bluuebunny/crossref_metadata_2025_split huggingface dataset:
Amplification lags nonlinearity in the recovery from reduced endocochlear potential
Authors: Strimbu C. Elliott , Wang Yi , Olson Elizabeth S. 
Published: May 2020

ABSTRACTThe mammalian hearing organ, the cochlea, contains an active amplifier to boost the vibrational response to low level sounds. Hallmarks of this active process are sharp location-dependent frequency tuning and compressive nonlinearity over a wide stimulus range. The amplifier relies on outer hair cell (OHC) generated forces driven in part by the endocochlear potential (EP), the ~ +80 mV potential maintained in scala media, generated by the stria vascularis. We transiently eliminated the EP in vivo by an intravenous injection of furosemide and measured the vibrations of different layers in the cochlea’s organ of Corti using optical coherence tomography. Distortion product otoacoustic emissions (DPOAE) were monitored at the same times. Following the injection, the vibrations of the basilar membrane lost the best frequency (BF) peak and showed broad tuning similar to a passive cochlea. The intra-organ of Corti vibrations measured in the region of the OHCs lost their BF peak and showed low-pass responses, but retained nonlinearity, indicating that OHC electromotility was still operational. Thus, while electromotility is presumably necessary for amplification, its presence is not sufficient for amplification. The BF peak recovered nearly fully within 2 hours, along with a non-monotonic DPOAE recovery that suggests that physical shifts in operating condition are a final step in the recovery process.SIGNIFICANCEThe endocochlear potential, the +80 mV potential difference across the fluid filled compartments of the cochlea, is essential for normal mechanoelectrical transduction, which leads to receptor potentials in the sensory hair cells when they vibrate in response to sound. Intracochlear vibrations are boosted tremendously by an active nonlinear feedback process that endows the cochlea with its healthy sensitivity and frequency resolution. When the endocochlear potential was reduced by an injection of furosemide, the basilar membrane vibrations resembled those of a passive cochlea, with broad tuning and linear scaling. The vibrations in the region of the outer hair cells also lost the tuned peak, but retained nonlinearity at frequencies below the peak, and these sub-BF responses recovered fairly rapidly. Vibration responses at the peak recovered nearly fully over 2 hours. The staged vibration recovery and a similarly staged DPOAE recovery suggests that physical shifts in operating condition are a final step in the process of cochlear recovery.
NLRP3 controls ATM activation in response to DNA damage
Authors: Bodnar-Wachtel Mélanie , Huber Anne-Laure , Gorry Julie , Hacot Sabine , Gerossier Laetitia , Guey Baptiste , Goutagny Nadège , Bartosch Birke , Ballot Elise , Ghiringhelli François , Py Bénédicte F. , Coute Yohann , Ballesta Annabelle , Lantuejoul Sylvie , Hall Janet , Petrilli Virginie 
Published: May 2020

ABSTRACTThe DNA damage response (DDR) is essential to preserve genomic integrity and acts as a barrier to cancer. The ATM pathway orchestrates the cellular response to DNA double strand breaks (DSBs), and its attenuation is frequent during tumorigenesis. Here, we show that NLRP3, a Pattern Recognition Receptor known for its role in the inflammasome complex formation, interacts with the ATM kinase to control the early phase of DDR, independently of its inflammasome activity. NLRP3 down-regulation in human bronchial epithelial cells impairs ATM pathway activation as shown by an altered ATM substrate phosphorylation profile, and due to impaired p53 activation, confers resistance to acute genomic stress. Moreover, we found that NLRP3 is down-regulated in Non-Small Cell Lung Cancer (NSCLC) tissues and NLRP3 expression is correlated with patient overall survival. NLRP3 re-expression in NSCLC cells restores appropriate ATM signaling. Our findings identify a non-immune function for NLRP3 in genome integrity surveillance and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways.
SORBS2is a genetic factor contributing to cardiac malformation of 4q deletion syndrome
Authors: Liang Fei , Zhang Xiaoqing , Wang Bo , Geng Juan , You Guoling , Fa Jingjing , Sun Huiying , Chen Huiwen , Fu Qihua , Zhang Zhen 
Published: May 2020

