bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multimodal Management of Congenital Orbital Malignant Rhabdoid Tumor: Review of Literature and Report of a Rare Case
Authors: Biswas Ahitagni , Kumar Ritesh , Bakhshi Sameer , Sen Seema , Sharma Mehar C. 
Published: January 2019

Background:
Malignant rhabdoid tumor (MRT) is a rare and aggressive tumor with a dismal prognosis. It commonly arises in the brain (65%), soft tissues (26%), and the kidney (9%). Primary orbital involvement is extremely rare. Although it has been mostly described in children below 2 years old, presentation at birth is sparsely reported.

Observation:
We have described a case of congenital orbital MRT, who presented with rapidly progressive right-sided proptosis and was initially treated with subtotal resection and postoperative chemotherapy with ICE (Ifosfamide, Carboplatin, Etoposide) regimen. On local progression the child was treated with palliative radiotherapy (20 Gy) to the right orbit and second-line chemotherapy with VAC (Vincristine, Adriamycin, Cyclophosphamide) regimen. Unfortunately he died due to progressive disease 4 months after the initial diagnosis.

Conclusions:
This report highlights the importance of awareness of orbital MRT as a differential diagnosis of rapidly progressing proptosis in the neonatal period. This tumor is often refractory to conventional multimodality treatment and more intensive and innovative treatment approaches are clearly needed in future.
Comparisons of Functional Apical Support After Sacral Hysteropexy Versus Sacral Colpopexy: A Cadaveric Study
Authors: Maldonado Pedro A. , Jackson Lindsey A. , Florian-Rodriguez Maria E. , Wai Clifford Y. 
Published: January 2019

Objectives
Prolapse procedures with uterine preservation offer an alternative to colpopexy with hysterectomy. Few studies have examined the differences in anatomic or subjective outcomes following sacral hysteropexy versus sacral colpopexy with hysterectomy. This study sought to compare the ability of sacral hysteropexy and sacral colpopexy with hysterectomy to resist downward traction as an estimate of apical support in human cadavers.

Methods
Sacral hysteropexy was performed on unembalmed female cadavers. A metal bolt/washer was threaded through the uterine fundus, down the cervical canal. and out the vagina and fastened to a waxed surgical filament, which ran over a fixed pulley at the table's end. Successive weights were added to provide increasing loads on the uterine fundus, and the distances traversed by the fundus were recorded. The same process was repeated after completion of a total hysterectomy (with vaginal cuff closure) and subsequent sacral colpopexy in the same specimen. Data were analyzed using paired-sample t test and repeated-measures analysis of variance (Sigma Plot version 13.0), with P ≤ 0.05 considered statistically significant.

Results
Eight female cadavers were utilized. With the addition of each weight, the average distance traversed by the uterine fundus or vaginal cuff gradually increased. There were no statistical differences in the distances moved by the apex between sacral hysteropexy and total hysterectomy/sacral colpopexy.

Conclusions
These results suggest that functional support provided by sacral hysteropexy and sacral colpopexy with hysterectomy may be similar. Further studies are needed to correlate these findings with patient satisfaction, which may vary despite similar anatomic results.
A Reaction Norm Perspective on Reproducibility
Authors: Voelkl Bernhard , Würbel Hanno 
Published: January 2019

AbstractReproducibility in biomedical research, and more specifically in preclinical animal research, has been seriously questioned. Several cases of spectacular failures to replicate findings published in the primary scientific literature have led to a perceived reproducibility crisis. Diverse threats to reproducibility have been proposed, including lack of scientific rigour, low statistical power, publication bias, analytical flexibility and fraud. An important aspect that is generally overlooked is the lack of external validity caused by rigorous standardization of both the animals and the environment. Here, we argue that a reaction norm approach to phenotypic variation, acknowledging gene-by-environment interactions, can help us seeing reproducibility of animal experiments in a new light. We illustrate how dominating environmental effects can affect inference and effect size estimates of studies and how elimination of dominant factors through standardization affects the nature of the expected phenotype variation through the reaction norms of small effect. Finally, we discuss the consequences of reaction norms of small effect for statistical analysis, specifically for random effect latent variable models and the random lab model.
Internally coupled middle ears enhance the range of interaural time differences heard by the chicken
Authors: Köppl Christine 
Published: January 2019

