Structure-Based Design of Residue 1 Analogs of the Direct Thrombin Inhibitor Pentapeptide FM 19

Myocardial ischemia and other acute coronary syndromes are leading causes of death worldwide, and often result from a thrombus that blocks an atherosclerotic coronary artery. A key enzyme in thrombus formation is the serine protease thrombin, which is responsible for both the conversion of soluble fibrinogen into insoluble fibrin, as well as the activation of the GPCRs, PAR1 and PAR4, which stimulate platelet aggregation. Thus, thrombin is an attractive target for anticoagulant and antithrombotic therapy. Previous studies in our laboratory led to the development of lead compound FM 19 ( d -Arg-Oic-Pro- d -Ala-Phe( p- Me)-NH 2 ), which shows modest potency as a thrombin inhibitor. The recently determined X-ray structure of FM 19 in the active site of thrombin has revealed potential sites for modification to improve potency. This study reports replacements to the first residue ( d -Arg 1 ) of FM 19, which seek to improve potency by removing the N-terminal amine to eliminate an adverse electrostatic interaction, and alterations to the length of the side chain to eliminate an unfavorable eclipsed conformation observed in the X-ray structure. This study produced two compounds, 1 and 9 , with improved α-thrombin inhibition (IC 50 values of 0.66 ± 0.20 μ m and 0.57 ± 0.12 μ m , respectively).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78658/1/j.1747-0285.2009.00915.x.pd

Modulation of Opioid Receptor Ligand Affinity and Efficacy Using Active and Inactive State Receptor Models

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94299/1/cbdd.12014.pd

Design of high affinity cyclic pentapeptide ligands for Κ-opioid receptors

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73319/1/j.1399-3011.2005.00295.x.pd

Roles of residues 3 and 4 in cyclic tetrapeptide ligand recognition by the Κ -opioid receptor

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75723/1/j.1399-3011.2005.00220.x.pd

Distinct physiological and behavioural functions for parental alleles of imprinted Grb10

Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development1, but also postnatal functions including energy homeostasis2 and behaviour3, 4. When the two parental alleles are unequally represented within a social group (when there is sex bias in dispersal and/or variance in reproductive success)5, 6, imprinted genes may evolve to modulate social behaviour, although so far no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules7. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue-specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues

A Microbial Survey of Lake Kivu: Mechanisms of Nitrogen Cycling

Ocean Anoxic Events (OAEs) are periods in Earth’s history during which large por-tions of the oceans contain decreased amounts of oxygen. OAEs can be very difficult to study since modern oceans are generally well-oxygenated. Here Lake Kivu, a meromictic lake with deep anoxic layers, is presented as a potential OAE analogue and is used to study a proposed nitrogen cycling mechanism that could explain the characteristic ¹⁵N excursions associated with OAEs. Biomarkers are isolated from sediment samples and analyzed across depth below the lake floor. The results are consistent with a biologically mediated nitrogen cycling mechanism, shedding more light on a potential mechanism to explain nitrogen cycling in OAEs.S.B

Rational design of peptide ligands for the kappa opioid receptor.

Interest in opioid receptors is focused on the development of strong analgesics devoid of abuse potential and adverse side effects. This task, however, cannot be accomplished without understanding the fundamental opioid receptors structure and function as well as the modes of interactions of ligands, and thus potential drugs, with these receptors. Research in our lab has generated data-verified ligand-receptor interaction models for closely related peptide series at the mu and delta types of opioid receptors. Together with mutagenesis and chimera studies, thus allowed the proposal of specific features of the ligands and their receptors that underlie the ligands' selectivity. Following the same approach, deciphering the details of ligand interactions with the third type of opioid receptor, the kappa opioid receptor (KOR), by analysis of a KOR homology model and examination of tetrapeptide and pentapeptide scaffolds for the development of KOR pharmacophore, is the broad scope of this dissertation project. Thus, starting with the homology model of KOR, structure-based ligands were designed based on JOM-13 (Tyr-c[D-Cys-Phe-D-Pen]OH, SS) and JOM-6 (Tyr-c[D-Cys-Phe-D-Pen]NH 2, SEtS) scaffolds. Specifically, cyclic tetrapeptides were synthesized with various changes in polarity, size, lipophilicity or electronic properties of residues in position 3 and 4 to investigate conformational preferences of diverse side chains within KOR binding pocket. Subsequently, cyclic pentapeptides were studied to develop a more flexible scaffold so that the energy difference between ground and bioactive state was smaller. This could potentially improve KOR binding affinity and selectivity. These studies resulted in the development of a tetrapeptide, MP133, with KOR affinity of 38.7 nM and a pentapeptide, MP148, with KOR affinity of 1.6 nM. In addition, we have developed a novel MOR ligand with 16 pM affinity and selectivity of more than 100 times higher for MOR over DOR or KOR. More importantly, we were able to understand the requirements and features of KOR selective ligands. Among them we discovered the importance of aromatic residue in positions 3 in trans conformation, the presence of D-Cys in place of D-Pen in position 4 (in tetrapeptides) or 5 (in pentapeptides), cyclization via disulfide, and a neutral C-terminus.Ph.D.Analytical chemistryHealth and Environmental SciencesPharmaceutical sciencesPharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125479/2/3192757.pd