AbstractChromosome 4q deletion is one of the most frequently detected genomic imbalance events in congenital heart disease (CHD) patients. However, a portion of CHD-associated 4q deletions do not include known CHD genes. Alignment of those 4q deletions defined a minimal overlapping region including only one gene-SORBS2. Histological analysis ofSorbs2-/-heart revealed atrial septal hypoplasia/aplasia or double atrial septum. Mechanistically,SORBS2had a dual role in maintaining sarcomeric integrity of cardiomyocytes and specifying the fate of second heart field (SHF) progenitors through c-ABL/NOTCH/SHH axis. In a targeted sequencing of a panel of known and candidate CHD genes on 300 CHD cases, we found that rareSORBS2variants were significantly enriched in CHD patients. Our findings indicate thatSORBS2is a regulator of cardiac development and its haploinsufficiency may contribute to cardiac phenotype of 4q deletion syndrome. The presence of double atrial septum inSorbs2-/-hearts reveals the first molecular etiology of this rare anomaly linked to paradoxical thromboembolism.
Human follicular CD4 T cell function is defined by specific molecular, positional and TCR dynamic signatures
Authors: Padhan Kartika , Moysi Eirini , Noto Alessandra , Chassiakos Alexander , Ghneim Khader , Shah Sanjana , Papaioannou Vasilis , Fabozzi Giulia , Ambrozak David , Poultsidi Antigoni , Ioannou Maria , Fenwik Craig , Darko Samuel , Douek Daniel C. , Sekaly Rafick-Pierre , Pantaleo Giuseppe , Koup Richard A. , Petrovas Constantinos 
Published: May 2020

AbstractThe orchestrated interaction between follicular helper CD4 T cells (TFH) and germinal center (GC) B cells is crucial for optimal humoral immunity. However, the regulatory mechanisms behind spatial distribution and function of TFH is not well understood. Here, we studied human TFH cells and found that transitioning to a CD57hiTFH status was associated with distinct positioning in the GC, phenotype, transcriptional signatures, function and downregulation of their T-cell receptor (TCR). Single cell TCR clonotype analysis indicated a unidirectional transition towards the CD57hiTFH status, which was marked with drastic changes in the nature of immunological synapse formation where peripheral microclusters become dominant. Lack of central supra molecular activation cluster (cSMAC) formation in TFH synapse was associated with enhanced ubiquitination/proteasome activity in these cells. Our data reveal significant aspects of the tissue organization and heterogeneity of follicular adaptive immunity and suggest that CD57hiTFH cells are endowed with distinctive programming and spatial positioning for optimal GC B cell help.One Sentence Summaryhuman TFH cell heterogeneity
Insights into the genetic architecture of the human face
Authors: White Julie D. , Indencleef Karlijne , Naqvi Sahin , Eller Ryan J. , Roosenboom Jasmien , Lee Myoung Keun , Li Jiarui , Mohammed Jaaved , Richmond Stephen , Quillen Ellen E. , Norton Heather L. , Feingold Eleanor , Swigut Tomek , Marazita Mary L. , Peeters Hilde , Hens Greet , Shaffer John R. , Wysocka Joanna , Walsh Susan , Weinberg Seth M. , Shriver Mark D. , Claes Peter 
Published: May 2020

AbstractThe human face is complex and multipartite, and characterization of its genetic architecture remains intriguingly challenging. Applying GWAS to multivariate shape phenotypes, we identified 203 genomic regions associated with normal-range facial variation, 117 of which are novel. The associated regions are enriched for both genes relevant to craniofacial and limb morphogenesis and enhancer activity in cranial neural crest cells and craniofacial tissues. Genetic variants grouped by their contribution to similar aspects of facial variation show high within-group correlation of enhancer activity, and four SNP pairs display evidence of epistasis, indicating potentially coordinated actions of variants within the same cell types or tissues. In sum, our analyses provide new insights for understanding how complex morphological traits are shaped by both individual and coordinated genetic actions.
Strain-dependent modifier genes determine survival inZfp423mice
Authors: Alcaraz Wendy A. , Liu Zheng , Valdes Phoebe , Chen Edward , Valdovino Gonzalez Alan G. , Wade Shelby , Wong Cinny , Kim Eunnie , Chen Hsiang-Hua M. , Ponn Alison , Concepcion Dorothy , Hamilton Bruce A. 
Published: May 2020

