HLA-C, DRB1 and DQB1 alleles involved in genetic predisposition to psoriasis vulgaris in the Slovak population

Psoriasis vulgaris is a complex chronic skin disease with immunological and genetic background. The most important predisposing genetic factors in psoriasis are genes of the human leukocyte antigen (HLA) region. Accumulative evidence has shown that several HLA alleles are closely associated with psoriasis; however, they tend to vary in different racial and ethnic backgrounds. One hundred forty-seven unrelated Slovak patients with psoriasis vulgaris (average age at onset 28?±?14 years) were genotyped for the HLA-C, DQB1 and DRB1 alleles by the polymerase chain reaction using sequence-specific primers. Allele frequencies observed in the group of psoriatic patients were compared to those obtained in the ethnically matched control group comprising 194 subjects with no history of psoriasis. Susceptibility to psoriasis vulgaris in our study group is significantly associated with HLA-C*06 (odds ratio (OR)?=?3.85), DRB1*07 (OR?=?2.56) and DQB1*02 (OR?=?1.09), respectively, whereas DRB*01 (OR?=?0.05) is associated negatively. Hereby, we provide the first report on the association of HLA-C, DRB1 and DQB1 alleles with psoriasis in the Slovak population. Our findings confirm HLA-C*06 and DRB1*07 as the most important genetic risk factors for psoriasis. However, the role of HLA genes as causative in the pathogenesis of the disease remains unclear. Identification of genetic factors that increase the risk of psoriasis is a precondition that helps to elucidate the pathogenesis of this troubling disease and identify targets for a more specific and effective therapy.     

The postnatal ontogeny of the sexually dimorphic vocal apparatus in goitred gazelles (Gazella subgutturosa)

This study quantitatively documents the progressive development of sexual dimorphism of the vocal organs along the ontogeny of the goitred gazelle (Gazella subgutturosa). The major, male‐specific secondary sexual features, of vocal anatomy in goitred gazelle are an enlarged larynx and a marked laryngeal descent. These features appear to have evolved by sexual selection and may serve as a model for similar events in male humans. Sexual dimorphism of larynx size and larynx position in adult goitred gazelles is more pronounced than in humans, whereas the vocal anatomy of neonate goitred gazelles does not differ between sexes. This study examines the vocal anatomy of 19 (11 male, 8 female) goitred gazelle specimens across three age‐classes, that is, neonates, subadults and mature adults. The postnatal ontogenetic development of the vocal organs up to their respective end states takes considerably longer in males than in females. Both sexes share the same features of vocal morphology but differences emerge in the course of ontogeny, ultimately resulting in the pronounced sexual dimorphism of the vocal apparatus in adults. The main differences comprise larynx size, vocal fold length, vocal tract length, and mobility of the larynx. The resilience of the thyrohyoid ligament and the pharynx, including the soft palate, and the length changes during contraction and relaxation of the extrinsic laryngeal muscles play a decisive role in the mobility of the larynx in both sexes but to substantially different degrees in adult females and males. Goitred gazelles are born with an undescended larynx and, therefore, larynx descent has to develop in the course of ontogeny. This might result from a trade‐off between natural selection and sexual selection requiring a temporal separation of different laryngeal functions at birth and shortly after from those later in life. J. Morphol. 277:826–844, 2016. © 2016 Wiley Periodicals, Inc.     

Distribution and Expression of Elicitin Genes in the Interspecific Hybrid Oomycete Phytophthora alni

Phytophthora alni subsp. alni, P. alni subsp. multiformis, and P. alni subsp. uniformis are responsible for alder disease in Europe. Class I and II elicitin gene patterns of P. alni subsp. alni, P. alni subsp. multiformis, P. alni subsp. uniformis, and the phylogenetically close species P. cambivora and P. fragariae were studied through mRNA sequencing and 3′ untranslated region (3′UTR)-specific PCRs and sequencing. The occurrence of multiple 3′UTR sequences in association with identical elicitin-encoding sequences in P. alni subsp. alni indicated duplication/recombination events. The mRNA pattern displayed by P. alni subsp. alni demonstrated that elicitin genes from all the parental genomes are actually expressed in this allopolyploid taxon. The complementary elicitin patterns resolved confirmed the possible involvement of P. alni subsp. multiformis and P. alni subsp. uniformis in the genesis of the hybrid species P. alni subsp. alni. The occurrence of multiple and common elicitin gene sequences throughout P. cambivora, P. fragariae, and P. alni sensu lato, not observed in other Phytophthora species, suggests that duplication of these genes occurred before the radiation of these species.     

