A stochastic model dissects cell states in biological transition processes

Many biological processes, including differentiation, reprogramming, and disease transformations, involve transitions of cells through distinct states. Direct, unbiased investigation of cell states and their transitions is challenging due to several factors, including limitations of single-cell assays. Here we present a stochastic model of cellular transitions that allows underlying single-cell information, including cell-state-specific parameters and rates governing transitions between states, to be estimated from genome-wide, population-averaged time-course data. The key novelty of our approach lies in specifying latent stochastic models at the single-cell level, and then aggregating these models to give a likelihood that links parameters at the single-cell level to observables at the population level. We apply our approach in the context of reprogramming to pluripotency. This yields new insights, including profiles of two intermediate cell states, that are supported by independent single-cell studies. Our model provides a general conceptual framework for the study of cell transitions, including epigenetic transformations

Chaperonin genes on the rise: new divergent classes and intense duplication in human and other vertebrate genomes

<p>Abstract</p> <p>Background</p> <p>Chaperonin proteins are well known for the critical role they play in protein folding and in disease. However, the recent identification of three diverged chaperonin paralogs associated with the human Bardet-Biedl and McKusick-Kaufman Syndromes (BBS and MKKS, respectively) indicates that the eukaryotic chaperonin-gene family is larger and more differentiated than previously thought. The availability of complete genome sequences makes possible a definitive characterization of the complete set of chaperonin sequences in human and other species.</p> <p>Results</p> <p>We identified fifty-four chaperonin-like sequences in the human genome and similar numbers in the genomes of the model organisms mouse and rat. In mammal genomes we identified, besides the well-known CCT chaperonin genes and the three genes associated with the MKKS and BBS pathological conditions, a newly-defined class of chaperonin genes named CCT8L, represented in human by the two sequences CCT8L1 and CCT8L2. Comparative analyses from several vertebrate genomes established the monophyletic origin of chaperonin-like MKKS and BBS genes from the CCT8 lineage. The CCT8L gene originated from a later duplication also in the CCT8 lineage at the onset of mammal evolution and duplicated in primate genomes. The functionality of CCT8L genes in different species was confirmed by evolutionary analyses and in human by expression data. Detailed sequence analysis and structural predictions of MKKS, BBS and CCT8L proteins strongly suggested that they conserve a typical chaperonin-like core structure but that they are unlikely to form a CCT-like oligomeric complex. The characterization of many newly-discovered chaperonin pseudogenes uncovered the intense duplication activity of eukaryotic chaperonin genes.</p> <p>Conclusions</p> <p>In vertebrates, chaperonin genes, driven by intense duplication processes, have diversified into multiple classes and functionalities that extend beyond their well-known protein-folding role as part of the typical oligomeric chaperonin complex, emphasizing previous observations on the involvement of individual CCT monomers in microtubule elongation. The functional characterization of newly identified chaperonin genes will be a challenge for future experimental analyses.</p

Phylogenetic and mutational analyses of human LEUTX, a homeobox gene implicated in embryogenesis

Recently, human PAIRED-LIKE homeobox transcription factor (TF) genes were discovered whose expression is limited to the period of embryo genome activation up to the 8-cell stage. One of these TFs is LEUTX, but its importance for human embryogenesis is still subject to debate. We confirmed that human LEUTX acts as a TAATCC-targeting transcriptional activator, like other K50-type PAIRED-LIKE TFs. Phylogenetic comparisons revealed that Leutx proteins are conserved across Placentalia and comprise two conserved domains, the homeodomain, and a Leutx-specific domain containing putative transcriptional activation motifs (9aa TAD). Examination of human genotype resources revealed 116 allelic variants in LEUTX. Twenty-four variants potentially affect function, but they occur only heterozygously at low frequency. One variant affects a DNA-specificity determining residue, mutationally reachable by a one-base transition. In vitro and in silico experiments showed that this LEUTX mutation (alanine to valine at position 54 in the homeodomain) results in a transactivational loss-of-function to a minimal TAATCC-containing promoter and a 36 bp motif enriched in genes involved in embryo genome activation. A compensatory change in residue 47 restores function. The results support the notion that human LEUTX functions as a transcriptional activator important for human embryogenesis.Peer reviewe

MEKHLA, a Novel Domain with Similarity to PAS Domains, Is Fused to Plant Homeodomain-Leucine Zipper III Proteins

Homeodomain (HD) proteins play important roles in the development of plants, fungi, and animals. Here we identify a novel domain, MEKHLA, in the C terminus of HD-Leu zipper (HD-ZIP) III plant HD proteins that shares similarity with a group of bacterial proteins and a protein from the green alga Chlamydomonas reinhardtii. The group of bacterial MEKHLA proteins is found in cyanobacteria and other bacteria often found associated with plants. Phylogenetic analysis suggests that a MEKHLA protein transferred, possibly from a cyanobacterium or an early chloroplast, into the nuclear genome of an early plant in a first step, and attached itself to the C terminus of an HD-ZIP IV homeobox gene in a second step. Further position-specific iterated-BLAST searches with the bacterial MEKHLA proteins revealed a subregion within the MEKHLA domain that shares significant similarity with the PAS domain. The PAS domain is a sensory module found in many proteins through all kingdoms of life. It is involved in light, oxygen, and redox potential sensation. The fact that HD-ZIP III proteins are transcription factors that have this sensory domain attached to their C terminus uncovers a potential new signaling pathway in plants

