On the Optimal Design of Disaster Insurance in a Federation

Recent experience with disasters and terrorist attacks in the US indicates that state and local governments rely on the federal sector for support after disasters occur. But these same governments are responsible for investing in infrastructure designed to reduce vulnerability to natural and man-made hazards. This division of responsibilities – state governments providing protection from disasters and federal government providing insurance against their occurrence – leads to the tension that is at the heart of our analysis. We explore these tensions building on the model of Persson and Tabellini (1996). We show that when the federal government is committed to full insurance against disasters, states will have incentives to underinvest in costly protective measures. We then show that when the central government cannot verify state investment choices, the optimal insurance system would be designed to reward states that succeed in avoiding disasters and punish those that do not, thereby giving states an incentive to increase investment in protective infrastructure. However, this raises the question of whether the central government can credibly commit to such a scheme, and we find in a simple political model that it cannot. In our political model, the central government will decrease transfers ex-post if a state provides protective infrastructure that increases its expected uncertain income, generating a soft-budget constraint for states. This provides an additional incentive for states to underinvest in protective infrastructure. We discuss these results in light of disaster policy in the US.

On the Optimal Design of Disaster Insurance in a Federation

Recent experience with disasters and terrorist attacks in the US indicates that state and local governments rely on the federal sector for support after disasters occur. But these same governments are responsible for investing in infrastructure designed to reduce vulnerability to natural and man-made hazards. This division of responsibilities – state governments providing protection from disasters and federal government providing insurance against their occurrence – leads to the tension that is at the heart of our analysis. We explore these tensions building on the model of Persson and Tabellini (1996). We show that when the federal government is committed to full insurance against disasters, states will have incentives to underinvest in costly protective measures. We then show that when the central government cannot verify state investment choices, the optimal insurance system would be designed to reward states that succeed in avoiding disasters and punish those that do not, thereby giving states an incentive to increase investment in protective infrastructure. However, this raises the question of whether the central government can credibly commit to such a scheme, and we find in a simple political model that it cannot. In our political model, the central government will decrease transfers ex-post if a state provides protective infrastructure that increases its expected uncertain income, generating a soft-budget constraint for states. This provides an additional incentive for states to underinvest in protective infrastructure. We discuss these results in light of disaster policy in the US.

Characterization of Melanin-concentrating Hormone Receptor Desensitization

Melanin-concentrating hormone (MCH) receptor 1-knockout mice have limited incidence of diet-induced obesity. This makes the MCH signaling pathway a potential pharmacological target to fight human obesity. MCHR1 is a G-protein coupled receptor (GPCR) that activates multiple signaling pathways, including ERK phosphorylation. Overstimulation of GPCR signaling is a hallmark of many diseases. Likewise, inadequate desensitization of MCH signaling could potentiate the obese phenotype. GPCR desensitization typically involves agonist-induced internalization of activated receptors, and subsequent degradation or receptor recycling. The broad aim of this study was to determine the length and intensity of ERK phosphorylation and it\u27s desensitization to MCHR1 activation by MCH. In order to measure this, we maximally stimulated MCHR1-transfected BHK-570 cells with 100 nM MCH for 10 min, then following three washes in serum-free media and a 30 min recovery period, cells were stimulated again. Western blots of lysates for phosphorylated-ERK and total ERK were performed. ImageJ was used to normalize activation levels. MCH was unable to signal a second round of ERK signaling unless we waited 70 minutes, indicating that the MCH signaling pathway is desensitized during this period. We hypothesized that MCHR1 internalization was responsible; however using a cell-based ELISA, we only measured a 15% loss of surface MCHR1 after 30 min of MCH treatment. We tested the hypothesis that G protein-coupled receptor kinases were limiting factors in preventing agonist-mediated endocytosis of MCHR1 however none showed significant gains in internalization. We conclude that MCHRl can undergo receptor-mediated endocytosis, but the fraction of available receptors on the plasma membrane does not account for the extensive loss of ERK signaling observed. We also tested the effect that a GRK2 dominant negative would have on MCHR1 desensitization. In a co-transfected BHK-570 model, we did not observe desensitization if GRK2 is not present. This suggests that GRK2 is necessary for MCHR1 desensitization at the plasma membrane. We have also observed similar ERK desensitization following both isoproterenol treatment and MCHR2 activation which could suggest that simply the ERK pathway desensitizing is being observed which could be independent of the agonist. This study suggests that MCH-mediated ERK signaling desensitizes while MCHR1 is at the plasma membrane, rather than via removal of the receptor from the cell surface. Future experiments will be aimed at determining whether this ERK pathway desensitization is homologous or heterologous in addition to observing downstream pathways of MCHR1 activation other than ERK

