pathways, and 23 genes were significantly correlated with the survival of KIRC patients. We demonstrated that the results are robust and not highly dependent upon the databases we selected. Compared with traditional supervised methods tested, TD achieves much better performance in selecting prognostic miRNAs and mRNAs.

These results suggest that integrated analysis using the TD-based unsupervised feature extraction technique is an effective strategy for identifying prognostic signatures in cancer studies.
RIPK3 inhibition prevents KRAS mutant p53 deficient lung tumor progression by impeding MDSCs
Authors: Jayakumar Asha
Published: November 2019

KRAS mutant p53 deficient (KP) non-small cell lung carcinoma (NSCLC) lacks targeted therapies. Existing treatments for lung cancer cause resistance and result in toxicities requiring novel effective therapies. By targeting mechanisms causing resistance such as myeloid derived suppressor cells (MDSCs), KP tumors could be inhibited. MDSCs are functionally diverse and suppress T cells in many cancers. RIPK3, a cell death inducing enzyme, also functions as a signaling component producing cytokines that mediate the suppressive function of MDSCs. Partial deletion of RIPK3 in myeloid cells reduced KP tumor growth. This also reduced accumulation of MDSCs with a consistent increase in antigen specific IFNγ producing CD8 T cells. Inhibiting RIPK3 with a small molecule inhibitor such as GSK 872 effectively reduces RIPK3 activity in myeloid cells including MDSCs and reduces growth of small and large KP tumors. GSK 872 in combination with checkpoint inhibitors such as anti PD-1 and anti CTLA-4 further decreased KP tumor size. Together, our findings show that inhibiting RIPK3 in MDSCs is effective in inhibiting KP NSCLC and is a viable therapeutic option for improving existing immunotherapeutic treatments.
PAX8 expressing epithelial cells are a cancer-prone source of clonal cyclical regeneration of endometrial epithelium
Authors: Fu Dah-Jiun , De Micheli Andrea J. , Bidarimath Mallikarjun , Ellenson Lora H. , Cosgrove Benjamin D. , Flesken-Nikitin Andrea , Yu Nikitin Alexander
Published: November 2019

bioRxiv has withdrawn this manuscript after a formal investigation by Cornell University that concluded that it was submitted and made public without listing all contributing authors. The list of authors in this preprint should have been: Dah-Jiun Fu, Andrea J. De Micheli, Blaine A. Harlan, Mallikarjun Bidarimath, Minseok Kim, Lora H. Ellenson, Benjamin D. Cosgrove, Andrea Flesken-Nikitin and Alexander Yu. Nikitin, with DJF, AJDM and BAH indicated as equal contributors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding authors.
Addition of insoluble fiber to isolation media allows for increased metabolite diversity of lab-cultivable microbes derived from zebrafish gut samples
Authors: Condren Alanna R. , Costa Maria S , Sanchez Natalia Rivera , Konkapaka Sindhu , Gallik Kristin L , Saxena Ankur , Murphy Brian T , Sanchez Laura M
Published: November 2019

There is a gap in measured microbial diversity when comparing genomic sequencing techniques versus cultivation from environmental samples in a laboratory setting. Standardized methods in artificial environments may not recapitulate the environmental conditions that native microbes require for optimal growth. For example, the intestinal tract houses microbes at various pH values as well as minimal oxygen and light environments. These microbes are also exposed to an atypical source of carbon: dietary fiber compacted in fecal matter. To investigate how the addition of insoluble fiber to isolation media could affect the cultivation of microbes from zebrafish intestines, an isolate library was built and analyzed using the bioinformatics pipeline IDBac. The addition of fiber led to an increase in bacterial growth and encouraged the growth of species from several phyla. Furthermore, fiber addition altered the metabolism of the cultivated gut-derived microbes and induced the production of unique metabolites that were not produced when microbes were otherwise grown on standard isolation media. Addition of this inexpensive carbon source to media supported the cultivation of a diverse community whose specialized metabolite production may more closely replicate their metabolite productionin vivo.
Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A
Authors: Petronikolou Nektaria , Longbotham James E. , Fujimori Danica Galonić
Published: November 2019