AbstractInteraural time differences (ITD) are one of several principle cues for localizing sounds. However, ITD are in the sub-millisecond range for most animals. Because the neural processing of such small ITDs pushes the limit of temporal resolution, the precise ITD-range for a given species and its usefulness - relative to other localization cues - was a powerful selective force in the evolution of the neural circuits involved. Birds and other non-mammals have internally coupled middle ears working as pressure-difference receivers that may significantly enhance ITD, depending on the precise properties of the interaural connection. Here, the extent of this internal coupling was investigated in chickens, specifically under the same experimental conditions as typically used in neurophysiology of ITD-coding circuits, i.e. with headphone stimulation. Cochlear microphonics (CM) were recorded simultaneously from both ears of anesthetized chickens under monaural and binaural stimulation, using pure tones from 0.1 to 3 kHz. Interaural transmission peaked at 1.5 kHz at a loss of only −5.5 dB; the mean interaural delay was 264 μs. CM amplitude strongly modulated as a function of ITD, confirming significant interaural coupling. The “ITD heard” derived from the CM phases in both ears showed enhancement, compared to the acoustic stimuli, by a factor of up to 1.8. However, the closed sound delivery systems impaired interaural transmission at low frequencies (< 1 kHz). We identify factors that need to be considered when interpreting neurophysiological data obtained under these conditions, and relating them to the natural free-field condition.Summary statementThe interaural time differences that chickens can use for sound localization are significantly greater than their small head size suggests. Closed-system sound stimulation can, however, produce complex artefacts.
In-silico Exploration of Mouse Brain Dynamics by Stimulation explains Functional Networks and Sensory Processing
Authors: Spiegler Andreas , Abadchi Javad Karimi , Mohajerani Majid , Jirsa Viktor K. 
Published: January 2019

ABSTRACTSensory and direct stimulation of the brain probes its functional repertoire and the information processing capacity of networks. However, a systematic exploration can only be performed in silico. Stimulation takes the system out of its attractor states and samples the environment of the flow to gain insight into the stability and multiplicity of trajectories. It is the only means of obtaining a complete understanding of the healthy brain network’s dynamic properties. We built a whole mouse brain model with connectivity derived from tracer studies. We systematically varied the stimulation location, the ratio of long- to short-range interactions, and the range of short connections. Functional networks appeared in the spatial motifs of simulated brain activity. Several motifs included the default mode network, suggesting a junction of functional networks. The model explains processing in sensory systems and replicates the in vivo dynamics after stimulation without parameter tuning, emphasizing the role of connectivity.
VGF in cerebrospinal fluid, when combined with conventional biomarkers, enhances prediction of conversion from mild cognitive impairment to Alzheimer’s Disease
Authors: Llano Daniel A. , Devanarayan Priya , Devanarayan Viswanath ,   for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2019

AbstractSensitive and accurate biomarkers for the prediction of conversion from mild cognitive impairment (MCI) to Alzheimer’s Disease (AD) are needed to both support clinical care and enhance clinical trial design. Here, we examined the potential of cerebrospinal fluid (CSF) levels of a peptide derived from a neural protein involved in synaptic transmission, VGF (a non-initialism), to enhance accuracy of prediction of conversion from MCI to AD. The performance of conventional biomarkers (CSF Aβ1-42 and phosphorylated tau +/− hippocampal volume) was compared to the same biomarkers with CSF VGF peptide levels. It was observed that VGF peptides are lowered in patients with AD compared to controls and that combinations of CSF Aβ1-42 and phosphorylated tau, hippocampal volume and VGF peptide levels outperformed conventional biomarkers alone (hazard ratio = 2.2 vs. 3.9). VGF peptide levels were correlated most strongly with total tau levels, but not hippocampal volume, suggesting that they serve as a marker for neuronal degradation, but not necessarily in the hippocampus. The latter point suggests that VGF may serve as a more general marker of neurodegeneration. Future work will be needed to determine the specificity of VGF for AD vs. other neurodegenerative diseases.
Divergent selection following speciation in two ectoparasitic honey bee mites
Authors: Techer Maeva A. , Rane Rahul V. , Grau Miguel L. , Roberts John M. K. , Sullivan Shawn T. , Liachko Ivan , Childers Anna K. , Evans Jay D. , Mikheyev Alexander S. 
Published: January 2019

AbstractMultispecies host-parasite evolution is common, but how parasites evolve after speciating remains poorly understood. Shared evolutionary history and physiology may propel species along similar evolutionary trajectories whereas pursuing different strategies can reduce competition. We test these scenarios in the economically important association between honey bees and ectoparasitic mites by sequencing the genomes of the sister mite speciesVarroa destructorandVarroa jacobsoni. These genomes were closely related, with 99.7% sequence identity. Among the 9,628 orthologous genes, 4.8% showed signs of positive selection in at least one species. Divergent selective trajectories were discovered in conserved chemosensory gene families (IGR, SNMP), and Halloween genes (CYP) involved in moulting and reproduction. However, there was little overlap in these gene sets and associated GO terms, indicating different selective regimes operating on each of the parasites. Based on our findings, we suggest that species-specific strategies may be needed to combat evolving parasite communities.
Buckling of epithelium growing under spherical confinement
Authors: Trushko Anastasiya , Di Meglio Ilaria , Merzouki Aziza , Blanch-Mercader Carles , Abuhattum Shada , Guck Jochen , Alessandri Kevin , Nassoy Pierre , Kruse Karsten , Chopard Bastien , Roux Aurélien 
Published: January 2019