Tourism in the Activities of the Association of Rural Sports Teams in 1946–1976 years

Od początku swojej działalności Ludowe Zespoły Sportowe (LZS) obok zadań stricte sporto-wych realizowały założenia z zakresu rekreacji oraz turystyki. Jednak dopiero od roku 1960 tury-styka w LZS stała się obowiązkowym elementem popularyzacyjnoideologicznym. Wiele kół LZS, szczególnie tych położonych w atrakcyjnych miejscach Polski, miało zadanie organizacji imprez, zlotów czy rajdów turystycznych. Głównym celem zaleceń władzy ludowej była integracja wiej-skiej młodzieży, przekazywanie haseł propagandowych i dalsza ingerencja w sprawy „odpowied-niego” wychowania młodszej części społeczeństwa wiejskiego.From the beginning of one’s activity Rural Sports Teams (Ludowe Zespoły Sportowe – LZS) besides tasks strictly sports, carried out during providing from the scope of the recreation and the tourism. However only from 1960 the tourism into the LZS became a compulsory popularizing-ideological element. Many wheels LZS, particularly of the ones located in attractive places of Po-land, setting the organization parties, rallyes, or tourist rallyes had. Integration of country young people, handing propaganda entries over and the further interference in cases were a main purpose of recommendations of the popular power „appropriate” of bringing up the younger section of so-ciety country

Żydowskie obiekty noclegowe turystyki letniej i zimowej w dwudziestoleciu międzywojennym

Jewish community before World War I practiced summer and winter tourism, participating in the activities of Polish tourist and sports associations. Numerous Jewish tourist and touring societies and sports clubs, which sought to develop their own infrastructure for accommodation in mountains or spa and recreational centers were established in the interwar period. The efforts of the Jewish community to obtain accommodations in the mountains were based on their own resources and contributions from their members. Jewish organizations did not express interest in state subsidies for most developed hostels, tourist stations or dormitories for the Jewish community.Społeczność żydowska jeszcze przed I wojną światową uprawiała turystykę letnią i zimową, uczestnicząc w działalności polskich stowarzyszeń turystycznych i sportowych. W okresie międzywojennym powstały liczne żydowskie towarzystwa turystyczno-krajoznawcze i kluby sportowe, które starały się o rozwój własnej infrastruktury noclegowej w górach lub ośrodkach uzdrowiskowo-wypoczynkowych. Starania wspólnoty żydowskiej o pozyskanie obiektów noclegowych w górach oparte były na własnych środkach i składkach członkowskich. Organizacje żydowskie nie wyrażały bowiem zainteresowania subwencjami państwowymi. W większości powstały schroniska, stacje turystyczne lub domy wycieczkowe służące społeczności żydowskiej

Sledge-bobsleigh sport in Zakopane to 1939

Początki saneczkarstwa w Zakopanem, a właściwie w całej Galicji, sięgały 1900 r. i były związane z działalnością Eugeniusza Piaseckiego na łamach czasopisma „Przegląd Zakopiański”. Opublikował w nim szereg artykułów o sportach zimowych, w tym saneczkarstwie w Zakopanem. Jego poglądy podchwyciła ówczesna elita zakopiańska, która doprowadziła do założenia „Towarzystwa Sportowego w Zakopanem”. Przed I wojną światową tor w Kuźnicach był, oprócz torów lwowskich, jedynym długim obiektem umożliwiającym organizowanie zawodów saneczkarsko-bobslejowych. Dzięki temu od początku XX w. na długie lata stał się areną zmagań sportowców z całej Polski. Tematyka sportu saneczkowo-bobslejowego w Zakopanem, a w szczególności kwestie związane z budową, zagospodarowaniem i działalnością torów saneczkowych były do tej pory poruszane dosyć sporadycznie. Celem niniejszego opracowania jest przedstawienie sportu saneczkowo-bobslejowego w Zakopanem, ze szczególnym uwzględnieniem rywalizacji na torze w Kuźnicach do 1939 roku.The origins of sledging in Zakopane, and actually in the whole of Galicia reached 1900 and were related to the activities of Eugeniusz Piasecki in the journal “Przegląd Zakopiański”. He has published a series of articles about winter sports, including sledging in Zakopane. His views picked up the present elite of Zakopane, which led to the founding “Sports Association in Zakopane”. Before World War I was Kuźnice track, in addition to the tracks of Lviv, the only long object that allows organization of competitions sledge-bobsleigh. As a result of beginning of XX century for many years to become an arena of struggle athletes from across the Poland. The subject of sledge-bobsleigh sport in Zakopane, in particular issues related to the construction, accessing and activities of sledge tracks have so far been discussed quite sporadically. The aim of this article is to present the sledge-bobsleigh sport in Zakopane, with particular emphasis on competition on the track in Kuźnice until 1939