Human lysine demethylase KDM5A is a chromatin modifying enzyme associated with transcriptional regulation due to its ability to catalyze removal of methyl groups from methylated lysine 4 of histone H3 (H3K4me3). Amplification of KDM5A is observed in a number of cancers, including breast cancer, prostate cancer, hepatocellular carcinoma, lung cancer and gastric cancer. In this study, we employed alanine scanning mutagenesis to investigate substrate recognition of KDM5A and identify the H3 tail residues necessary for KDM5A-catalyzed demethylation. Our data show that the H3Q5 residue is critical for substrate recognition by KDM5A. Our data also reveal that the protein-protein interactions between KDM5A and the histone H3 tail extend beyond the amino acids proximal to the substrate mark. Specifically, demethylation activity assays show that deletion or mutation of residues at positions 14-18 on the H3 tail results in an 8-fold increase in the KMapp compared to wild-type 18mer peptide, suggesting this distal epitope is important in histone engagement. Finally, we demonstrate that post-translational modifications on this distal epitope can modulate KDM5A-dependent demethylation. Our findings provide insights into H3K4-specific recognition by KDM5A as well as how chromatin context can regulate KDM5A activity and H3K4 methylation status.
CiteFuse enables multi-modal analysis of CITE-seq data
Authors: Kim Hani Jieun , Lin Yingxin , Geddes Thomas A. , Yang Jean , Yang Pengyi
Published: November 2019

Multi-modal profiling of single cells represents one of the latest technological advancements in molecular biology. Among various single-cell multi-modal strategies, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) allows simultaneous quantification of two distinct species: RNA and surface marker proteins (ADT). Here, we introduce CiteFuse, a streamlined package consisting of a suite of tools for pre-processing, modality integration, clustering, differential RNA and ADT expression analysis, ADT evaluation, ligand-receptor interaction analysis, and interactive web-based visualization of CITE-seq data. We show the capacity of CiteFuse to integrate the two data modalities and its relative advantage against data generated from single modality profiling. Furthermore, we illustrate the pre-processing steps in CiteFuse and in particular a novel doublet detection method based on a combined index of cell hashing and transcriptome data. Collectively, we demonstrate the utility and effectiveness of CiteFuse for the integrative analysis of transcriptome and epitope profiles from CITE-seq data.
Investigation of the quorum-sensing regulon of the biocontrol bacterium Pseudomonas chlororaphis strain PA23
Authors: Shah Nidhi , Gislason April , Becker Michael , Belmonte Mark F. , Fernando W.G. Dilantha , de Kievit Teresa R.
Published: November 2019

Pseudomonas chlororaphis strain PA23 is a biocontrol agent capable of protecting canola from stem rot disease caused by the fungal pathogen Sclerotinia sclerotiorum. PA23 produces several of inhibitory compounds that are under control of a complex regulatory network. Included in this cascade is the PhzRI quorum sensing (QS) system, which plays an essential role in PA23 biocontrol. The focus of the current study was to employ RNA sequencing to explore the spectrum of PA23 genes under QS control. Transcriptomic profiling revealed 545 differentially expressed genes (365 downregulated; 180 upregulated) in the phzR mutant and 534 genes (382 downregulated; 152 upregulated) in the AHL-deficient PA23-6863. In both strains, decreased expression of phenazine, pyrrolnitrin, and exoprotease biosynthetic genes was observed. We have previously reported that QS activates expression of these genes and their encoded products. In addition, elevated siderophore and decreased chitinase gene expression was observed in the QS-deficient stains, which was confirmed by phenotypic analysis. Inspection of the promoter regions revealed the presence of “phz-box” sequences in only 58 of the 807 differentially expressed genes, suggesting that much of the QS regulon is indirectly regulated. Consistent with this notion, 41 transcriptional regulators displayed altered expression in one or both of the QS-deficient strains. Collectively, our findings indicate that QS governs expression of approximately 13% of the PA23 genome affecting diverse functions ranging from secondary metabolite production to general metabolism. To the best of our knowledge, this represents the first global transcriptomic analysis of the QS regulon of a biocontrol pseudomonad.
A Partially Phase-Separated Genome Sequence Assembly of the Vitis Rootstock ‘Börner’ (Vitis riparia x Vitis cinerea) and its Exploitation for Marker Development and Targeted Mapping
Authors: Holtgräwe Daniela , Sörensen Thomas Rosleff , Hausmann Ludger , Pucker Boas , Viehöver Prisca , Töpfer Reinhard , Weisshaar Bernd
Published: November 2019