Analysis of gene order data supports vertical inheritance of the leukotoxin operon and genome rearrangements in the 5' flanking region in genus <Emphasis Type="Italic">Mannheimia</Emphasis>

Background  

The Mannheimia subclades belong to the same bacterial genus, but have taken divergent paths toward their distinct lifestyles. For example, M. haemolytica + M. glucosida are potential pathogens of the respiratory tract in the mammalian suborder Ruminantia, whereas M. ruminalis, the supposed sister group, lives as a commensal in the ovine rumen. We have tested the hypothesis that vertical inheritance of the leukotoxin (lktCABD) operon has occurred from the last common ancestor of genus Mannheimia to any ancestor of the diverging subclades by exploring gene order data.     

On secondary hyperparathyroidism in orang-utans, Pongo satyrus (Linnaeus, 1758)

Orang-utan crania with alterations in bone structure which could be determined morphologically were studied and evaluated. The alterations in bone structure were referred to in the literature up to about 1939 as "rickets"; when vitamin D was given to the animals, the alterations diminished, until they were almost unnoticeable. From about 1941/52, the alterations were diagnosed as "Morbus Paget". Research on orang-utan crania has become possible through comparison of a larger number of single symptoms, occurring in a number of individuals. Out of a larger sample, the study was carried out on 5 individuals, showing these alterations in varying degrees. The individuals also covered various age groups, both sexes and both subspecies of orang-utans. The findings permit a diagnosis of secondary (or tertiary) hyperparathyroidism (= Morbus Engel-von Recklinghausen = fibrous cystic osteitis). The study also showed that orang-utans fall prey to Morbus Engel-von Recklinghausen in a shorter period and suffer more severely than humans. The frequency of orang-utans suffering from this disease, which are kept captive in zoos, is statistically far higher than the occurrence in humans. Orang-utans living under natural conditions do not suffer from the disease at all; according to the study of 500 animals. The authors also believe that there is a psychogenic basis for the occurrence of Morbus Engel-von Recklinghausen in zoo animals; psychological conditions such as apathy, disinterest, etc. are part of the illness, and these symptoms are also shown by animals having no outward signs of fibrous cystic osteitis. The authors believe that improved prophylaxis of orang-utans in zoos would lead to discovery of Morbus Engel-von Recklinghausen in early stages, and allow early therapy to arrest the disease. This is necessary for preservation of the species.     

Synthesis and Evaluation of Biphenyl Compounds as Kinesin Spindle Protein Inhibitors

Kinesin spindle protein (KSP), an ATP‐dependent motor protein, plays an essential role in bipolar spindle formation during the mitotic phase (M phase) of the normal cell cycle. KSP has emerged as a novel target for antimitotic anticancer drug development. In this work, we synthesized a range of new biphenyl compounds and investigated their properties in vitro as potential antimitotic agents targeting KSP expression. Antiproliferation (MTT (=3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide)) assays, combined with fluorescence‐assisted cell sorting (FACS) and Western blot studies analyzing cell‐cycle arrest confirmed the mechanism and potency of these biphenyl compounds in a range of human cancer cell lines. Structural variants revealed that functionalization of biphenyl compounds with bulky aliphatic or aromatic groups led to a loss of activity. However, replacement of the urea group with a thiourea led to an increase in antiproliferative activity in selected cell lines. Further studies using confocal fluorescence microscopy confirmed that the most potent biphenyl derivative identified thus far, compound 7 , exerts its pharmacologic effect specifically in the M phase and induces monoaster formation. These studies confirm that chemical scope remains for improving the potency and treatment efficacy of antimitotic KSP inhibition in this class of biphenyl compounds.     

