Med livet som insats : Biografin som humanistisk genre

This book discusses the theories, methods and perspectives of the scholarly biography. The point of departure is the continuously growing interest in biography as a genre over the last decade in history, literature and other fields of the humanities. In the first section of the anthology, “The Biographical Genre”, three articles highlight general tendencies and problems in biography writing. Adopting a historical perspective, the contributors discuss the relationship between various cultural and intellectual currents and changing practices and standings in the writing of biographies.“The Biographical Gaze”, the second part of the book, is directed towards opportunities for and challenges to biography within four academic fields: history, literature, the history of ideas and archaeology. By focusing on the traditions of particular disciplines, the authors draw attention both to peculiarities in their own scholarly field and more wide-ranging issues in the writing of biographies. The third part, “The Biographical Dialogue”, is dedicated to the interaction between the biographer and the object of the biography. The shifting feelings of frustration and pleasure in the encounter with another human being are a frequent theme in these articles, and also discussed are the need for ethical reflection, critical distance and power of insight. The fourth and final section presents an overview of important biographies and scholarly biographical research. The contributors to the anthology include: Yvonne Hirdman, Alf W Johansson, Kristina Josefson, Martin Kylhammar, Lisbeth Larsson, Ingmar Lundkvist, Birgitte Possing, Henrik Rosengren, Johan Svedjedal, Eva Helen Ulvros, Christina Carlsson Wetterberg and Johan Östling

Side‐chain dynamics of the <scp>α_1B‐</scp>adrenergic receptor determined by <scp>NMR</scp> via methyl relaxation

G protein‐coupled receptors (GPCRs) are medically important membrane proteins that sample inactive, intermediate, and active conformational states characterized by relatively slow interconversions (~μs–ms). On a faster timescale (~ps–ns), the conformational landscape of GPCRs is governed by the rapid dynamics of amino acid side chains. Such dynamics are essential for protein functions such as ligand recognition and allostery. Unfortunately, technical challenges have almost entirely precluded the study of side‐chain dynamics for GPCRs. Here, we investigate the rapid side‐chain dynamics of a thermostabilized α$_{1B}$‐adrenergic receptor (α$_{1B}$‐AR) as probed by methyl relaxation. We determined order parameters for Ile, Leu, and Val methyl groups in the presence of inverse agonists that bind orthosterically (prazosin, tamsulosin) or allosterically (conopeptide ρ‐TIA). Despite the differences in the ligands, the receptor's overall side‐chain dynamics are very similar, including those of the apo form. However, ρ‐TIA increases the flexibility of Ile176$^{4×56}$ and possibly of Ile214$^{5×49}$, adjacent to Pro215$^{5×50}$ of the highly conserved P$^{5×50}$I$^{3×40}$F$^{6×44}$ motif crucial for receptor activation, suggesting differences in the mechanisms for orthosteric and allosteric receptor inactivation. Overall, increased Ile side‐chain rigidity was found for residues closer to the center of the membrane bilayer, correlating with denser packing and lower protein surface exposure. In contrast to two microbial membrane proteins, in α$_{1B}$‐AR Leu exhibited higher flexibility than Ile side chains on average, correlating with the presence of Leu in less densely packed areas and with higher protein‐surface exposure than Ile. Our findings demonstrate the feasibility of studying receptor‐wide side‐chain dynamics in GPCRs to gain functional insights

Whole-genome genotyping and resequencing reveal the association of a deletion in the complex interferon alpha gene cluster with hypothyroidism in dogs