Grapevine breeding becomes highly relevant due to upcoming challenges like climate change, a decrease in the number of available fungicides, increasing public concern about plant protection, and the demand for a sustainable production. Downy mildew caused by Plasmopara viticola is one of the most devastating diseases worldwide of cultivated Vitis vinifera. Therefore, in modern breeding programs genetic marker technologies and genomic data are used to develop new cultivars with defined and stacked resistance loci. Potential sources of resistance are wild species of American or Asian origin. The interspecific hybrid of Vitis riparia Gm 183 x V. cinerea Arnold, available as the rootstock cultivar ‘Börner’, carries several relevant resistance loci. We applied next generation sequencing to enable the reliable identification of simple sequence repeats (SSR) and also generated a draft genome sequence assembly of ‘Börner’ to access genome wide sequence variations in a comprehensive and highly reliable way. These data were used to cover the ‘Börner’ genome with genetic marker positions. A subset of these marker positions was used for targeted mapping of the P. viticola resistance locus, Rpv14, to validate the marker position list. Based on the reference genome sequence PN40024, the position of this resistance locus can be narrowed down to less than 0.5 Mbp on chromosome 5.
The role of host phenology for parasite transmission
Authors: MacDonald Hannelore , Akçay Erol , Brisson Dustin
Published: November 2019

Phenology is a fundamental determinant of species distributions, abundances, and interactions. In host-parasite interactions, host phenology can affect parasite fitness due to the temporal constraints it imposes on host contact rates. However, it remains unclear how parasite transmission is shaped by the wide range of phenological patterns observed in nature. We develop a mathematical model of the Lyme disease system to study the consequences of differential tick developmental-stage phenology for the transmission ofB. burgdorferi. Incorporating seasonal tick activity can increaseB. burgdorferifitness compared to continuous tick activity but can also prevent transmission completely.B. burgdorferifitness is greatest when the activity period of the infectious nymphal stage slightly precedes the larval activity period. Surprisingly,B. burgdorferiis eradicated if the larval activity period begins long after the end of nymphal activity due to a feedback with mouse population dynamics. These results highlight the importance of phenology, a common driver of species interactions, for the fitness of a parasite.
Transcriptional signatures of participant-derived neural progenitor cells and neurons implicate altered Wnt signaling in Phelan McDermid syndrome and autism
Authors: Breen Michael S. , Browne Andrew , Hoffman Gabriel E. , Stathopoulos Sofia , Brennand Kristen , Buxbaum Joseph D. , Drapeau Elodie
Published: November 2019

Background

Phelan-McDermid syndrome (PMS) is a rare genetic disorder with high risk of autism spectrum disorder (ASD), intellectual disability and language delay, and is caused by 22q13.3 deletions or mutations in the SHANK3 gene. To date, the molecular and pathway changes resulting from SHANK3 haploinsufficiency in PMS remain poorly understood. Uncovering these mechanisms is critical for understanding pathobiology of PMS and, ultimately, for the development of new therapeutic interventions.

Methods

We developed human induced pluripotent stem cell (hiPSC)-based models of PMS by reprogramming peripheral blood samples from individuals with PMS (n=7) and their unaffected siblings (n=6). For each participant, up to three hiPSC clones were generated and differentiated into induced neural progenitor cells (iNPCs; n=32) and induced forebrain neurons (iNeurons; n=42). Genome-wide RNA-sequencing was applied to explore transcriptional differences between PMS probands and unaffected siblings.

