Differentially correlated genes in co-expression networks control phenotype transitions.

BackgroundCo-expression networks are a tool widely used for analysis of "Big Data" in biology that can range from transcriptomes to proteomes, metabolomes and more recently even microbiomes. Several methods were proposed to answer biological questions interrogating these networks. Differential co-expression analysis is a recent approach that measures how gene interactions change when a biological system transitions from one state to another. Although the importance of differentially co-expressed genes to identify dysregulated pathways has been noted, their role in gene regulation is not well studied. Herein we investigated differentially co-expressed genes in a relatively simple mono-causal process (B lymphocyte deficiency) and in a complex multi-causal system (cervical cancer).MethodsCo-expression networks of B cell deficiency (Control and BcKO) were reconstructed using Pearson correlation coefficient for two mus musculus datasets: B10.A strain (12 normal, 12 BcKO) and BALB/c strain (10 normal, 10 BcKO). Co-expression networks of cervical cancer (normal and cancer) were reconstructed using local partial correlation method for five datasets (total of 64 normal, 148 cancer). Differentially correlated pairs were identified along with the location of their genes in BcKO and in cancer networks. Minimum Shortest Path and Bi-partite Betweenness Centrality where statistically evaluated for differentially co-expressed genes in corresponding networks.    Results: We show that in B cell deficiency the differentially co-expressed genes are highly enriched with immunoglobulin genes (causal genes). In cancer we found that differentially co-expressed genes act as "bottlenecks" rather than causal drivers with most flows that come from the key driver genes to the peripheral genes passing through differentially co-expressed genes. Using in vitro knockdown experiments for two out of 14 differentially co-expressed genes found in cervical cancer (FGFR2 and CACYBP), we showed that they play regulatory roles in cancer cell growth.ConclusionIdentifying differentially co-expressed genes in co-expression networks is an important tool in detecting regulatory genes involved in alterations of phenotype

Structure of plastically compacting granular packings

The developing structure in systems of compacting ductile grains were studied experimentally in two and three dimensions. In both dimensions, the peaks of the radial distribution function were reduced, broadened, and shifted compared with those observed in hard disk- and sphere systems. The geometrical three--grain configurations contributing to the second peak in the radial distribution function showed few but interesting differences between the initial and final stages of the two dimensional compaction. The evolution of the average coordination number as function of packing fraction is compared with other experimental and numerical results from the literature. We conclude that compaction history is important for the evolution of the structure of compacting granular systems.Comment: 12 pages, 12 figure

Inverse Design of All-dielectric Metasurfaces with Bound States in the Continuum

Metasurfaces with bound states in the continuum (BICs) have proven to be a powerful platform for drastically enhancing light-matter interactions, improving biosensing, and precisely manipulating near- and far-fields. However, engineering metasurfaces to provide an on-demand spectral and angular position for a BIC remains a prime challenge. A conventional solution involves a fine adjustment of geometrical parameters, requiring multiple time-consuming calculations. In this work, to circumvent such tedious processes, we develop a physics-inspired, inverse design method on all-dielectric metasurfaces for an on-demand spectral and angular position of a BIC. Our suggested method predicts the core-shell particles that constitute the unit cell of the metasurface, while considering practical limitations on geometry and available materials. Our method is based on a smart combination of a semi-analytical solution, for predicting the required dipolar Mie coefficients of the meta-atom, and a machine learning algorithm, for finding a practical design of the meta-atom that provides these Mie coefficients. Although our approach is exemplified in designing a metasurface sustaining a BIC, it can, also, be applied to many more objective functions. With that, we pave the way toward a general framework for the inverse design of metasurfaces in specific and nanophotonic structures in general.Comment: 20 pages, 5 figures, Supplementary Materia

Inverse design of all-dielectric metasurfaces with accidental bound states in the continuum

Metasurfaces with bound states in the continuum (BICs) have proven to be a powerful platform for drastically enhancing light–matter interactions, improving biosensing, and precisely manipulating near- and far-fields. However, engineering metasurfaces to provide an on-demand spectral and angular position for a BIC remains a prime challenge. A conventional solution involves a fine adjustment of geometrical parameters, requiring multiple time-consuming calculations. In this work, to circumvent such tedious processes, we develop a physics-inspired, inverse design method on all-dielectric metasurfaces for an on-demand spectral and angular position of a BIC. Our suggested method predicts the core–shell particles that constitute the unit cell of the metasurface, while considering practical limitations on geometry and available materials. Our method is based on a smart combination of a semi-analytical solution, for predicting the required dipolar Mie coefficients of the meta-atom, and a machine learning algorithm, for finding a practical design of the meta-atom that provides these Mie coefficients. Although our approach is exemplified in designing a metasurface sustaining a BIC, it can, also, be applied to many more objective functions. With that, we pave the way toward a general framework for the inverse design of metasurfaces in specific and nanophotonic structures in general

USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis

Topographical and Cell Type-Specific Connectivity of Rostral and Caudal Forelimb Corticospinal Neuron Populations