Removal of cadmium by in-situ Cu nanoparticle enhanced ceramic-supported-polymeric composite NF membrane

A novel ceramic-polymer composite nanofiltration membrane was fabricated using in-situ generated Cu nanoparticles by dip coating over modified ceramic support tube. The prepared membrane was used for Cd (II) removal from contaminated water. Generation of in-situ Cu NPs on/in the membrane was characterized by SEM and XPS analysis. Incorporation of NPs formed by in-situ chemical reduction technique improved the pore size of modified ceramic substrate towards NF range (similar to 1 nm). The positively charged composite NF membrane exhibited satisfactory performance with respect to pure water permeability (8.09 L m(-2) h(-1) bar(-1)) and Cd(II) rejection of 95.5%. (C) 2021 Elsevier Ltd. All rights reserved

Development of high performance pervaporation desalination membranes: A brief review

Water scarcity rises as the level of water pollution continues to increase with the progress of urbanization, industrialization and exponential growth of population. Therefore, saline water of the sea should also be made suitable rather than river water to meet the huge global demand of clean and safe drinking water. Pervaporation (PV) desalination, among many purification and separation processes, is a promising technology to reduce the crisis of global drinking water supply. From this perspective, the key success of PV desalination relies on its remarkable salt rejection from highly saline water with appropriate flux to obtain fresh water by using a suitable membrane. In this review we aim to provide a comprehensive assessment of PV desalination membrane materials, transport phenomena, the advantages of the process over comparable technologies (e.g., fractional distillation, membrane distillation, reverse osmosis) and the advantages of crosslinking during the preparation of composite membranes. This review further highlights the advantages of inorganic ceramic substrates as a support of composite membranes and the use of hydrophilic polymers as active layer for preparing stable and robust crosslinked PV desalination membranes.(c) 2022 Institution of Chemical Engineers. Published by Elsevier Ltd. All rights reserved

Removal of heavy metals by surface tailored copper ion enhanced ceramic-supported-polymeric composite nanofiltration membrane

Ceramic-supported-polymeric (CSP) composite membranes combine the benefits of robust ceramic support with tunable surface properties of polymeric active layer. The present work reports the fabrication of novel CSP composite nanofiltration membranes wherein surface ionization of the membrane active layers has been carried out by a facile process of chelating copper ions with the crosslinked polyethyleneimine polymer matrix of membrane top layer. Different concentrations of copper chloride solutions were used and their effect on mem-brane surface properties was investigated using EDX, XPS and AFM analyses. Performance of the membranes in removal of both cationic and anionic heavy metals, namely, Ni(II), Cd(II), Pb(II), Zn(II), As(V) and Cr(VI) from aqueous solution was studied. Excellent removal (> 95%) of all the heavy metals and optimum flux was achieved in case of GPCu0.5 membrane (surface modified with 0.5 wt% copper chloride solution). No significant decrease in flux and rejection rate of the membrane during 10 h high pressure (8 bar) operation suggested longevity of the membrane. The slow release of copper ions indicated the much-expected anti-biofouling nature of the mem-brane. Appreciable rejection behavior of the copper ion enhanced CSP composite membrane towards multiple heavy metals demonstrates its potential for practical water treatment application

Evolution of a Novel Antiviral Immune-Signaling Interaction by Partial-Gene Duplication

<div><p>The RIG-like receptors (RLRs) are related proteins that identify viral RNA in the cytoplasm and activate cellular immune responses, primarily through direct protein-protein interactions with the signal transducer, IPS1. Although it has been well established that the RLRs, RIG-I and MDA5, activate IPS1 through binding between the twin caspase activation and recruitment domains (CARDs) on the RLR and a homologous CARD on IPS1, it is less clear which specific RLR CARD(s) are required for this interaction, and almost nothing is known about how the RLR-IPS1 interaction evolved. In contrast to what has been observed in the presence of immune-modulating K63-linked polyubiquitin, here we show that—in the absence of ubiquitin—it is the first CARD domain of human RIG-I and MDA5 (CARD1) that binds directly to IPS1 CARD, and not the second (CARD2). Although the RLRs originated in the earliest animals, both the IPS1 gene and the twin-CARD domain architecture of RIG-I and MDA5 arose much later in the deuterostome lineage, probably through a series of tandem partial-gene duplication events facilitated by tight clustering of RLRs and IPS1 in the ancestral deuterostome genome. Functional differentiation of RIG-I CARD1 and CARD2 appears to have occurred early during this proliferation of RLR and related CARDs, potentially driven by adaptive coevolution between RIG-I CARD domains and IPS1 CARD. However, functional differentiation of MDA5 CARD1 and CARD2 occurred later. These results fit a general model in which duplications of protein-protein interaction domains into novel gene contexts could facilitate the expansion of signaling networks and suggest a potentially important role for functionally-linked gene clusters in generating novel immune-signaling pathways.</p></div