ABSTRACTZfp423encodes a transcriptional regulatory protein that interacts with canonical signaling and lineage pathways. Mutations in mouseZfp423or its human orthologZNF423are associated with a range of developmental abnormalities reminiscent of ciliopathies, including cerebellar vermis hypoplasia and other midline brain defects. Null mice have reduced viability in most strain backgrounds. Here we show complete lethality on a C57BL/6J background, dominant rescue in backcrosses to any of 13 partner strains, with strain-dependent survival frequencies, and evidence for a BALB/c-derived survival modifier locus on chromosome 5. Survival data indicate both perinatal and postnatal periods of lethality. Anatomical data from a hypomorphic gene trap allele observed on both C57BL/6J and BALB/c congenic backgrounds shows an aggregate effect of background on sensitivity to Zfp423 loss rather than a binary effect on viability.
The role of conidia in the dispersal of Ascochyta rabiei
Authors: Khaliq Ihsanul , Fanning Joshua , Melloy Paul , Galloway Jean , Moore Kevin , Burrell Daniel , Sparks Adam H 
Published: May 2020

AbstractAscochyta rabiei asexual spores (conidia) were assumed to spread over short distances (∼10 m) in a combination of rain and strong wind. The potential distance of conidial spread was investigated in three rainfall and three sprinkler irrigation events. Chickpea trap plants were distributed at the distances of 0, 10, 25, 50 and 75 m from infected chickpea plots before scheduled irrigation and forecast rainfall events. Trap plants were transferred to a controlled temperature room (20 °C) for 48 h (100% humidity) after being exposed in the field for 2–6 days for rainfall events, and for one day for irrigation events. After a 48 h incubation period, trap plants were transferred to a glasshouse (20 °C) to allow lesion development. Lesions on all plant parts were counted after two weeks, which gave an estimate of the number of conidia released and the distance travelled. Trap plants at all distances were infected in all sprinkler irrigation and rainfall events. The highest number of lesions on trap plants were recorded closest to the infected plots – the numbers decreased as the distance from the infected plots increased. There was a positive relationship between the amount of rainfall and the number of lesions recorded. A generalised additive model was developed that efficiently described spatial patterns of conidial spread. With further development, the model can be used to predict the spread of A. rabiei. This is the first systematic study to show that conidia distribute A. rabiei over longer distances than previously reported.
Conserved anti-inflammatory effects and sensing of butyrate in zebrafish
Authors: Cholan Pradeep Manuneedhi , Han Alvin , Woodie Brad R , Kurz Angela RM , Britton Warwick J , Ye Lihua , Holmes Zachary C , McCann Jessica R , David Lawrence A , Rawls John F , Oehlers Stefan H 
Published: May 2020

AbstractShort chain fatty acids (SCFAs) are produced by microbial fermentation of dietary fiber in the gut. Butyrate is a particularly important SCFA with anti-inflammatory properties and is generally present at lower levels in inflammatory diseases associated with gut microbiota dysbiosis in mammals. We aimed to determine if SCFAs are produced by the zebrafish microbiome and if SCFAs exert conserved effects on zebrafish immunity as an example of the non-mammalian vertebrate immune system. We demonstrate that bacterial communities from adult zebrafish intestines synthesize all three main SCFAin vitro, although SCFA were below our detectable limits in zebrafish intestinesin vivo. Immersion in butyrate, but not acetate or propionate, reduced the recruitment of neutrophils and M1-type pro-inflammatory macrophages to wounds. We found conservation of butyrate sensing by neutrophils via orthologs of thehydroxycarboxylic acid receptor 1(hcar1) gene. Neutrophils from Hcar1-depeleted embryos were no longer responsive to the anti-inflammatory effects of butyrate, while macrophage sensitivity to butyrate was independent of Hcar1. Our data demonstrate conservation of anti-inflammatory butyrate effects and identify the presence of a conserved molecular receptor in fish.
Predicting Parallelism and Quantifying Divergence in Experimental Evolution
Authors: Shoemaker William R. , Lennon Jay T. 
Published: May 2020