Results

Transcriptome analyses identified 391 differentially expressed genes (DEGs) in iNPCs and 82 DEGs in iNeurons, when comparing cells from PMS probands and unaffected siblings (FDR <5%). Genes under-expressed in PMS were implicated in Wnt signaling, embryonic development and protein translation, while over-expressed genes were enriched for pre- and post-synaptic density genes, regulation of synaptic plasticity, and G-protein-gated potassium channel activity. Gene co-expression network analysis identified two modules in iNeurons that were over-expressed in PMS, implicating postsynaptic signaling and GDP binding, and both modules harbored a significant enrichment of genetic risk loci for developmental delay and intellectual disability. Finally, PMS-associated genes were integrated with other ASD iPSC transcriptome findings and several points of convergence were identified, indicating altered Wnt signaling, extracellular matrix and glutamatergic synapses.

Limitations

Given the rarity of the condition, we could not carry out experimental validation in independent biological samples. In addition, functional and morphological phenotypes caused by loss of SHANK3 were not characterized here.

Conclusions

This is the largest human neural sample analyzed in PMS. Genome-wide RNA-sequencing in hiPSC-derived neural cells from individuals with PMS revealed both shared and distinct transcriptional signatures across iNPCs and iNeurons, including many genes implicated in risk for ASD, as well as specific neurobiological pathways, including the Wnt pathway.
The Oscillatory ReConstruction Algorithm (ORCA) adaptively identifies frequency bands to improve spectral decomposition in human and rodent neural recordings
Authors: Watrous Andrew J , Buchanan Robert
Published: November 2019

Neural oscillations are routinely analyzed using methods that measure activity in canonical frequency bands (e.g. alpha, 8-12 Hz), though the frequency of neural signals is not fixed and varies within and across individuals based on numerous factors including neuroanatomy, behavioral demands, and species. Further, band-limited activity is an often assumed, typically unmeasured model of neural activity and band definitions vary considerably across studies. These factors together mask individual differences and can lead to noisy spectral estimates and interpretational problems when linking electrophysiology to behavior. We developed the Oscillatory ReConstruction Algorithm (“ORCA”), an unsupervised method to measure the spectral characteristics of neural signals in adaptively identified bands which incorporates two new methods for frequency band identification. ORCA uses the instantaneous power, phase, and frequency of activity in each band to reconstruct the signal and directly quantify spectral decomposition performance using each of four different models. To reduce researcher bias, ORCA provides spectral estimates derived from the best model and requires minimal hyperparameterization. Analyzing human scalp EEG data during eyes open and eyes-closed “resting” conditions, we first identify variability in the frequency content of neural signals across subjects and electrodes. We demonstrate that ORCA significantly improves spectral decomposition compared to conventional methods and captures the well-known increase in low-frequency activity during eyes closure in electrode- and subject-specific frequency bands. We further illustrate the utility of our method in rodent CA1 recordings. ORCA is a novel analytic tool that will allow researchers to investigate how non-stationary neural oscillations vary across behaviors, brain regions, individuals, and species.
Delta glutamate receptor conductance drives excitation of dorsal raphe neurons
Authors: Gantz Stephanie C. , Moussawi Khaled , Hake Holly S.
Published: November 2019

The delta glutamate receptors, GluD1R and GluD2R, are mysterious members of the ionotropic glutamate receptor family in that they are not gated by glutamate1,2. One theory is that they are scaffolding proteins or synaptic organizers strictly, rather than ion conducting channels. Although mutant forms and wild type channels have been reported to conduct3,4,5, conduction, gating, and biophysical properties of native GluD1R remain unexplored. Here we show that the inward current induced by activation of α1-adrenergic receptors (α1-ARs) in the dorsal raphe nucleus (DR) is mediated by GluD1R. Native GluD1R channels are functional ion channels that are constitutively active under basal conditions and α1-ARs increase the tonic current. This inward current is responsible for the α1-AR-dependent induction of persistent pacemaker-type firing of neurons in the DR. Given the extensive distribution of these receptors, the ionotropic nature of GluDR is proposed to be widespread in the nervous system.
RiboFlow, RiboR and RiboPy: An ecosystem for analyzing ribosome profiling data at read length resolution
Authors: Ozadam Hakan , Geng Michael , Cenik Can
Published: November 2019

