The Brain–Skin Axis in Psoriasis—Psychological, Psychiatric, Hormonal, and Dermatological Aspects

Psoriasis is a chronic inflammatory skin disease with systemic manifestation, in which psychological factors play an important role. The etiology of psoriasis is complex and multifactorial, including genetic background and environmental factors such as emotional or physical stress. Psychological stress may also play a role in exacerbation of psoriasis, by dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, sympathetic–adrenal–medullary axis, peripheral nervous system, and immune system. Skin cells also express various neuropeptides and hormones in response to stress, including the fully functional analog of the HPA axis. The deterioration of psoriatic lesions is accompanied by increased production of inflammatory mediators, which could contribute to the imbalance of neurotransmitters and the development of symptoms of depression and anxiety. Therefore, deregulation of the crosstalk between endocrine, paracrine, and autocrine stress signaling pathways contributes to clinical manifestations of psoriasis, which requires multidisciplinary approaches.

A structured RNA motif locks Argonaute2:miR-122 onto the 5’ end of the HCV genome

AbstractmicroRNAs (miRNAs) form regulatory networks in metazoans. Viruses engage miRNA networks in numerous ways, with Flaviviridae members exploiting direct interactions of their RNA genomes with host miRNAs. For hepatitis C virus (HCV), binding of liver-abundant miR-122 stabilizes the viral RNA and regulates viral translation. Here, we investigate the structural basis for these activities, taking into consideration that miRNAs function in complex with Argonaute (Ago) proteins. The crystal structure of the Ago2:miR-122:HCV complex reveals a structured RNA motif that traps Ago2 on the viral RNA, masking its 5’ end from enzymatic attack. The trapped Ago2 can recruit host factor PCBP2, implicated in viral translation, while binding of a second Ago2:miR-122 competes with PCBP2, creating a potential molecular switch for translational control. Combined results reveal a viral RNA structure that modulates Ago2:miR-122 dynamics and repurposes host proteins to generate a functional analog of the mRNA cap-binding complex.

Task-specific roles of local interneurons for inter- and intraglomerular signaling in the insect antennal lobe

Local interneurons (LNs) mediate complex interactions within the antennal lobe, the primary olfactory system of insects, and the functional analog of the vertebrate olfactory bulb. In the cockroach Periplaneta americana, as in other insects, several types of LNs with distinctive physiological and morphological properties can be defined. Here, we combined whole-cell patch-clamp recordings and Ca2+ imaging of individual LNs to analyze the role of spiking and nonspiking LNs in inter- and intraglomerular signaling during olfactory information processing. Spiking GABAergic LNs reacted to odorant stimulation with a uniform rise in [Ca2+]i in the ramifications of all innervated glomeruli. In contrast, in nonspiking LNs, glomerular Ca2+ signals were odorant specific and varied between glomeruli, resulting in distinct, glomerulus-specific tuning curves. The cell type-specific differences in Ca2+ dynamics support the idea that spiking LNs play a primary role in interglomerular signaling, while they assign nonspiking LNs an essential role in intraglomerular signaling.

A Covalent Calmodulin Inhibitor as a Tool to Study Cellular Mechanisms of K-Ras-Driven Stemness

Recently, the highly mutated oncoprotein K-Ras4B (hereafter K-Ras) was shown to drive cancer cell stemness in conjunction with calmodulin (CaM). We previously showed that the covalent CaM inhibitor ophiobolin A (OphA) can potently inhibit K-Ras stemness activity. However, OphA, a fungus-derived natural product, exhibits an unspecific, broad toxicity across all phyla. Here we identified a less toxic, functional analog of OphA that can efficiently inactivate CaM by covalent inhibition. We analyzed a small series of benzazulenones, which bear some structural similarity to OphA and can be synthesized in only six steps. We identified the formyl aminobenzazulenone 1, here named Calmirasone1, as a novel and potent covalent CaM inhibitor. Calmirasone1 has a 4-fold increased affinity for CaM as compared to OphA and was active against K-Ras in cells within minutes, as compared to hours required by OphA. Calmirasone1 displayed a 2.5–4.5-fold higher selectivity for KRAS over BRAF mutant 3D spheroid growth than OphA, suggesting improved relative on-target activity. Importantly, Calmirasone1 has a 40–260-fold lower unspecific toxic effect on HRAS mutant cells, while it reaches almost 50% of the activity of novel K-RasG12C specific inhibitors in 3D spheroid assays. Our results suggest that Calmirasone1 can serve as a new tool compound to further investigate the cancer cell biology of the K-Ras and CaM associated stemness activities.

