Some results on the dynamics generated by the Bazykin model

A predator-prey model formerly proposed by A. Bazykin et al. [Bifurcation diagrams of planar dynamical systems (1985)] is analyzed in the case when two of the four parameters are kept fixed. Dynamics and bifurcation results are deduced by using the methods developed by D. K. Arrowsmith and C. M. Place [Ordinary differential equations (1982)], S.-N. Chow et al. [Normal forms and bifurcation of planar fields (1994)], Y. A. Kuznetsov [Elements of applied bifurcation theory (1998)], and A. Georgescu [Dynamic bifurcation diagrams for some models in economics and biology (2004)]. The global dynamic bifurcation diagram is constructed and graphically represented. The biological interpretation is presented, too

H3K36-dependent anchoring of the KAT Mst2C is required to maintain the balance between euchromatic and heterochromatic domains in S. pombe

PWWP domains are highly conserved in eukaryotes and act in recruiting histone modifiers to chromatin that is decorated by methylation. In S. cerevisiae, the NuA3b subunit Pdp3 targets this H3K14-specific HAT complex histone H3 (di- and) trimethylated at K36, which promotes transcriptional elongation. However, in its S. pombe homolog Mst2C the function and target of Pdp3 have yet remained unknown. In this doctoral thesis, I provide evidence that Mst2C functions in euchromatic and heterochromatic transcription but through entirely different means. My research revealed that the deletion of pdp3+ in S. pombe results in perturbed silencing at pericentromeric and subtelomeric heterochromatin domains. However, this is suppressed in the absence of Mst2, a catalytic subunit of Mst2C, which is also required for the functional integrity of the complex. Based on this observation, and in cooperation with the Bühler group in Basel, I studied the distribution of Mst2 and Pdp3 on chromatin. We could show that pdp3+ deletion or mutation of its PWWP domain led to a loss of Mst2 binding and its encroachment on heterochromatin, thereby demonstrating that Mst2 localization to euchromatin is dependent on Pdp3. In addition, I could reveal that the PWWP domain of Pdp3 is able to discriminate between the different methylation states of H3K36. Both binding of Mst2 and of Pdp3 was abolished in a Set2 truncation mutant, which mediates mono- and dimethylation but not trimethylation of H3K36. Lastly, my collaborators could show that in addition to H3K14, euchromatic Mst2C acetylates the HULC subunit Brl1, thereby promoting transcription and preventing the initiation of ectopic silencing. Several studies have reported that loss of Set2 results in a silencing defect itself. Through studying heterochromatic transcription in set2∆ in conjunction with deletion mutants of pdp3+, mst2+, and nto1+ and ptf2+, which are essential for Mst2C integrity, I determined that, as in pdp3∆, the silencing defect of set2∆ is solely founded in the encroachment of Mst2C on heterochromatin. Intriguingly, the deletion of any of the three critical subunits resulted in suppression below the level found in wild-type strains, implying that Mst2C is required to maintain basal transcription in heterochromatin. Together with the previous observations, this suggests that loss of Pdp3 and Set2 leads to a silencing defect via the same pathway that promotes basal transcription. Surprisingly, I found that Mst2C promotes heterochromatin transcription via an entirely different Pdp3-independent mechanism than in euchromatin, as it functions neither through Brl1 nor H3K14ac, but a yet unknown target. In conclusion, this thesis has demonstrated that Pdp3-dependent anchoring of Mst2C to H3K36me3 has a dual purpose: (a) in euchromatin, it prevents the formation of ectopic heterochromatin at regions decorated with H3K36me3 and promoting transcription in a Brl1-dependent manner; (b) in heterochromatin, this