Divergent platforms

Models of electoral competition between two opportunistic, office-motivated parties typically predict that both parties become indistinguishable in equilibrium. I show that this strong connection between the office motivation of parties and their equilibrium choice of identical platforms depends on two—possibly false—assumptions: (1) Issue spaces are uni-dimensional and (2) Parties are unitary actors whose preferences can be represented by expected utilities. I provide an example of a two-party model in which parties offer substantially different equilibrium platforms even though no exogenous differences between parties are assumed. In this example, some voters’ preferences over the 2-dimensional issue space exhibit non-convexities and parties evaluate their actions with respect to a set of beliefs on the electorate

Are people following hip and knee arthroplasty at greater risk of experiencing a fall and fracture? Data from the Osteoarthritis Initiative

Introduction: Falls are a major challenge for older people and are a significant source of mortality and morbidity. There has been uncertainty as to whether people with total hip (THA) or knee (TKA) arthroplasty have a greater risk of falls and associated fractures. This analysis was to explore this question with a large community dataset. Materials and Methods: Data from all people enrolled onto the US Osteoarthritis Initiative programme who had undergone a THA (n=104) or TKA (n=165), within a 12 month period, were compared to those who had not undergone an arthroplasty (n=4631). Data was collected on: the number of participants who reported a fall within a 12 month period; the frequency of falls in this period; and whether a fracture was sustained during this period. Odd ratios were calculated for the probability of experiencing a fall or fracture between the groups. Results: There was no statistical difference in falls between people following THA (OR 0.90; 95% CI: 0.58 to 1.41) or TKA (OR: 0.95; 0.67 to 1.35) compared to a non-arthroplasty cohort. Whilst there was no statistical difference in fracture risk between people following TKA compared to non-arthroplasty individuals (OR: 1.25; 95% CI: 0.57 to 2.70), those who underwent THA had a 65% lower chance of experiencing a fracture in the initial 12 post-operative months compared to the non-THA cohort (OR 0.35; 95% CI: 0.19 to 0.65; p<0.01). Conclusions: There appears a lower chance of experiencing a fracture for people following THA compared to those who have not

Measuring Central Bank Independence: Ordering, Ranking, or Scoring?

Central bank independence (CBI)as an area for international comparison and for study by international political economists has been around for approximately two decades, spurred on by the work of Bade and Parkin (1982). It probably reached its full fruition with the work of Cukierman and others, centering on work done at the World Bank. There are others too, and we should not ignore them, but since the mid-1990s most of the work done has centered on the Cukierman-type model. Interest in the CBI intensified after models of monetary policy found the likelihood of an inflationary bias in monetary policy operated by democratic governments. That analysis turned on the potential for monetary surprises being perpetrated by governments seeking electoral advantage. Later analysis found that if such incentives were fully anticipated by the public, inflation rates in democracies are higher than they would be if somehow government could make a credible commitment to price stability. The search began for how to establish monetary institutions that can be viewed as credible commitments. Delegation of monetary policy to an independent central bank was one strand of that exploration

Immigrant fertility in West Germany: is there a socialization effect in transitions to second and third births?

In this paper on immigrant fertility in West Germany, we estimate the transition rates to second and third births, using intensity-regression models. The data come from the German Socio-Economic Panel Study. We distinguish women of the first and the second immigrant generations originating from Turkey, the former Yugoslavia, Greece, Italy, and Spain, and compare their fertility levels to those of West German women. In the theoretical framework, we discuss competing hypotheses on migrant fertility. The findings support mainly the socialization hypothesis: the transition rates of first-generation immigrants vary by country of origin, and the fertility patterns of migrant descendants resemble more closely those of West Germans than those of the first immigrant generation. In addition, the analyses show that fertility differentials between immigrants and women of the indigenous population can largely, though not in full, be explained by compositional differences.Dans cet article relatif à la fécondité des immigrées en Allemagne, le passage du premier au deuxieme enfant et dans celui du deuxieme au troisieme enfant est estimé à partir de modèles de régression à risques instantanés. Les données utilisées proviennent de l’étude de Panel socio-économique allemand. On distingue les femmes immigrées de première ou de seconde génération originaires de Turquie, d’ex-Yougoslavie, de Grèce, d’Italie et d’Espagne, et leurs niveaux de fécondité sont comparés à ceux des femmes ouest-allemandes d’origine. Des hypothèses concurrentes sur la fécondité des immigrés sont discutées dans le cadre théorique. Les résultats vérifient principalement l’hypothèse de la socialisation : le passage au deuxieme et au troisieme enfant de la première génération d’immigrés varie selon le pays d’origine, et le profil de fécondité par âge des descendantes d’immigrées se rapproche plus de celui des femmes ouest-allemandes que de celui des immigrées de première génération. De plus, les analyses montrent que les différences de fécondité entre les immigrées et les femmes ouest-allemandes peuvent être en grande partie, mais pas totalement, expliquées par des différences de structure