Corticospinal neurons (CSNs) synapse directly on spinal neurons, a diverse assortment of cells with unique structural and functional properties necessary for body movements. CSNs modulating forelimb behavior fractionate into caudal forelimb area (CFA) and rostral forelimb area (RFA) motor cortical populations. Despite their prominence, the full diversity of spinal neurons targeted by CFA and RFA CSNs is uncharted. Here, we use anatomical and RNA sequencing methods to show that CSNs synapse onto a remarkably selective group of spinal cell types, favoring inhibitory populations that regulate motoneuron activity and gate sensory feedback. CFA and RFA CSNs target similar spinal neuron types, with notable exceptions that suggest that these populations differ in how they influence behavior. Finally, axon collaterals of CFA and RFA CSNs target similar brain regions yet receive highly divergent inputs. These results detail the rules of CSN connectivity throughout the brain and spinal cord for two regions critical for forelimb behavior

U-series Disequilibria in Guatemalan Lavas, Crustal Contamination, and Implications for Magma Genesis Along the Central American Subduction Zone

New U-series results indicate that Guatemalan volcanic rocks display both 238U and 230Th excesses. 230Th excess is restricted to volcanoes in central Guatemala, both along and behind the front. 230Th excess correlates with a number of incompatible element ratios, such as Th/Nb and Ba/Th. It also shows a negative correlation with MgO. Guatemalan volcanic rocks have (230Th/232Th) ratios that overlap those of Costa Rican volcanics and are therefore considerably lower than the unusually high ratios characterizing volcanic rocks from Nicaragua. Along-arc variations in (230Th/232Th) therefore mirror those of a number of diagnostic geochemical parameters, such as Ba/La, which are symmetrical about a peak in west central Nicaragua. The one siliceous lava analyzed, from the Cerro Quemado dome complex, has a recognizable crustal imprint, distinguished, for instance, by high Th/Nb and low Ba/Th. In mafic samples, 238U excess is attributed to addition of a U-enriched fluid component from the subducting Cocos plate. Our preferred explanation for 230Th excess in Guatemalan mafic samples, on the other hand, is crustal contamination, consistent with the relatively high Th/Nb and low Ba/Th ratios in these samples. We suspect, however, that crustal contamination only exerts a sizable control over the U-series disequilibrium of mafic magmas in Guatemala, and not elsewhere along the Central American volcanic front. This agrees with previously published trace element and isotopic evidence that throughout Central America, with the exception of Guatemala, mafic magmas are largely uncontaminated by crustal material.The work was supported by NSF grant OCE-0405666

Isolation and characterization of 17 polymorphic microsatellite loci for a sea urchin (Echinometra lucunter: Echinometridae)

As a first step to establish the genetic structure of the sea urchin Echinometra lucunter lucunterthroughout the Caribbean Sea, 26 microsatellite loci were isolated using Illumina paired-end sequencing, Next Generation Sequencing (NGS). We successfully optimized 17 loci for genotyping and the variation tested for 23 individuals from the Caribbean Sea and Tropical Eastern Atlantic Ocean. The allele number per locus (Na) ranged from four to 24, the observed heterozygosity (Ho) from 0.682 to 1, and the expected heterozygosity (He) from 0.609 to 0.9304. We detected no linkage disequilibrium between pairs of loci. These microsatellites will be used for the first time to detect the influence of marine barriers to genetic flow in the sea urchin E. lucunter lucunter throughout the Caribbean Sea. These new validated markers will be essential for current conservation and connectivity studies across the Caribbean Sea and the Atlantic Ocean

Staphylococcal entertotoxins of the enterotoxin gene cluster (egcSEs) induce nitrous oxide- and cytokine dependent tumor cell apoptosis in a broad panel of human tumor cells

International audienceThe egcSEs comprise five genetically linked staphylococcal enterotoxins, SEG, SEI, SElM, SElN, and SElO and two pseudotoxins which constitute an operon present in up to 80% of Staphylococcus aureus isolates. A preparation containing these proteins was recently used to treat advanced lung cancer with pleural effusion. We investigated the hypothesis that egcSEs induce nitrous oxide (NO) and associated cytokine production and that these agents may be involved in tumoricidal effects against a broad panel of clinically relevant human tumor cells. Preliminary studies showed that egcSEs and SEA activated T cells (range: 11-25%) in a concentration dependent manner. Peripheral blood mononuclear cells (PBMCs) stimulated with equimolar quantities of egcSEs expressed NO synthase and generated robust levels of nitrite (range: 200-250 μM), a breakdown product of NO; this reaction was inhibited by NG-monomethyl-L-arginine (L-NMMA) (0.3 mM), an NO synthase antagonist. Cell free supernatants (CSFs) of all egcSE-stimulated PBMCs were also equally effective in inducing concentration dependent tumor cell apoptosis in a broad panel of human tumor cells. The latter effect was due in part to the generation of NO and TNF-α since it was significantly abolished by L-NMMA, anti-TNF-α antibodies, respectively, and a combination thereof. A hierarchy of tumor cell sensitivity to these CFSs was as follows: lung carcinoma > osteogenic sarcoma > melanoma > breast carcinoma >neuroblastoma. Notably, SEG induced robust activation of NO/TNFα-dependent tumor cell apoptosis comparable to the other egcSEs and SEA despite TNF-α and IFN-γ levels that were 2 and 8 fold lower, respectively, than the other egcSEs and SEA. Thus, egcSEs produced by S. aureus induce NO synthase and the increased NO formation together with TNF-α appear to contribute to egcSE-mediated apoptosis against a broad panel of human tumor cells