Background: Hypothyroidism is a common complex endocrinopathy that typically has an autoimmune etiology, and it affects both humans and dogs. Genetic and environmental factors are both known to play important roles in the disease development. In this study, we sought to identify the genetic risk factors potentially involved in the susceptibility to the disease in the high-risk Giant Schnauzer dog breed. Results: By employing genome-wide association followed by fine-mapping (top variant p-value=5.7x10(-6)), integrated with whole-genome resequencing and copy number variation analysis, we detected a similar to 8.9 kbp deletion strongly associated (p-value=0.0001) with protection against development of hypothyroidism. The deletion is located between two predicted Interferon alpha (IFNA) genes and it may eliminate functional elements potentially involved in the transcriptional regulation of these genes. Remarkably, type I IFNs have been extensively associated to human autoimmune hypothyroidism and general autoimmunity. Nonetheless, the extreme genomic complexity of the associated region on CFA11 warrants further long-read sequencing and annotation efforts in order to ascribe functions to the identified deletion and to characterize the canine IFNA gene cluster in more detail. Conclusions: Our results expand the current knowledge on genetic determinants of canine hypothyroidism by revealing a significant link with the human counterpart disease, potentially translating into better diagnostic tools across species, and may contribute to improved canine breeding strategies

Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer.

Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3-9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker-negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions

Two proteins for the price of one: structural studies of the dual-destiny protein preproalbumin with sunflower trypsin inhibitor-1

Seed storage proteins are both an important source of nutrition for humans and essential for seedling establishment. Interestingly, unusual napin-type 2S seed storage albumin precursors in sunflowers contain a sequence that is released as a macrocyclic peptide during post-translational processing. The mechanism by which such peptides emerge from linear precursor proteins has received increased attention; however, the structural characterization of intact precursor proteins has been limited. Here, we report the 3D NMR structure of the Helianthus annuus PawS1 (preproalbumin with sunflower trypsin inhibitor-1) and provide new insights into the processing of this remarkable dual-destiny protein. In seeds, PawS1 is matured by asparaginyl endopeptidases (AEPs) into the cyclic peptide SFTI-1 (sunflower trypsin inhibitor-1) and a heterodimeric 2S albumin. The structure of PawS1 revealed that SFTI-1 and the albumin are independently folded into well-defined domains separated by a flexible linker. PawS1 was cleaved in vitro with recombinant sunflower HaAEP1 and in situ using a sunflower seed extract in a way that resembled the expected in vivo cleavages. Recombinant HaAEP1 cleaved PawS1 at multiple positions, and in situ, its flexible linker was removed, yielding fully mature heterodimeric albumin. Liberation and cyclization of SFTI-1, however, was inefficient, suggesting that specific seed conditions or components may be required for in vivo biosynthesis of SFTI-1. In summary, this study has revealed the 3D structure of a macrocyclic precursor protein and provided important mechanistic insights into the maturation of sunflower proalbumins into an albumin and a macrocyclic peptide

Stabilization of the Cysteine-Rich Conotoxin MrIA by Using a 1,2,3-Triazole as a Disulfide Bond Mimetic

The design of disulfide bond mimetics is an important strategy for optimising cysteine-rich peptides in drug development. Mimetics of the drug lead conotoxin MrIA, in which one disulfide bond is selectively replaced of by a 1,4-disubstituted-1,2,3-triazole bridge, are described. Sequential copper-catalyzed azide–alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazole–disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4–Cys13 disulfide bond retained tertiary structure and full in vitro and in vivo activity as norepinephrine reuptake inhibitors. Importantly, these mimetics are resistant to reduction in the presence of glutathione, thus resulting in improved plasma stability and increased suitability for drug development.NHMRC 1045964 & 107211

Distinct but overlapping binding sites of agonist and antagonist at the relaxin family peptide 3 (RXFP3) receptor