Intracellular Serine Protease Inhibitor SERPINB4 Inhibits Granzyme M-Induced Cell Death

Granzyme-mediated cell death is the major pathway for cytotoxic lymphocytes to kill virus-infected and tumor cells. In humans, five different granzymes (i.e. GrA, GrB, GrH, GrK, and GrM) are known that all induce cell death. Expression of intracellular serine protease inhibitors (serpins) is one of the mechanisms by which tumor cells evade cytotoxic lymphocyte-mediated killing. Intracellular expression of SERPINB9 by tumor cells renders them resistant to GrB-induced apoptosis. In contrast to GrB, however, no physiological intracellular inhibitors are known for the other four human granzymes. In the present study, we show that SERPINB4 formed a typical serpin-protease SDS-stable complex with both recombinant and native human GrM. Mutation of the P2-P1-P1′ triplet in the SERPINB4 reactive center loop completely abolished complex formation with GrM and N-terminal sequencing revealed that GrM cleaves SERPINB4 after P1-Leu. SERPINB4 inhibited GrM activity with a stoichiometry of inhibition of 1.6 and an apparent second order rate constant of 1.3×104 M−1s−1. SERPINB4 abolished cleavage of the macromolecular GrM substrates α-tubulin and nucleophosmin. Overexpression of SERPINB4 in tumor cells inhibited recombinant GrM-induced as well as NK cell-mediated cell death and this inhibition depended on the reactive center loop of the serpin. As SERPINB4 is highly expressed by squamous cell carcinomas, our results may represent a novel mechanism by which these tumor cells evade cytotoxic lymphocyte-induced GrM-mediated cell death

Characterising differences between self-reported and wastewater-identified drug use at two consecutive years of an Australian music festival.

BackgroundIn the context of drug prohibition, potential adulteration and variable purity pose additional health risks for people who use drugs, with these risks often compounded by the outdoor music festival environment. Ahead of the imminent implementation of drug checking services in Queensland, Australia, this study aims to characterise this problem using triangulated survey and wastewater data to understand self-reported and detected drug use among attendees of a multi-day Queensland-based music festival in 2021 and 2022.MethodsWe administered an in-situ survey focusing on drug use at the festival to two convenience samples of 136 and 140 festival attendees in 2021 and 2022 respectively. We compared survey findings to wastewater collected concurrently from the festival's site-specific wastewater treatment plant, which was analysed using Liquid Chromatography Tandem Mass Spectrometry.ResultsMost survey respondents (82 % in 2021, 92 % in 2022) reported using or intending to use an illicit drug at the festival. Some respondents reported potentially risky drug use practices such as using drugs found on the ground (2 % in 2021, 4 % in 2022). Substances detected in wastewater but not surveys include MDEA, mephedrone, methylone, 3-MMC, alpha-D2PV, etizolam, eutylone, and N,N-dimethylpentylone.ConclusionMany substances detected in wastewater but not self-reported in surveys likely represent substitutions or adulterants. These findings highlight the benefits of drug checking services to prevent harms from adulterants and provide education on safer drug use practices. These findings also provide useful information on socio-demographic characteristics and drug use patterns of potential users of Queensland's future drug checking service

Cleavage of von Willebrand Factor by Granzyme M Destroys Its Factor VIII Binding Capacity

Von Willebrand factor (VWF) is a pro-hemostatic multimeric plasma protein that promotes platelet aggregation and stabilizes coagulation factor VIII (FVIII) in plasma. The metalloproteinase ADAMTS13 regulates the platelet aggregation function of VWF via proteolysis. Severe deficiency of ADAMTS13 is associated with thrombotic thrombocytopenic purpura, but does not always correlate with its clinical course. Therefore, other proteases could also be important in regulating VWF activity. In the present study, we demonstrate that VWF is cleaved by the cytotoxic lymphocyte granule component granzyme M (GrM). GrM cleaved both denaturated and soluble plasma-derived VWF after Leu at position 276 in the D3 domain. GrM is unique in that it did not affect the multimeric size and pro-hemostatic platelet aggregation ability of VWF, but instead destroyed the binding of VWF to FVIII in vitro. In meningococcal sepsis patients, we found increased plasma GrM levels that positively correlated with an increased plasma VWF/FVIII ratio in vivo. We conclude that, next to its intracellular role in triggering apoptosis, GrM also exists extracellularly in plasma where it could play a physiological role in controlling blood coagulation by determining plasma FVIII levels via proteolytic processing of its carrier VWF