Ribosome occupancy measurements enable protein abundance estimation and infer mechanisms of translation. Recent studies have revealed that sequence read lengths in ribosome profiling data are highly variable and carry critical information. Consequently, data analyses require the computation and storage of multiple metrics for a wide range of ribosome footprint lengths. We developed a software ecosystem including a new efficient binary file format named ‘ribo’. Ribo files store all essential data grouped by ribosome footprint lengths. Users can assemble ribo files using our RiboFlow pipeline that processes raw ribosomal profiling sequencing data. RiboFlow is highly portable and customizable across a large number of computational environments with built-in capabilities for parallelization. We also developed interfaces for writing and reading ribo files in the R (RiboR) and Python (RiboPy) environments. Using RiboR and RiboPy, users can efficiently access ribosome profiling quality control metrics, generate essential plots, and carry out analyses. Altogether, these components create a complete software ecosystem for researchers to study translation through ribosome profiling.

Availability and Implementation

For a quickstart, please see https://ribosomeprofiling.github.io. Source code, installation instructions and links to documentation are available on GitHub: https://github.com/ribosomeprofiling
Wolbachiapromote successful sex with siblings
Authors: Bagheri Zeynab , Talebi Ali Asghar , Asgari Sassan , Mehrabadi Mohammad
Published: November 2019

Wolbachiaare intracellular α-proteobacteria that have a wide distribution among various arthropods and nematodes. They affect the host reproduction favoring their maternal transmission, which sets up a potential conflict in inbreeding situations when the host avoids sexual reproduction preventing inbreeding depression, whileWolbachiapushes it. In this study, we used the waspHabrobracon hebetorto test the hypothesis thatWolbachiamodulate inbreeding avoidance behaviour and promote sib mating. To test this, we first cured wasps ofWolbachiausing tetracycline treatment and produced infected and uninfected isolines. Then, we paired the uninfected and infected females with sibling (inbred) and non-sibling (outbred) males in choice and non-choice experiments. Our results showed no obvious precopulatory inbreeding avoidance in this wasp as brother-sister mating rates (in both choice and nonchoice experiments) were not significantly different form non-sibling pairs, regardless ofWolbachiainfection. However, our results indicated thatH. hebetorshows a strong postcopulatory inbreeding avoidance behaviour that results in a low fertilization rate of uninfected siblings and therefore high rate of production of male progeny was obtained. We observed higher rates of fertilization success in theWolbachia-infected lines that resulted in significantly higher female progeny production compared to the uninfected sib mates. Since diploid females are the result of successful fertilization due to haplodiploidy sex determination system in this insect, our results indicate thatWolbachiapromoted fertile sib mating inH. hebetor.Interestingly, the rate of adult emergence in the progeny ofWolbachia-infected sib mates were almost similar to the non-sib mate crosses and significantly more than those observed in the uninfected sib mate crosses. We support the idea thatWolbachiamodulate inbreeding avoidance and promote sib mating and also mitigate inbreeding depression. The waspHabrobracon hebetorsiblings infected withWolbachiashow higher rates of fertilization success and higher adult emergence rates compared to the uninfected sib mates. By promoting successful sex with siblings and increasing the probability of female progeny,Wolbachiaenhance their transmission to the next generation and also mitigate inbreeding depression. This is an undescribed effect ofWolbachia(symbiont) on the host reproduction.
Presence of orange tubercles does not always indicate accelerated low water corrosion
Authors: Phan Hoang C. , Wade Scott A. , Blackall Linda L.
Published: November 2019

