The people of the inland lake burial grounds : An osteological analysis of bone material from the Vindförberg burial ground

Vindförbergs gravfält ligger i Ore socken, Dalarna, och klassificeras av många som ett insjögravfält. Dessa har varit aktiva under järnåldern till den tidiga medeltiden, och många frågetecken kvarstår ännu kring den eller de kulturer som etablerat dem. Den här uppsatsen undersöker de deponeringar av hornmaterial som påträffats vid Vindförbergs gravfält. Syftet är att undersöka dessas funktion och betydelse, skillnader mellan gravar med respektive utan deponeringar samt skillnader och likheter mellan Vindförberg och Krankmårtenhögen. Uppsatsen tillämpar osteologiska metoder, kompletterade med arkeologiska metoder, samt komparativa metoder. Den komparativa metoden har tillämpats gentemot Krankmårtenhögen, för att försätta de övriga resultaten i en större kontext. Studien har kunnat konstatera att hornen placerats medvetet på gravarna som statussymboler eller okända ritualistiska skäl. Studien har även kunnat konstatera att det finns vissa betydelsefulla skillnader mellan gravar med respektive utan deponeringar av horn, då främst gällande åldern då de begravda individerna avled. Vidare har studien kunnat konstatera starka likheter mellan Vindförbergs och Krankmårtenhögens respektive gravfält, vilket styrker en kulturell koppling trots vissa skillnader i mängden deponerat material.Vindförberg's burial ground is located in Ore parish, Dalarna, and is classified by many as a inland lake burial ground. These have been active during the Iron Age to the early Middle Ages, and many questions still remain about the culture(s) that established them. This paper examines the deposits of horn material found at the Vindförberg burial ground. The aim is to investigate their function and significance, differences between graves with and without deposits, and differences and similarities between Vindförberg and Krankmårtenhögen. The essay applies osteological methods, supplemented with archaeological methods, as well as comparative methods. The comparative method has been applied to Krankmårtenhögen, in order to put the other results in a larger context. The study has been able to establish that the horns were deliberately placed on the graves as status symbols or for unknown ritualistic reasons. The study has also been able to establish that there are some significant differences between graves with and without deposits of horns, mainly regarding the age at which the buried individuals died. Furthermore, the study has been able to establish strong similarities between Vindförberg's and Krankmårtenhögen's respective burial grounds, which proves a cultural connection, despite some differences in the amount of deposited material

The people of the inland lake burial grounds : An osteological analysis of bone material from the Vindförberg burial ground

Vindförbergs gravfält ligger i Ore socken, Dalarna, och klassificeras av många som ett insjögravfält. Dessa har varit aktiva under järnåldern till den tidiga medeltiden, och många frågetecken kvarstår ännu kring den eller de kulturer som etablerat dem. Den här uppsatsen undersöker de deponeringar av hornmaterial som påträffats vid Vindförbergs gravfält. Syftet är att undersöka dessas funktion och betydelse, skillnader mellan gravar med respektive utan deponeringar samt skillnader och likheter mellan Vindförberg och Krankmårtenhögen. Uppsatsen tillämpar osteologiska metoder, kompletterade med arkeologiska metoder, samt komparativa metoder. Den komparativa metoden har tillämpats gentemot Krankmårtenhögen, för att försätta de övriga resultaten i en större kontext. Studien har kunnat konstatera att hornen placerats medvetet på gravarna som statussymboler eller okända ritualistiska skäl. Studien har även kunnat konstatera att det finns vissa betydelsefulla skillnader mellan gravar med respektive utan deponeringar av horn, då främst gällande åldern då de begravda individerna avled. Vidare har studien kunnat konstatera starka likheter mellan Vindförbergs och Krankmårtenhögens respektive gravfält, vilket styrker en kulturell koppling trots vissa skillnader i mängden deponerat material.Vindförberg's burial ground is located in Ore parish, Dalarna, and is classified by many as a inland lake burial ground. These have been active during the Iron Age to the early Middle Ages, and many questions still remain about the culture(s) that established them. This paper examines the deposits of horn material found at the Vindförberg burial ground. The aim is to investigate their function and significance, differences between graves with and without deposits, and differences and similarities between Vindförberg and Krankmårtenhögen. The essay applies osteological methods, supplemented with archaeological methods, as well as comparative methods. The comparative method has been applied to Krankmårtenhögen, in order to put the other results in a larger context. The study has been able to establish that the horns were deliberately placed on the graves as status symbols or for unknown ritualistic reasons. The study has also been able to establish that there are some significant differences between graves with and without deposits of horns, mainly regarding the age at which the buried individuals died. Furthermore, the study has been able to establish strong similarities between Vindförberg's and Krankmårtenhögen's respective burial grounds, which proves a cultural connection, despite some differences in the amount of deposited material