sequestration protects Mst2C-mediated but Pdp3 and Brl1-independent basal transcription from becoming hyperactivated and interfering with maintenance of this region.PWWP-Domänen sind in Eukaryoten hochkonserviert und werden dazu verwendet Histonmodifizierer zu mit Methylierung gekennzeichnetem Chromatin zu rekrutieren. In S. cerevisiae lotst Pdp3, eine Untereinheit von NuA3b, diesen H3K14-spezifischen HAT-Komplex zu Histon H3, welches an K36 (di- und) trimethyliert ist, was wiederum transkriptionelle Elongation begünstigt. Jedoch blieben die Funktion und der Interaktionspartner von Pdp3 in seinem Homolog Mst2C in S. pombe bis dato unbekannt. Anhand dieser Doktorarbeit liefere ich nun Beweise dafür, dass Mst2C sowohl an euchromatischer als auch an heterochromatischer Transkription beteiligt ist, aber auf gänzlich verschiedene Art und Weise. Meine Nachforschungen enthüllten, dass Deletion von pdp3+ in S. pombe in einer Beeinträchtigung der Stilllegung perizentromerischer and subtelomerer Heterochromatindomänen resultiert. Dies wird bei Fehlen von Mst2, einer katalytischen Untereinheit von Mst2C, welche auch für den Erhalt der Komplexfunktion benötigt wird, supprimiert. Basierend auf dieser Beobachtung untersuchte ich zusammen mit unseren Kollaborationspartnern, der in Basel ansässigen Bühler-Gruppe, die Verteilung von Mst2 und Pdp3 auf Chromatin. Wir konnten zeigen, dass Deletion von pdp3+ oder Mutation seiner PWWP-Domäne zum Verlust der Bindung von Mst2 und einem Vordringen dessen in Heterochromatin führt, wodurch demonstriert wurde, dass die euchromatische Positionierung von Mst2 von Pdp3 abhängt. Darüber hinaus konnte ich enthüllen, dass die PWWP-Domäne von Pdp3 dazu in der Lage ist zwischen den Methylierungsstadien von H3K36 zu unterscheiden. Sowohl die Anbindung von Mst2 also auch Pdp3 wurden in einer trunkierten Set2-Mutante, welche zwar Mono- und Dimethylierung, jedoch keine Trimethylierung von H3K36 vermitteln kann, aufgehoben. Schlussendlich konnten meine Mitpartner darlegen, dass euchromatisches Mst2C zusätzlich zu H3K14 die HULC-Untereinheit Brl1 acetyliert, wodurch Transkription begünstigt und die Initiierung ektopischer Stilllegung verhindert wird. Aus einigen Studien ist bekannt, dass der Verlust von Set2 selbst in einem Stilllegungsdefekt resultiert. Dadurch, dass ich heterochromatische Transkription in set2∆ im Zusammenhang mit der Deletion von pdp3+, mst2+, nto1+ and ptf2+, welche ebenfalls essentiell für den Erhalt von Mst2C sind, untersuchte, stellte ich fest, dass sich, wie bei pdp3∆, der Stilllegungsdefekt von set2∆ allein auf dem Vordringen von Mst2C in Heterochromatin begründet. Interessanterweise resultierte die Deletion jeglicher kritischen Untereinheit in einer Suppression, die unterhalb des Niveaus in Wildtyp lag, was impliziert, dass Mst2C zum Erhalt der basalen Transkription innerhalb von Heterochromatin notwendig ist. Zusammengenommen mit den vorherigen Beobachtungen deutet dies an, dass die Stilllegungsdefekte durch Verlust von Pdp3 und Set2 auf dieselbe Weise entstehen, in der basale Transkription unterstützt wird. Zu meiner Überraschung stellte sich heraus, dass Mst2C basale Transkription von Heterochromatin durch einen völlig anderen, Pdp3-unabhängigen, Mechanismus vorantreibt als in Euchromatin, da dieser weder über Brl1 noch über H3K14 agiert, sondern über ein noch unbekanntes Zielobjekt. Im Großen und Ganzen hat diese Arbeit demonstriert, das Pdp3-vermittelte Verankerung von Mst2C an H3K36me3 zwei Aufgaben erfüllt: (a) in Euchromatin verhindert diese die Bildung von ektopischem Heterochromatin in Regionen, die mit H3K36me3 markiert sind und unterstützt Transkription in Abhängigkeit von Brl1; (b) in Heterochromatin schützt diese Abtrennung davor, dass Mst2-vermittelte, aber Pdp3- und Brl1-unabhängige basale Transkription hyperaktiviert wird und dadurch mit der Instandhaltung dieser Region interferiert