The rapid degradation of marine infrastructure at the low tide level due to accelerated low water corrosion (ALWC) is a problem encountered worldwide. Despite this, there is limited understanding of the microbial communities involved in this process. We obtained samples of the orange-coloured tubercles commonly associated with ALWC from two different types of steel sheet piling, located adjacent to each other but with different levels of localised corrosion, at a seaside harbour. The microbial communities from the outer and inner layers of the orange tubercles, and from adjacent seawater, were studied by pure culture isolation and metabarcoding of the 16S rRNA genes. A collection of 119 bacterial isolates was obtained from one orange tubercle sample, using a range of media with anaerobic and aerobic conditions. The metabarcoding results showed that sulfur and iron oxidisers were more abundant on the outer section of the orange tubercles compared to the inner layers, where Deltaproteobacteria (which includes many sulfate reducers) were more abundant. The microbial communities varied significantly between the inner and outer layers of the orange tubercles and also with the seawater, but overall did not differ significantly between the two steel sheet types. Metallurgical analysis found differences in composition, grain size, ferrite-pearlite ratio and the extent of inclusions present between the two steel types investigated.

IMPORTANCE

The presence of orange tubercles on marine steel pilings is often used as an indication that accelerated low water corrosion is taking place. We studied the microbial communities in attached orange tubercles on two closely located sheet pilings that were of different steel types. The attached orange tubercles were visually similar, but the extent of underlying corrosion on the different steel surfaces were substantially different. No clear difference was found between the microbial communities present on the two different types of sheet piling. However, there were clear differences in the microbial communities in the corrosion layers of tubercles, which were also different to the microbes present in adjacent seawater. The overall results suggest that the presence of orange tubercles, a single measurement of water quality, or the detection of certain general types of microbes (e.g. sulfate reducing bacteria) should not be taken alone as definitive indications of accelerated corrosion.
Intestinal dysbiosis in carbapenem-resistant Enterobacteriaceae carriers
Authors: Korach-Rechtman Hila , Hreish Maysaa , Fried Carmit , Gerassy-Vainberg Shiran , Azzam Zaher S , Kashi Yechezkel , Berger Gidon
Published: November 2019

Infection with Carbapenem-Resistant Enterobacteriaceae (CRE) became an important challenge in health-care settings and a growing concern worldwide. Since infection is preceded by colonization, an understanding of the latter may reduce CRE-infections. We aimed to characterize the gut microbiota after colonization by CRE, assuming that an imbalanced gastrointestinal tract (GIT)-associated microbiota precedes CRE-colonization.

We evaluated the GIT-microbiota using 16S rRNA genes sequencing extracted of fecal samples, collected from hospitalized CRE-carriers, and two control groups of hospitalized non-carriers and healthy adults. The microbiota diversity and composition in CRE-colonized patients differed from that of the control groups participants. These CRE-carriers displayed lower phylogenetic diversity and dysbiotic microbiota, enriched with members of the Enterobacteriaceae family. Concurrent with the bloom in Enterobacteriaceae, a depletion of anaerobic commensals was observed. Additionally, changes in several predicted metabolic pathways were observed for the CRE-carriers. Concomitant, we found higher prevalence of bacteremia in the CRE-carriers.

Several clinical factors that might induce change in the microbiota were examined and found as insignificant between the groups.

CRE-colonized patients have dysbiotic gut microbiota in terms of diversity and community membership, associated with increased risk for systemic infection. Our study results provides justification for attempts to restore the dysbiotic microbiota with probiotics or fecal transplantation.
Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling
Authors: Lawlor Katerina , Marques-Torrejon Maria Angeles , Dharmalingham Gopuraja , El-Azhar Yasmine , Schneider Michael D. , Pollard Steven M. , Rodríguez Tristan A.
Published: November 2019

