START domains generate paralog-specific regulons from a single network architecture.

Functional divergence of transcription factors (TFs) has driven cellular and organismal complexity throughout evolution, but its mechanistic drivers remain poorly understood. Here we test for new mechanisms using CORONA (CNA) and PHABULOSA (PHB), two functionally diverged paralogs in the CLASS III HOMEODOMAIN LEUCINE ZIPPER (HD-ZIPIII) family of TFs. We show that virtually all genes bound by PHB ( ~ 99%) are also bound by CNA, ruling out occupation of distinct sets of genes as a mechanism of functional divergence.

FlhE functions as a chaperone to prevent formation of periplasmic flagella in Gram-negative bacteria.

The bacterial flagellum, which facilitates motility, is composed of ~20 structural proteins organized into a long extracellular filament connected to a cytoplasmic rotor-stator complex via a periplasmic rod. Flagellum assembly is regulated by multiple checkpoints that ensure an ordered gene expression pattern coupled to the assembly of the various building blocks. Here, we use epifluorescence, super-resolution, and transmission electron microscopy to show that the absence of a periplasmic protein (FlhE) prevents proper flagellar morphogenesis and results in the formation of periplasmic flagella in Salmonella enterica.

Attenuating ribosome load improves protein output from mRNA by limiting translation-dependent mRNA decay.

Developing an effective mRNA therapeutic often requires maximizing protein output per delivered mRNA molecule. We previously found that coding sequence (CDS) design can substantially affect protein output, with mRNA variants containing more optimal codons and higher secondary structure yielding the highest protein outputs due to their slow rates of mRNA decay. Here, we demonstrate that CDS-dependent differences in translation initiation and elongation rates lead to differences in translation- and deadenylation-dependent mRNA decay rates, thus explaining the effect of CDS on mRNA half-life.

FlhE functions as a chaperone to prevent formation of periplasmic flagella in Gram-negative bacteria.

The bacterial flagellum is an organelle utilized by many Gram-negative bacteria to facilitate motility. The flagellum is composed of a several µm long, extracellular filament that is connected to a cytoplasmic rotor-stator complex via a periplasmic rod. Composed of ∼20 structural proteins, ranging from a few subunits to several thousand building blocks, the flagellum is a paradigm of a complex macromolecular structure that utilizes a highly regulated assembly process.

Diverse domain architectures of CheA histidine kinase, a central component of bacterial and archaeal chemosensory systems.

We found that in contrast to the best-studied model organisms, such as and , most bacterial and archaeal species have a CheA protein with a different domain composition. We report variations in CheA architecture, such as domain duplication and acquisition as well as class-specific domain composition. Our results will be of interest to those working on signal transduction in bacteria and archaea and lay the foundation for experimental studies.

Cancer Relevance of Circulating Antibodies Against LINE-1 Antigens in Humans.

Unlabelled: Long interspersed nuclear element-1 (LINE-1 or L1), the most abundant family of autonomous retrotransposons occupying over 17% of human DNA, is epigenetically silenced in normal tissues by the mechanisms involving p53 but is frequently derepressed in cancer, suggesting that L1-encoded proteins may act as tumor-associated antigens recognized by the immune system. In this study, we established an immunoassay to detect circulating autoantibodies against L1 proteins in human blood. Using this assay in >2,800 individuals with or without cancer, we observed significantly higher IgG titers against L1-encoded ORF1p and ORF2p in patients with lung, pancreatic, ovarian, esophageal, and liver cancers than in healthy individuals.

Diverse domain architectures of CheA histidine kinase, a central component of bacterial and archaeal chemosensory systems.

Chemosensory systems in bacteria and archaea are complex, multi-protein pathways that enable rapid cellular responses to environmental changes. The CheA histidine kinase is a central component of chemosensory systems. In contrast to other histidine kinases, it lacks a sensor (input) domain and utilizes dedicated chemoreceptors for sensing.

Two disulfide-reducing pathways are required for the maturation of plastid c-type cytochromes in Chlamydomonas reinhardtii.

In plastids, conversion of light energy into ATP relies on cytochrome f, a key electron carrier with a heme covalently attached to a CXXCH motif. Covalent heme attachment requires reduction of the disulfide-bonded CXXCH by CCS5 and CCS4. CCS5 receives electrons from the oxidoreductase CCDA, while CCS4 is a protein of unknown function.

Evolutionary history of MEK1 illuminates the nature of deleterious mutations.

Mutations in signal transduction pathways lead to various diseases including cancers. MEK1 kinase, encoded by the human gene, is one of the central components of the MAPK pathway and more than a hundred somatic mutations in the gene were identified in various tumors. Germline mutations deregulating MEK1 also lead to congenital abnormalities, such as the cardiofaciocutaneous syndrome and arteriovenous malformation.

Diverse Sensory Repertoire of Paralogous Chemoreceptors Tlp2, Tlp3, and Tlp4 in .

Campylobacter jejuni responds to extracellular stimuli via transducer-like chemoreceptors (Tlps). Here, we describe receptor-ligand interactions of a unique paralogue family of dCache_1 (double lcium channels and motaxis) chemoreceptors: Tlp2, Tlp3, and Tlp4. Phylogenetic analysis revealed that Tlp2, Tlp3, and Tlp4 receptors may have arisen through domain duplications, followed by a divergent evolutionary drift, with Tlp3 emerging more recently, and unexpectedly, responded to glycans, as well as multiple organic and amino acids with overlapping specificities.