Modern leadership in business organisations during economic disruption

This paper represents a functional and global overview of what modern leadership is and what global leaders should be. Its purpose is to build the needed traits for achieving high performance, develop power traits for better insight in employee development and also understanding the ecosystem that represents a modern company’s growth process

Indolizines and pyrrolo[1,2- c ]pyrimidines decorated with a pyrimidine and a pyridine unit respectively

The three possible structural isomers of 4-(pyridyl)pyrimidine were employed for the synthesis of new pyrrolo[1,2-c]pyrimidines and new indolizines, by 1,3-dipolar cycloaddition reaction of their corresponding N-ylides generated in situ from their corresponding cycloimmonium bromides. In the case of 4-(3-pyridyl)pyrimidine and 4-(4-pyridyl)pyrimidine the quaternization reactions occur as expected at the pyridine nitrogen atom leading to pyridinium bromides and consequently to new indolizines via the corresponding pyridinium N-ylides. However, in the case of 4-(2-pyridyl)pyrimidine the steric hindrance directs the reaction to the pyrimidinium N-ylides and, subsequently, to the formation of the pyrrolo[1,2-c]pyrimidines. The new pyrrolo[1,2-c]pyrimidines and the new indolizines were structurally characterized through NMR spectroscopy. The X-ray structures of two of the starting materials, 4-(2-pyridyl)pyrimidine and 4-(4-pyridyl)pyrimidine, are also reported

Globalization of the corruption phenomenon – human capital gone wild

This research article tries to analyse the way corruption evolves and finds its fine tuning in developed countries around the world. Corruption represents a disease similar to a cancer that consumes organizations, entire societies, cultures or economic and political ideologies, all these being vital for the survival of the species in an almost normal social environment. Through this research the authors try to emphasize the true nature and relationship between corruption and social evolution and economic growth of a mature economy

Efficacy of cognitive bias modification interventions in anxiety and depressive disorders:a systematic review and network meta-analysis

Background: Cognitive bias modification (CBM) therapies, including attention bias modification, interpretation bias modification, or approach and avoidance training, are prototypical examples of mechanistically derived treatments, but their effectiveness is contentious. We aimed to assess the relative effectiveness of various CBM interventions for anxious and depressive symptomatology. Methods: For this systematic review and network meta-analysis, we searched PubMed, PsycINFO, Embase, and Cochrane Central Register from database inception up until Feb 7, 2020. We included randomised controlled trials of CBM versus control conditions or other forms of CBM for adults aged 18 years and older with clinical or subclinical anxiety or depression measured with a diagnostic interview or a validated clinical scale. We excluded studies comparing CBM with a non-CBM active intervention. Two researchers independently selected studies and evaluated risk of bias with the Cochrane Collaboration tool. Primary outcomes encompassed anxiety and depressive symptoms measured with validated clinical scales. We computed standardised mean differences (SMDs) with a restricted maximum likelihood random effects model. This study is registered with PROSPERO, CRD42018086113. Findings: From 2125 records we selected 85 trials, 65 (n=3897) on anxiety and 20 (n=1116) on depression. In a well connected network of anxiety trials, interpretation bias modification outperformed waitlist (SMD −0·55, 95% CI −0·91 to −0·19) and sham training (SMD −0·30, −0·50 to −0·10) for the primary outcome. Attention bias modification showed benefits only in post-hoc sensitivity analyses excluding post-traumatic stress disorder trials. Prediction intervals for all findings were large, including an SMD of 0. Networks of depression trials displayed evidence of inconsistency. Only four randomised controlled trials had low risk of bias on all six domains assessed. Interpretation: CBM interventions showed consistent but small benefits; however heterogeneity and risk of bias undermine the reliability of these findings. Larger, definitive trials for interpretation bias modification for anxiety might be warranted, but insufficient evidence precludes conclusions for depression. Funding: Romanian Ministry of Research and Innovation, The National Council for Scientific Research—The Executive Agency for Higher Education, Research, Development and Innovation Funding