4-AMINOTHIAZOLYL ANALOGS OF GE2270 A: DESIGN, SYNTHESIS AND EVALUATION OF IMIDAZOLE ANALOGS

Imidazole analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and evaluated for Gram positive bacteria growth inhibition. A recently reported, copper-mediated synthesis was exploited to prepare the 4-thiazolyl imidazole analogs of GE2270 A. The synthesis described represents a structurally complex, natural product-based application of this recently reported synthetic methodology. In addition, the biological evaluation of the imidazole-based analogs further define the SAR of the 4-aminothiazolyl-based template

4-Aminothiazolyl Analogs of GE2270 A: Antibacterial Lead Finding

4-Aminothiazolyl analogs of the antibacterial natural product GE2270 A (1) were designed, synthesized, and evaluated for G+ bacteria growth inhibition. The aminothiazole-based chemical template was evaluated for chemical stability and its decomposition revealed a novel, structurally simplified, des-thiazole analog of GE2270 A. Subsequent stabilization of the 4-aminothiazolyl functional motif was achieved and initial structure activity relationships defined

Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (1) were initiated in order to improve chemical stability and physicochemical properties. Functional group manipulation of thiomuracin A included: removal of the C2-C7 sidechain, derivatization of the C84 epoxide region, and removal of the C44 hydroxyphenylalanine motif. The resulting derivatives stabilized and simplified the chemical structure while retaining potent antibacterial activity as compared to thiomuracin A, and facilitated isolation and further material supply for continued medicinal chemistry optimization

ANTIBACTERIAL LEAD OPTIMIZATION OF 4-AMINOTHIAZOLYL ANALOGUES OF GE2270 A: THE CYCLOALKYLCARBOXYLIC ACIDS

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of Gram positive bacterial infections. Lead optimization efforts of the 4-aminothiazolyl natural product template focused on improving aqueous solubility while maintaining in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved. These studies culminated in the identification of the cycloalkyl-carboxylic acid class of EF-Tu inhibitors, and development candidates amide 48 and urethane 58

Antibiotic Optimization and Chemical Structure Stabilization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (<b>1</b>) were initiated to improve chemical stability and physicochemical properties. Functional group modifications of <b>1</b> included removing the C2–C7 side chain, derivatizing the C84 epoxide region, and altering the C44 hydroxyphenylalanine motif. The resulting derivatives simplified and stabilized the chemical structure and were evaluated for antibacterial activity relative to <b>1</b>. The simplified structure and improved organic solubility of the derivatives facilitated isolation yields from fermentation broths and simplified the procedures involved for the process. These advancements increased material supply for continued medicinal chemistry optimization and culminated in the identification of <b>2</b>, a structurally simplified and chemically stable analogue of <b>1</b> which retained potent antibiotic activity

Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A were designed, synthesized, and optimized for the treatment of Gram positive bacterial infections which culminated in the identification of development candidates 1 and 2. In support of development candidate selection, amide 1 and urethane 2 were profiled for antibacterial activity, mechanism of action, antibacterial, selectivity, solubility, formulability, in pharmacokinetic studies, and in the mouse sepsis and thigh animal models of infection. In addition, 1 and 2 were compared to marketed antibiotics used to treat Gram positive bacterial infections

DISCOVERY OF LFF571 AS AN INVESTIGATIONAL AGENT FOR Clostridium difficile INFECTION

Clostridium difficile is a Gram positive, spore-forming, anaerobic bacterium which infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. The prevalence and severity of C. difficile infection are increasing, causing increased morbidity and mortality. 4-Aminothiazolyl analogs of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of serious Gram positive bacterial infections, including C. difficile infection. Optimization of the 4-aminothiazolyl-natural product template focused on improving aqueous solubility over the natural product and previous development candidates (2, 3), and improving in vitro and in vivo antibacterial activity. Structure-activity relationships, structure-solubility relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies culminated in the identification of a dicarboxylic acid chemical series, which enhanced the solubility/efficacy profile by several orders of magnitude as compared to previous monoacid-based development candidates and led to the selection of LFF571 (4) as an investigational new drug for the treatment of C. difficile infection

Antibacterial and Solubility Optimization of Thiomuracin A

Synthetic studies of the antimicrobial secondary metabolite thiomuracin A (<b>1</b>) provided access to analogues in the Northern region (C2–C10). Selective hydrolysis of the C10 amide of lead compound <b>2</b> and subsequent derivatization led to novel carbon- and nitrogen-linked analogues (e.g., <b>3</b>) which improved antibacterial potency across a panel of Gram-positive organisms. In addition, congeners with improved physicochemical properties were identified which proved efficacious in murine sepsis and hamster <i>C. difficile</i> models of disease. Optimal efficacy in the hamster model of <i>C. difficile</i> was achieved with compounds that possessed both potent antibacterial activity and high aqueous solubility