Covalent Protein Modification with ISG15 via a Conserved Cysteine in the Hinge Region

The ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) is strongly induced by type I interferons and displays antiviral activity. As other ubiquitin-like proteins (Ubls), ISG15 is post-translationally conjugated to substrate proteins by an isopeptide bond between the C-terminal glycine of ISG15 and the side chains of lysine residues in the substrates (ISGylation). ISG15 consists of two ubiquitin-like domains that are separated by a hinge region. In many orthologs, this region contains a single highly reactive cysteine residue. Several hundred potential substrates for ISGylation have been identified but only a few of them have been rigorously verified. In order to investigate the modification of several ISG15 substrates, we have purified ISG15 conjugates from cell extracts by metal-chelate affinity purification and immunoprecipitations. We found that the levels of proteins modified by human ISG15 can be decreased by the addition of reducing agents. With the help of thiol blocking reagents, a mutational analysis and miRNA mediated knock-down of ISG15 expression, we revealed that this modification occurs in living cells via a disulphide bridge between the substrates and Cys78 in the hinge region of ISG15. While the ISG15 activating enzyme UBE1L is conjugated by ISG15 in the classical way, we show that the ubiquitin conjugating enzyme Ubc13 can either be classically conjugated by ISG15 or can form a disulphide bridge with ISG15 at the active site cysteine 87. The latter modification would interfere with its function as ubiquitin conjugating enzyme. However, we found no evidence for an ISG15 modification of the dynamin-like GTPases MxA and hGBP1. These findings indicate that the analysis of potential substrates for ISG15 conjugation must be performed with great care to distinguish between the two types of modification since many assays such as immunoprecipitation or metal-chelate affinity purification are performed with little or no reducing agent present

Botulinum Neurotoxin Devoid of Receptor Binding Domain Translocates Active Protease

Clostridium botulinum neurotoxin (BoNT) causes flaccid paralysis by disabling synaptic exocytosis. Intoxication requires the tri-modular protein to undergo conformational changes in response to pH and redox gradients across endosomes, leading to the formation of a protein-conducting channel. The ∼50 kDa light chain (LC) protease is translocated into the cytosol by the ∼100 kDa heavy chain (HC), which consists of two modules: the N-terminal translocation domain (TD) and the C-terminal Receptor Binding Domain (RBD). Here we exploited the BoNT modular design to identify the minimal requirements for channel activity and LC translocation in neurons. Using the combined detection of substrate proteolysis and single-channel currents, we showed that a di-modular protein consisting only of LC and TD was sufficient to translocate active protease into the cytosol of target cells. The RBD is dispensable for cell entry, channel activity, or LC translocation; however, it determined a pH threshold for channel formation. These findings indicate that, in addition to its individual functions, each module acts as a chaperone for the others, working in concert to achieve productive intoxication

Dendritic Cell-Mediated-Immunization with Xenogenic PrP and Adenoviral Vectors Breaks Tolerance and Prolongs Mice Survival against Experimental Scrapie

In prion diseases, PrPc, a widely expressed protein, is transformed into a pathogenic form called PrPSc, which is in itself infectious. Antibodies directed against PrPc have been shown to inhibit PrPc to PrPSc conversion in vitro and protect in vivo from disease. Other effectors with potential to eliminate PrPSc-producing cells are cytotoxic T cells directed against PrP-derived peptides but their ability to protect or to induce deleterious autoimmune reactions is not known. The natural tolerance to PrPc makes difficult to raise efficient adaptive responses. To break tolerance, adenovirus (Ad) encoding human PrP (hPrP) or control Ad were administered to wild-type mice by direct injection or by transfer of Ad-transduced dendritic cells (DCs). Control Ad-transduced DCs from Tg650 mice overexpressing hPrP were also used for immunization. DC-mediated but not direct administration of AdhPrP elicited antibodies that bound to murine native PrPc. Frequencies of PrP-specific IFNγ-secreting T cells were low and in vivo lytic activity only targeted cells strongly expressing hPrP. Immunohistochemical analysis revealed that CD3+ T cell infiltration was similar in the brain of vaccinated and unvaccinated 139A-infected mice suggesting the absence of autoimmune reactions. Early splenic PrPSc replication was strongly inhibited ten weeks post infection and mean survival time prolonged from 209 days in untreated 139A-infected mice to 246 days in mice vaccinated with DCs expressing the hPrP. The efficacy appeared to be associated with antibody but not with cytotoxic cell-mediated PrP-specific responses