Mitofusins and OPA1 Mediate Sequential Steps in Mitochondrial Membrane Fusion

Mitochondrial fusion requires the coordinated fusion of the outer and inner membranes. Three large GTPases—OPA1 and the mitofusins Mfn1 and Mfn2—are essential for the fusion of mammalian mitochondria. OPA1 is mutated in dominant optic atrophy, a neurodegenerative disease of the optic nerve. In yeast, the OPA1 ortholog Mgm1 is required for inner membrane fusion in vitro; nevertheless, yeast lacking Mgm1 show neither outer nor inner membrane fusion in vivo, because of the tight coupling between these two processes. We find that outer membrane fusion can be readily visualized in OPA1-null mouse cells in vivo, but these events do not progress to inner membrane fusion. Similar defects are found in cells lacking prohibitins, which are required for proper OPA1 processing. In contrast, double Mfn-null cells show neither outer nor inner membrane fusion. Mitochondria in OPA1-null cells often contain multiple matrix compartments bounded together by a single outer membrane, consistent with uncoupling of outer versus inner membrane fusion. In addition, unlike mitofusins and yeast Mgm1, OPA1 is not required on adjacent mitochondria to mediate membrane fusion. These results indicate that mammalian mitofusins and OPA1 mediate distinct sequential fusion steps that are readily uncoupled, in contrast to the situation in yeast.     

Constitutively Active Mitogen-Activated Protein Kinase Versions Reveal Functions of Arabidopsis MPK4 in Pathogen Defense Signaling

Plant mitogen-activated protein kinases (MAPKs) are involved in important processes, including stress signaling and development. In a functional yeast screen, we identified mutations that render Arabidopsis thaliana MAPKs constitutively active (CA). Importantly, CA-MAPKs maintain their specificity toward known activators and substrates. As a proof-of-concept, Arabidopsis MAPK4 (MPK4) function in plant immunity was investigated. In agreement with the phenotype of mpk4 mutants, CA-MPK4 plants were compromised in pathogen-induced salicylic acid accumulation and disease resistance. MPK4 activity was found to negatively regulate pathogen-associated molecular pattern-induced reactive oxygen species production but had no impact on callose deposition, indicating that CA-MPK4 allows discriminating between processes regulated by MPK4 activity from processes indirectly affected by mpk4 mutation. Finally, MPK4 activity was also found to compromise effector-triggered immunity conditioned by the Toll Interleukin-1 Receptor–nucleotide binding (NB)–Leu-rich repeat (LRR) receptors RPS4 and RPP4 but not by the coiled coil–NB-LRR receptors RPM1 and RPS2. Overall, these data reveal important insights on how MPK4 regulates plant defenses and establishes that CA-MAPKs offer a powerful tool to analyze the function of plant MAPK pathways.     

Engineering seed dormancy by the modification of zeaxanthin epoxidase gene expression

Abscisic acid (ABA) is a plant hormone synthesized during seed development that is involved in the induction of seed dormancy. Delayed germination due to seed dormancy allows long-term seed survival in soil but is generally undesirable in crop species. Freshly harvested seeds of wild-type Nicotiana plumbaginifolia plants exhibit a clear primary dormancy that results in delayed germination, the degree of primary dormancy being influenced by environmental culture conditions of the mother plant. In contrast, seeds, obtained either from ABA-deficient mutant aba2-s1 plants directly or aba2-s1 plants grafted onto wild-type plant stocks, exhibited rapid germination under all conditions irrespective of the mother plant culture conditions. The ABA biosynthesis gene ABA2 of N. plumbaginifolia, encoding zeaxanthin epoxidase, was placed under the control of the constitutive 35S promoter. Transgenic plants overexpressing ABA2 mRNA exhibited delayed germination and increased ABA levels in mature seeds. Expression of an antisense ABA2 mRNA, however, resulted in rapid seed germination and in a reduction of ABA abundance in transgenic seeds. It appears possible, therefore, that seed dormancy can be controlled in this Nicotiana model species by the manipulation of ABA levels.