The postcranial skeleton of Cerrejonisuchus improcerus (Crocodyliformes: Dyrosauridae) and the unusual anatomy of dyrosaurids

Dyrosauridae is a clade of neosuchian crocodyliforms that diversified in terrestrial and aquatic environments across the Cretaceous-Paleogene transition. The postcranial anatomy of dyrosaurids has long been overlooked, obscuring both their disparity and their locomotive adaptations. Here we thoroughly describe of the postcranial remains of an unusually small dyrosaurid, Cerrejonisuchus improcerus, from the middle-late Paleocene Cerrejón Formation of Colombia, and we provide a wealth of new data concerning the postcranial anatomy of the key dyrosaurids: Congosaurus bequaerti and Hyposaurus rogersii. We identify a series of postcranial autapomorphies in Cerrejonisuchus improcerus (an elliptic-shaped odontoid laterally wide, a ulna possessing a double concavity, a fibula bearing a widely flattened proximal end, a pubis showing a large non-triangular distal surface) as well as functionally-important traits such as a relatively long ulna (85% of the humerus’ length), short forelimb (83% of hindlimb’s length), or thoracic vertebra bearing comparatively large lateral process (with widened parapophysis and diapophysis) along with strongly arched thoracic ribs allowing a more sturdy and cylindrical rib cage. These indicate a more terrestrial lifestyle for Cerrejonisuchus compared to the derived members of the clade. We also built a dataset of 187 traits on 27 taxa, that extensively samples the cranial and postcranial architectures of exemplar crocodyliforms. We analyze these data in via Principal Coordinate Analysis (PCoA) to visualize the postcranial morphospace occupation of Dyrosauridae, Thalattosuchia, and Crocodylia. Our data reveal the existence of a distinctive postcranial anatomy for Dyrosauridae that is markedly distinct from that of crocodylians. As a result, modern crocodylians are probably not good functional analog for extinct crocodyliformes. Postcranial data should also be more widely used in phylogenetic and disparity analyses of Crocodyliformes.

Stress-responsive Long Non-coding RNA, hsrω, is a genetic modifier of JNK-dependent Intrinsic Tumor Suppression in Drosophila

Cells incurring oncogenic hits are often eliminated by cell death via built-in anti-cancer defense mechanisms, broadly termed as intrinsic tumor suppression (ITS). Identification of genetic modifiers of ITS-induced cell death would provide better understanding of inherent tumor-resistance and/or susceptibility. Using a Drosophila model of loss of a tumor suppressor-mediated epithelial tumorigenesis, here we show that perturbations in levels of stress-responsive nuclear long non-coding RNA (lncRNA) hsrω gene, promote epithelial tumorigenesis. Thus, while somatic clones with loss of a tumor suppressor, Lgl, are eliminated by JNK-induced cell death, lgl mutant somatic clones induced either in an hsrω loss-of-function heterozygous genetic background, or upon cell autonomous up- or down-regulation of hsrω in lgl somatic clones, override the JNK-mediated cell death and progress to full blown tumors. These tumors display deregulation of Hippo pathway as seen from a gain of downstream target of inhibition, Diap1, an inhibitor of cell death. We finally show that downregulation in sat III non-coding RNA, a functional analog of hsrω in humans, increases sensitivity of cancer cells to cytotoxic stress-induced cell death. lncRNA hsrω, therefore, constitutes a novel genetic modifier of ITS in Drosophila and of stress-induced cell death in human cancers.SummaryA long non-coding RNA, hsrω, is a novel regulator of JNK-mediated intrinsic tumor suppression in Drosophila.Highlightslgl clones induced in hsrω heterozygous loss-of-function genetic background escape intrinsic tumor suppression (ITS).Perturbation of hsrω in lgl mutant clones, too, leads to their escape from ITS.hsrω homeostasis required for JNK-dependent ITS.Human sat III, a functional analog of hsrω, confers stress-resistant to human cancer cells.

Low-cost drug discovery with engineered E. coli reveals an anti-mycobacterial activity of benazepril

Whole-cell screening for Mycobacterium tuberculosis (Mtb) inhibitors is complicated by the pathogen's slow growth and biocontainment requirements. Here we present a synthetic biology framework for assaying Mtb drug targets in engineered E. coli. We construct Target Essential Surrogate E. coli (TESEC) in which an essential metabolic enzyme is deleted and replaced with an Mtb-derived functional analog, linking bacterial growth to the activity of the target enzyme. High throughput screening of a TESEC model for Mtb alanine racemase (ALR) revealed benazepril as a targeted inhibitor. In vitro biochemical assays indicated a noncompetitive mechanism unlike that of clinical ALR inhibitors. This is the first report of an antimicrobial activity in an approved Angiotensin Converting Enzyme (ACE) inhibitor and may explain clinical data associating use of ACE inhibitors with reduced Mtb infection risk. We establish the scalability of TESEC for drug discovery by characterizing TESEC strains for four additional targets.

FUNCTIONAL-SEMANTIC FIELD OF COMPOUND CONJUNCTIVE CONSTRUCTIONS WITH THE MEANING OF SIMULTANEITY IN THE ASPECT-TEMPORAL COMPLEX OF FIELDS OF THE MODERN RUSSIAN LANGUAGE

The article presents the construction of a functional-semantic field of compound conjunctive constructions with the meaning of simultaneous actions. Criteria for determining the central and peripheral components of the field are developed. The understanding of the temporal means of communication of complex constructions as a functional element, which is a causator of temporal relations and a formal indicator of the relationship between predicative units, is proposed. On the basis, the concept of a functive as a functional analog of a conjunction is introduced. Within each component of the constructed field, the means of expressing the total and partial simultaneity of actions are analysed.