Unsupervised learning of aging principles from longitudinal data.

Age is the leading risk factor for prevalent diseases and death. However, the relation between age-related physiological changes and lifespan is poorly understood. We combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements.

Phyletic Distribution and Diversification of the Phage Shock Protein Stress Response System in Bacteria and Archaea.

Maintaining cell envelope integrity is of vital importance for all microorganisms. Not surprisingly, evolution has shaped conserved protein protection networks that connect stress perception, transmembrane signal transduction, and mediation of cellular responses upon cell envelope stress. The phage shock protein (Psp) stress response is one such conserved protection network.

Amino acid sensor conserved from bacteria to humans.

SignificanceAmino acids are the building blocks of life and important signaling molecules. Despite their common structure, no universal mechanism for amino acid recognition by cellular receptors is currently known. We discovered a simple motif, which binds amino acids in various receptor proteins from all major life-forms.

The species of Oxytropis DC. of section Gloeocephala Bunge (Fabaceae) from Northeast Asia: genetic diversity and relationships based on sequencing of the intergenic spacers of cpDNA and ITS nrDNA.

Phylogenetic relationships within Oxytropis DC. sect. Gloeocephala Bunge from Northeast Asia were studied using plastid intergenic spacers (psbA-trnH + trnL-trnF + trnS-trnG) and ITS nrDNA.

Development of infrastructure for a systemic multidisciplinary approach to study aging in retired sled dogs.

Canines represent a valuable model for mammalian aging studies as large animals with short lifespans, allowing longitudinal analyses within a reasonable time frame. Moreover, they develop a spectrum of aging-related diseases resembling that of humans, are exposed to similar environments, and have been reasonably well studied in terms of physiology and genetics. To overcome substantial variables that complicate studies of privately-owned household dogs, we have focused on a more uniform population composed of retired Alaskan sled dogs that shared similar lifestyles, including exposure to natural stresses, and are less prone to breed-specific biases than a pure breed population.

A species-specific functional module controls formation of pollen apertures.

Pollen apertures are an interesting model for the formation of specialized plasma-membrane domains. The plant-specific protein INP1 serves as a key aperture factor in such distantly related species as Arabidopsis, rice and maize. Although INP1 orthologues probably play similar roles throughout flowering plants, they show substantial sequence divergence and often cannot substitute for each other, suggesting that INP1 might require species-specific partners.

A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications.

The Toll-like receptor 5 (TLR5) agonist entolimod, a derivative of Salmonella flagellin, has therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 human studies, entolimod induced a rapid neutralizing immune response, presumably due to immune memory from prior exposure to flagellated enterobacteria. To enable multi-dose applications, we used structure-guided reengineering to develop a next-generation, substantially deimmunized entolimod variant, GP532.

Diversity of bacterial chemosensory systems.

Chemosensory system is the most complex, specialized mode of signal transduction in bacteria and archaea. It is composed of several core and auxiliary protein components that are highly organized in order to deliver a fast response to changing environmental conditions. Chemosensory pathways were studied in-depth in a handful of model organisms and experimentally characterized at least to some degree in approximately thirty other species.

The chemoreceptor Tlp10 has a bimodal ligand-binding domain and specificity for multiple classes of chemoeffectors.

is a bacterial pathogen that is a common cause of enteritis in humans. We identified a previously uncharacterized type of sensory domain in the periplasmic region of the chemoreceptor Tlp10, termed the DAHL domain, that is predicted to have a bimodular helical architecture. Through two independent ligand-binding sites in this domain, Tlp10 responded to molecular aspartate, isoleucine, fumarate, malate, fucose, and mannose as attractants and to arginine, galactose, and thiamine as repellents.

Origins and Molecular Evolution of the NusG Paralog RfaH.

The only universally conserved family of transcription factors comprises housekeeping regulators and their specialized paralogs, represented by well-studied NusG and RfaH. Despite their ubiquity, little information is available on the evolutionary origins, functions, and gene targets of the NusG family members. We built a hidden Markov model profile of RfaH and identified its homologs in sequenced genomes.

Outcomes of Interrupted Aortic Arch Repair in Children With Biventricular Circulation.

Background: To evaluate the outcomes after surgical repair of interrupted aortic arch in patients with biventricular circulation.

Methods: We reviewed all children from a single institution (N = 177) who had interrupted aortic arch repair between 1978 and 2018. Patients were separated into simple (n = 122) and complex (n = 55) group based on their concomitant anomalies.

Superior cancer preventive efficacy of low versus high dose of mTOR inhibitor in a mouse model of prostate cancer.

The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy.

OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis.

Effective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt's lymphoma in vitro and in mouse xenograft models.

[Post Radiotherapy Lesions of the Heart Valves. Principles of Diagnosis and Results of Treatment].

Background: The use of radiation therapy for the treatment of tumors of the chest сan lead to the development of cardiac pathology, including that of the valves and coronary arteries.

Study Aim: to analyze the specifics of post-radiation lesions of the valvular apparatus and coronary arteries, and to assess the immediate results and risks of surgical correction of detected defects. Materials and  methods.