The relaxin-3 neuropeptide activates the relaxin family peptide 3 (RXFP3) receptor to modulate stress, appetite and cognition. RXFP3 shows promise as a target for treating neurological disorders, but realization of its clinical potential requires development of smaller RXFP3-specific drugs that can penetrate the blood brain barrier. Designing such drugs is challenging and requires structural knowledge of agonist- and antagonist-binding modes. Here, we used structure-activity data for relaxin-3 and a peptide RXFP3 antagonist termed R3 B1-22R, to guide receptor mutagenesis and develop models of their binding modes. RXFP3 residues were alanine substituted individually and in combination and tested in cell-based binding and functional assays to refine models of agonist and antagonist binding to active- and inactive-state homology models of RXFP3, respectively. These models suggested that both agonists and antagonists interact with RXFP3 via similar residues in their B-chain central helix. The models further suggested that the B-chain Trp-27 inserts into the binding pocket of RXFP3 and interacts with Trp-138 and Lys-271, the latter through a salt bridge with the C-terminal carboxyl group of Trp-27 in relaxin-3. R3 B1-22R, which does not contain Trp-27, used a non-native Arg-23 residue to form cation-pi and salt bridge interactions with Trp-138 and Glu-141 in RXFP3, explaining a key contribution of Arg-23 to affinity. Overall, relaxin-3 and R3 B1-22R appear to share similar binding residues but may differ in binding modes, leading to active and inactive RXFP3 conformational states, respectively. These mechanistic insights may assist structure-based drug design of smaller relaxin-3 mimetics to manage neurological disorders

Investigation of Receptor Heteromers Using NanoBRET Ligand Binding

Receptor heteromerization is the formation of a complex involving at least two different receptors with pharmacology that is distinct from that exhibited by its constituent receptor units. Detection of these complexes and monitoring their pharmacology is crucial for understanding how receptors function. The Receptor-Heteromer Investigation Technology (Receptor-HIT) utilizes liganddependent modulation of interactions between receptors and specific biomolecules for the detection and profiling of heteromer complexes. Previously, the interacting biomolecules used in ReceptorHIT assays have been intracellular proteins, however in this study we have for the first time used bioluminescence resonance energy transfer (BRET) with fluorescently-labeled ligands to investigate heteromerization of receptors on the cell surface. Using the Receptor-HIT ligand binding assay with NanoBRET, we have successfully investigated heteromers between the angiotensin II type 1 (AT1 ) receptor and the β2 adrenergic receptor (AT1-β2AR heteromer), as well as between the AT1 and angiotensin II type 2 receptor (AT1-AT2 heteromer)

Earthquake forecasting in Italy, before and after Umbria-Marche seismic sequence 1997. A review of the earthquake occurrence modeling at different spatio-temporal-magnitude scales.

The main goal of this work is to review the scientific researches carried out before and after the Umbria-Marche sequence related to the earthquake forecasting/prediction in Italy. In particular, I focus the attention on models that aim addressing three main practical questions: was (is) Umbria-Marche a region with high probability of occurrence of a destructive earthquake? Was a precursory activity recorded before the mainshock(s)? What was our capability to model the spatio-temporal-magnitude evolution of that seismic sequence? The models are reviewed pointing out what we have learned after the Umbria-Marche earthquakes, in terms of physical understanding of earthquake occurrence process, and of improving our capability to forecast earthquakes and to track in real-time seismic sequences

The effect of leisure-time physical activity on the risk of acute myocardial infarction depending on Body Mass Index: a population-based case-control study

BACKGROUND: High body mass index (BMI) and lack of physical activity have been recognized as important risk factors for coronary heart disease. The aim of the present study was to evaluate whether leisure-time physical activity compensates for the increased risk of acute myocardial infarction associated with overweight and obesity. METHODS: Data from the SHEEP (Stockholm Heart Epidemiology Program) study were used. The SHEEP study is a large Swedish population-based case-control study, comprising 1204 male and 550 female cases, and 1538 male and 777 female controls, conducted in Stockholm County, Sweden, during the period 1992–1994. Odds ratios (OR), together with 95 % confidence intervals (95% CI), were calculated using unconditional logistic regression, as estimates of the relative risks. RESULTS: Regular leisure-time physical activity was associated with a decreased risk of myocardial infarction among lean, normal-weight and overweight subjects, but not among obese subjects. Obese (BMI ≥ 30) and physically active persons had an almost twofold risk of myocardial infarction, compared with normal-weight and sedentary persons (OR 1.85, 95% CI 1.07–3.18). The results were similar for men and women. CONCLUSION: While regular leisure-time physical activity seems to provide protection against myocardial infarction among lean, normal-weight and overweight subjects, this does not appear to be the case in obese subjects