ABSTRACTThe degree that the environment determines what genes contribute towards adaptation is a fundamental question in microbial evolution. Microbial populations are often experimentally passaged in different environments and sequenced in order to identify candidates for adaptation in a particular environment. However, there remains the need to develop an appropriate statistical framework to identify genes that acquired more mutations in one environment over the other (i.e., divergent evolution). Here we demonstrate how the evolutionary outcomes among replicate populations in the same environment, known as parallel evolution, can be leveraged to construct an intuitive statistical test for identifying the genes that contribute towards divergent evolution. To accomplish this task, we examined publicly available evolve-and-resequence experiment datasets and found that the distribution of mutation counts among genes can be predicted using an ensemble of independent Poisson random variables. Building on this result, we propose that the degree of divergent evolution at a given gene between populations from two different environments can be modeled as the difference between two Poisson random variables, known as the Skellam distribution. We then propose and apply a statistical test to identify specific genes that contribute towards divergent evolution. IMPORTANCE: There is currently no existing framework that can be leveraged to identify genes that contribute towards divergent evolution in microbial evolution experiments. To correct for this absence, we investigated the distribution of mutation counts among genes in order to identify an appropriate null model. Our observations suggest that divergent evolution within a given gene can be modeled as the difference in the total number of mutations observed between two environments. This quantity is described by a probability distribution known as the Skellam distribution, providing an appropriate statistical test for researchers seeking to identify the set of genes that contribute towards divergent evolution in evolution experiments.
Recombination proteins differently control the acquisition of homeologous DNA duringBacillus subtilisnatural chromosomal transformation
Authors: Serrano Ester , Ramos Cristina , Alonso Juan C. , Ayora Silvia 
Published: May 2020

AbstractIn naturally competentBacillus subtiliscells the acquisition of closely related genes occursviahomology-directed chromosomal transformation (CT), and its frequency decreases log-linearly with increased sequence divergence (SD) up to 15%. Beyond this and up to 23% SD the interspecies boundary prevails, the CT frequency marginally decreases, and short (<10-nucleotides) segments are integratedviahomology-facilitated micro-homologous integration. Both poorly known CT mechanisms are RecA-dependent. Here we identify the recombination proteins required for the acquisition of interspecies DNA. The absence of AddAB, RecF, RecO, RuvAB or RecU, crucial for repair-by-recombination, does not affect CT. However, inactivation ofdprA, radA, recJ, recXorrecD2strongly interfered with CT. Interspecies CT was abolished beyond ~8% SD in ΔdprA, ~10% in ΔrecJ, ΔradA, ΔrecXand 14% in ΔrecD2cells. We propose that DprA, RecX, RadA/Sms, RecJ and RecD2 help RecA to unconstrain speciation and gene flow. These functions are ultimately responsible for generating genetic diversity and facilitate CT and gene acquisition from bacteria of the same genus.
SIRPα on mouse B1 cells restricts lymphoid tissue migration and natural antibody production
Authors: Franke Katka , Pillai Saravanan Y. , Hoogenboezem Mark , Gijbels Marion J.J. , Matlung Hanke , Geissler Judy , Olsman Hugo , Pottgens Chantal , van Gorp Patrick J. , Ozsvar-Kozma Maria , Saito Yasuyuki , Matozaki Takashi , Kuijpers Taco W. , Hendriks Rudi W. , Kraal Georg , Binder Christoph J. , de Winther Menno P.J. , van den Berg Timo K. 
Published: May 2020

SummaryThe inhibitory immunoreceptor SIRPα is expressed on myeloid and neuronal cells and interacts with the broadly expressed CD47. CD47-SIRPα interactions form an innate immune checkpoint and its targeting has shown promising results in cancer patients. Here, we report expression of SIRPα on B1 lymphocytes, a non-conventional subpopulation of murine B cells responsible for the production of natural antibodies. Mice defective in SIRPα signaling (SIRPαΔCYTmice) displayed an enhanced CD11b/CD18 integrin-dependent B1 cell migration from the peritoneal cavity to the spleen, local B1 cell accumulation, and enhanced circulating natural antibody levels, which was further amplified upon immunization with T-independent type 2 antigen. As natural antibodies are atheroprotective we investigated the involvement of SIRPα signaling in atherosclerosis development. Bone marrow (SIRPαΔCYT>LDLR−/−) chimaeric mice developed reduced atherosclerosis accompanied by increased natural antibody production. Collectively, our data identify SIRPα as a unique B1 cell inhibitory receptor acting to control B1 cell migration, and imply SIRPα as a potential therapeutic target in atherosclerosis.
Lung Disease Network Reveals the Impact of Comorbidity on SARS-CoV-2 infection
Authors: Das Asim Bikas 
Published: May 2020