SummaryMany organs, such as the gut or the spine are formed through folding of an epithelium. This change in shape is usually attributed to tissue heterogeneities, for example, local apical contraction. In contrast, compressive stresses have been proposed to fold a homogeneous epithelium by buckling. While buckling is an appealing mechanism, demonstrating that it underlies folding requires to measure the stress field and the material properties of the tissue, which is currently inaccessiblein vivo. Here we show that monolayers of identical cells proliferating on the inner surface of elastic spherical shells can spontaneously fold. By measuring the elastic deformation of the shell, we infer the forces acting within the monolayer and its elastic modulus. Using analytical and numerical theories linking forces to shape, we find that buckling quantitatively accounts for the shape changes of our monolayers. Our study shows that forces arising from epithelium growth in three-dimensional confinement are sufficient to drive folding by buckling.
NOTCH assembles a transcriptional repressive complex containing NuRD and PRC1 to repress genes involved in cell proliferation and differentiation
Authors: Doyen Cecile M. , Depierre David , Yatim Ahmad , Heurteau Alex , Lelievre Jean Daniel , Levy Yves , Cuvier Olivier , Benkirane Monsef 
Published: January 2019

SummaryNOTCH1 is best known as a master regulator of T-cell development with a strong oncogenic potential in developing T-cells. Upon induction of Notch, cells go through major transcriptional reprogramming that involves both activation and repression of gene expression. Although much is known about the transcriptional programs activated by Notch, the identity of the genes silenced downstream of Notch signaling and the mechanisms by which Notch down-regulates their expression remain unclear. Here, we show that upon induction of Notch signaling, ICN1-CSL-MAML1 ternary complex assembles a transcriptional Notch Repressive Complex (NRC) containing NuRD and PRC1. Genome wide analysis revealed set of genes bound and transcriptionally repressed by the NRC. Remarkably, among those genes, we found master regulators of cell differentiation and cell proliferation such as PAX5, master B-cell regulator and the DNA-binding transcriptional repressor MAD4. We propose that Notch possesses a dual role as direct activator and repressor by serving as a platform for the recruitment of co-activators and co-repressors on target genes and that both activities are required for Notch nuclear functions.
Species-specific enhancement of enterohemorrhagic E. Coli pathogenesis mediated by microbiome metabolites
Authors: Tovaglieri Alessio , Sontheimer-Phelps Alexandra , Geirnaert Annelies , Prantil-Baun Rachelle , Camacho Diogo M. , Chou David B. , Jalili-Firoozinezhad Sasan , de Wouters Tomás , Kasendra Magdalena , Super Michael , Cartwright Mark , Richmond Camilla A. , Breault David T. , Lacroix Christophe , Ingber Donald E. 
Published: January 2019

ABSTRACTBackgroundSpecies-specific differences in tolerance to infection are exemplified by the high susceptibility of humans to enterohemorrhagic E. coli (EHEC) infection whereas mice are relatively resistant to this pathogen. This intrinsic species-specific difference in EHEC infection limits the translation of murine research to human. Furthermore, studying the mechanisms underlying this differential susceptibility is a difficult problem due to complex in vivo interactions between the host, pathogen, and disparate commensal microbial communities.ResultsWe utilize organ-on-a-chip (Organ Chip) microfluidic culture technology to model damage of the human colonic epithelium induced by EHEC infection, and show that epithelial injury is greater when exposed to metabolites derived from the human gut microbiome compared to mouse. Using a multi-omics approach, we discovered four human microbiome metabolites — 4-methyl benzoic acid, 3,4-dimethylbenzoic acid, hexanoic acid, and heptanoic acid — that are sufficient to mediate this effect. The active human microbiome metabolites preferentially induce expression of flagellin, a bacterial protein associated with motility of EHEC and increased epithelial injury. Thus, the decreased tolerance to infection observed in humans versus other species may be due in part to the presence of compounds produced by the human intestinal microbiome that actively promote bacterial pathogenicity.ConclusionOrgan on chip technology allowed the identification of specific human microbiome metabolites modulating EHEC pathogenesis. These identified metabolites are sufficient to increase susceptibility to EHEC in our human Colon Chip model and they contribute to species-specific tolerance. This work suggests that higher concentrations of these metabolites could be the reason for higher susceptibility to EHEC infection in certain human populations, such as children. Furthermore, this research lays the foundation for therapeutic-modulation of microbe products in order to prevent and treat human bacterial infection.
CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain
Authors: Thomas Luke W. , Stephen Jenna M. , Esposito Cinzia , Hoer Simon , Antrobus Robin , Ahmed Afshan , Al-Habib Hasan , Ashcroft Margaret 
Published: January 2019

ABSTRACTBACKGROUNDTumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) is critical for maintaining intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of CHCHD4 in human cancers, correlates with increased tumour progression and poor patient survival.RESULTSHere, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS).CONCLUSIONSOur study highlights an important role for CHCHD4 in regulating tumour cell metabolism, and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology.
Recruitment and disruption of value encoding during alcohol seeking
Authors: Ottenheimer David , Wang Karen , Haimbaugh Alexandria , Janak Patricia H. , Richard Jocelyn M. 
Published: January 2019

AbstractA critical area of inquiry in the neurobiology of alcohol abuse is the neural mechanisms by which cues gain the ability to elicit alcohol use. We previously showed that cue-evoked activity in rat ventral pallidum (VP) robustly encodes the value of cues trained under both Pavlovian and instrumental contingencies, despite a stronger relationship between cue-evoked responses and behavioral latency after instrumental training. Here, we assessed VP neural representations of cue value in rats trained with a Pavlovian conditioned stimulus (CS+) that predicted alcohol delivery, and in rats trained with an instrumental discriminative stimulus (DS) that predicted alcohol availability if the rat entered the reward port during the cue. We also examined the impact of alcohol exposure itself on the integrity of this type of signaling in rats trained with sucrose. Decoding of cue value based on VP firing was blunted for an alcohol CS+ versus an alcohol DS, as well as in comparison to a sucrose DS or CS+. Further, homecage alcohol exposure had opposing effects on VP encoding of cue value for a sucrose DS versus a sucrose CS+, enhancing decoding accuracy for the DS and reducing decoding accuracy for the CS+. These findings suggest that problem alcohol seeking may result from biased engagement of specific reward-related processes via changes in VP signaling.
Collagen Density Modulates the Immunosuppressive Functions of Tumor-Associated Macrophages
Authors: Larsen Anne Mette H. , Kuczek Dorota E. , Kalvisa Adrija , Siersbæk Majken S. , Thorseth Marie-Louise , Johansen Astrid Zedlitz , Carretta Marco , Grøntved Lars , Vang Ole , Madsen Daniel H. 
Published: January 2019

AbstractTumor-associated macrophages (TAMs) support tumor growth by suppressing the activity of tumor infiltrating T cells. Consistently, the number of TAMs has been correlated with a poor prognosis of cancer. The immunosuppressive TAMs are also considered a major limitation for the efficacy of cancer immunotherapy. However, the molecular reason behind the acquisition of an immunosuppressive TAM phenotype is still not completely understood. During solid tumor growth, the extracellular matrix (ECM) is degraded and substituted with a tumor specific collagen-rich ECM. The collagen density of this tumor ECM has been associated with a poor prognosis of several cancers, but the underlying reason for this correlation is not well understood. Here, we have investigated whether the collagen density could modulate the immunosuppressive activity of TAMs and thereby promote tumor progression.In this study, the macrophage cell line RAW 264.7 was 3D cultured in collagen matrices of low- and high collagen densities mimicking healthy and tumor tissue, respectively. The effects of collagen density on macrophage phenotype and function were investigated by confocal microscopy, flow cytometry, RNA sequencing, qRT-PCR, and ELISA analysis. To investigate the effect of collagen density on the immune modulatory activity of macrophages, co-culture assays with primary T cells to assess T cell chemotaxis and proliferation were conducted. Lastly, the effects of collagen density on primary cells were investigated using murine bone-marrow derived macrophages (BMDMs) and TAMs isolated from murine 4T1 breast tumors.Collagen density did not affect the proliferation, viability or morphology of macrophages. However, whole-transcriptome analysis revealed a striking response to the surrounding collagen density including the differential regulation of many immune regulatory genes and genes encoding chemokines. The transcriptional changes in RAW 264.7 macrophages were shown to be similar in murine BMDMs and TAMs. Strikingly, the collagen density-induced changes in the gene expression profile had functional consequences for the macrophages. Specifically, macrophages cultured in high density collagen were less efficient at attracting cytotoxic T cells and also capable of inhibiting T cell proliferation to a greater extent than macrophages cultured in low density collagen.Our study demonstrates that a high collagen density can instruct TAMs to acquire an immunosuppressive phenotype. This could be one of the mechanisms decreasing the efficacy of immunotherapy and linking increased collagen density to poor patient prognosis.