There is increasing evidence suggesting that adult neural stem cells (NSCs) are a cell of origin of glioblastoma, the most aggressive form of malignant glioma. The earliest stages of hyperplasia are not easy to explore, but likely involve a cross-talk between normal and transformed NSCs. How normal cells respond to this cross-talk and if they expand or are outcompeted is poorly understood. Here we have analysed the interaction of transformed and wild-type NSCs isolated from the adult mouse subventricular zone neural stem cell niche. We find that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, however, we also demonstrate that these cells induce a quiescent-like state in surrounding wild-type NSC. We find that this response is cell-cell contact-dependent and that transformed cells activate the Notch pathway in adjacent wild-type NSCs, an event that stimulates their entry into quiescence. Our findings therefore suggest that oncogenic mutations may be propagated in the stem cell niche not just though cell-intrinsic advantages, but also by outcompeting neighbouring stem cells through signalling repression of their proliferation.
Synthesis, spectroscopic (FT–IR and UV–Vis), crystallographic and theoretical studies, and a molecular docking simulation of an imatinib-like template
Authors: Moreno-Fuquen Rodolfo , Arango-Daraviña Kevin , Garcia Esteban , Tenorio Juan-C. , Ellena Javier
Published: November 2019

The aim of the present study was to report the crystal structure and spectroscopic, electronic, supramolecular and electrostatic properties of a new polymorph of 4-(pyridin-2-yl)pyrimidin-2-amine (C9H8N4). The compound was synthesized under microwave irradiation. The single-crystal X-ray structure analysis revealed an angle of 13.36 (8)° between the planes of the rings, as well as molecules linked by Nsp2—H...N hydrogen bonds forming dimers along the crystal. The material was analyzed by FT–IR vibrational spectroscopy, while a computational approach was used to elucidate the vibrational frequency couplings. The existence of Nsp2—H...N hydrogen bonds in the crystal was confirmed spectroscopically by the IR peaks from the N—H stretching vibration shifting to lower wavenumbers in the solid state relative to those in the gas phase. The supramolecular studies confirmed the formation of centrosymmetricR22(8) rings, which correspond to the formation of dimers that stack parallel to thebdirection. Other weak C—H...π interactions, essential for crystal growth, were found. The UV–Vis spectroscopic analysis showed a donor–acceptor process, where the amino group acts as a donor and the pyridine and pyrimidine rings act as acceptors. The reactive sites of the molecule were identified and their quantitative values were defined using the electrostatic potential model proposed in the multifunctional wave function analyzermultiwfn. The calculated interaction energies between pairs of molecules were used to visualize the electrostatic terms as the leading factors against the dispersion factors in the crystal-growth process. The docking results showed that the amino group of the pyrimidine moiety was simultaneously anchored by hydrogen-bonding interactions with the Asp427 and His407 protein residues. This compound could be key for the realization of a series of syntheses of molecules that could be used as possible inhibitors of chronic myelogenous leukemia.
The first example of the stereoselective synthesis and crystal structure of a spirobicycloquinazolinone based on (–)-fenchone and anthranilamide
Authors: Chernyshov Vladimir V. , Gatilov Yuri V. , Yarovaya Olga I. , Koskin Igor P. , Yarovoy Spartak S. , Brylev Konstantin A. , Salakhutdinov Nariman F.
Published: November 2019

The possibility of a single-stage solvent-free stereoselective synthesis of a spirocyclic compound from the natural bicyclic monoterpenoid (−)-fenchone and anthranilamide has been shown for the first time. The molecular and crystal structure of (1R,2S,4S)-1,3,3-trimethyl-1′H-spiro[bicyclo[2.2.1]heptane-2,2′-quinazolin]-4′(3′H)-one, C17H22N2O, was established by X-ray diffraction though the chirality was assumed via the known reactant connectivity and 1H and 13C NMR spectroscopy. It has shown that in the molecule, for steric reasons, there is an elongation of the Me2C—C(N)N bond to 1.603 (5) Å. The formation of dimers via N—H...O=C hydrogen bonds with an interaction energy of 93.30 kJ mol−1 and through cavities (33.7% of the unit-cell volume) was established in the packing of the molecules. There are no π-stacking interactions in the structure.