AbstractHigher mortality of COVID19 patients with comorbidity is the formidable challenge faced by the health care system. In response to the present crisis, understanding the molecular basis of comorbidity is essential to accelerate the development of potential drugs. To address this, we have measured the genetic association between COVID19 and various lung disorders and observed a remarkable resemblance. 141 lung disorders directly or indirectly linked to COVID19 result in a high-density disease-disease association network that shows a small-world property. The clustering of many lung diseases with COVID19 demonstrates a greater complexity and severity of SARS-CoV-2 infection. Furthermore, our results show that the functional protein-protein interaction modules involved RNA and protein metabolism, substantially hijacked by SARS-CoV-2, are connected to several lung disorders. Therefore we recommend targeting the components of these modules to inhibit the viral growth and improve the clinical conditions in comorbidity.
Convergence in sympatry: evolution of blue-banded wing pattern inMorphobutterflies
Authors: Llaurens V , Le Poul Y , Puissant A , Noûs C , Blandin P , Debat V 
Published: May 2020

AbstractSpecies interactions such as mimicry can promote trait convergence but disentangling this effect from those of shared ecology, evolutionary history and niche conservatism is often challenging. Here by focusing on wing color pattern variation within and between three butterfly species living in sympatry in a large proportion of their range, we tested the effect of species interactions on trait diversification. These butterflies display a conspicuous iridescent blue coloration on the dorsal side of their wings and a cryptic brownish colour on the ventral side. Combined with an erratic and fast flight, these color patterns increase the difficulty of capture by predators and contribute to the high escape abilities of these butterflies. We hypothesize that, beyond their direct contribution to predator escape, these wing patterns can be used as signals of escape abilities by predators, resulting in positive frequency-dependent selection favouring convergence in wing pattern in sympatry. To test this hypothesis, we quantified dorsal wing pattern variations of 723 butterflies from the three species sampled throughout their distribution, including sympatric and allopatric situations and compared the phenotypic distances between species, sex and localities. We detected a significant effect of localities on colour pattern, and higher inter-specific resemblance in sympatry as compared to allopatry, consistent with the hypothesis of local convergence of wing patterns. Our results provide some support to the existence of escape mimicry in the wild and stress the importance of estimating trait variation within species to understand trait variation between species, and to a larger extent, trait diversification at the macro-evolutionary scale.
Evaluation Of SYBR Green Real Time PCR For Detecting SARS-CoV-2 From Clinical Samples
Authors: Fajardo Álvaro , Pereira-Gómez Marianoel , Echeverría Natalia , López-Tort Fernando , Perbolianachis Paula , Aldunate Fabián , Moreno Pilar , Moratorio Gonzalo 
Published: May 2020

ABSTRACTThe pandemic caused by SARS-CoV-2 has triggered an extraordinary collapse of healthcare systems and hundred thousand of deaths worldwide. Following the declaration of the outbreak as a Public Health Emergency of International Concern by the World Health Organization (WHO) on January 30th, 2020, it has become imperative to develop diagnostic tools to reliably detect the virus in infected patients. Several methods based on real time reverse transcription polymerase chain reaction (RT-qPCR) for the detection of SARS-CoV-2 genomic RNA have been developed. In addition, these methods have been recommended by the WHO for laboratory diagnosis. Since all these protocols are based on the use of fluorogenic probes and one-step reagents (cDNA synthesis followed by PCR amplification in the same tube), these techniques can be difficult to perform given the limited supply of reagents in low and middle income countries. In the interest of economy, time and availability of chemicals and consumables, the SYBR Green-based detection was implemented to establish a convenient assay. Therefore, we adapted one of WHO recommended Taqman-based one-step real time PCR protocols (from the University of Hong Kong) to SYBR Green. Our results suggest that SYBR-Green detection represents a reliable cost-effective alternative to increase the testing capacity.