On the optimal design of disaster insurance in a federation

Recent experience with disasters and terrorist attacks in the US indicates that state and local governments rely on the federal sector for support after disasters occur. But these same governments are responsible for investing in infrastructure designed to reduce vulnerability to natural and man-made hazards. This division of responsibilities – regional governments providing protection from disasters and federal government providing insurance against their occurrence – leads to the tensions that are at the heart of our analysis. We show that when the federal government is committed to full insurance against disasters, regions will have incentives to under-invest in costly protective measures. We derive the structure of the optimal second-best insurance system when regional governments choose investment levels non-cooperatively and the central government cannot verify regional investment choices. Normally (though not always) this will result in lower intergovernmental transfers and greater investment. However, the second-best transfer scheme suffers from a time-inconsistency problem. Ex-post, the central government will be driven towards equalizing rather than the second-best grants, which results in a type of soft budget constraint problem. Sub-national governments will anticipate this and reduce their investment in protective infrastructure even further. We discuss these results in light of recent disaster policy outcomes in the US

Практикум по Британска литература 3 (19 век)

Ракописот со наслов „Практикум по Британска литература 3 (19 век)“ од д-р Ендру Гудспид, д-р Наталија Поп Зариева и м-р Крсте Илиев претставува учебно помагало прилагодено на содржините од вежбите по предметот Британска книжевност 3 (19 век), кој студентите од групата Англиски јазик и книжевност на Филолошкиот факултет при Универзитет „Гоце Делчев“ – Штип го слушаат во третиот семестар. Ракописот е структуриран со цел да одговори на наставните содржини поделени во поглавја. Целта на практикумот е да се овозможи полесно совладување на материјалот на неколку начини: 1. Преку прашања со повеќе избори кои проверуваат знаење поврзано со авторите и делата кои се обработуваат, дефинирање на литературни поими и карактеристики на одреден литературен период; 2. Прашања со одговор точно-грешно, кои ги поттикнуваат вештините: разбирање и употреба; 3. Прашања за размислување и дискусија со кои се развива способноста за анализа, синтеза и евалуација преку толкувања на дадените книжевни примери во однос на теми, идеји, мотиви, правење споредба и контрастирање, како и оценување на делата во рамка на литературниот, културниот и историскиот контекст на времето во кое се напишани. Целта на овој практикум е студентите да развиваат способност за критичко интерпретирање на книжевни текстови преку прашања кои поттикнуваат повисоки нивоа на размислување како што се анализа, синтеза и евалуација со што ќе се здобијат со компетенции за пишување на аргументативна литературна критика. Стекнати знаења и вештини имаат за цел да им помогнат на студентите во успешна подготовка за колоквиумите, испитот и изготвување на проектната задача по предметот Британска книжевност 3 (19 век)

Improving the value of public RNA-seq expression data by phenotype prediction.

Publicly available genomic data are a valuable resource for studying normal human variation and disease, but these data are often not well labeled or annotated. The lack of phenotype information for public genomic data severely limits their utility for addressing targeted biological questions. We develop an in silico phenotyping approach for predicting critical missing annotation directly from genomic measurements using well-annotated genomic and phenotypic data produced by consortia like TCGA and GTEx as training data. We apply in silico phenotyping to a set of 70 000 RNA-seq samples we recently processed on a common pipeline as part of the recount2 project. We use gene expression data to build and evaluate predictors for both biological phenotypes (sex, tissue, sample source) and experimental conditions (sequencing strategy). We demonstrate how these predictions can be used to study cross-sample properties of public genomic data, select genomic projects with specific characteristics, and perform downstream analyses using predicted phenotypes. The methods to perform phenotype prediction are available in the phenopredict R package and the predictions for recount2 are available from the recount R package. With data and phenotype information available for 70,000 human samples, expression data is available for use on a scale that was not previously feasible

NPEPPS Is a Druggable Driver of Platinum Resistance

There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations.</p

Rapid Chromosome Evolution in Recently Formed Polyploids in Tragopogon (Asteraceae)

Polyploidy, frequently termed "whole genome duplication", is a major force in the evolution of many eukaryotes. Indeed, most angiosperm species have undergone at least one round of polyploidy in their evolutionary history. Despite enormous progress in our understanding of many aspects of polyploidy, we essentially have no information about the role of chromosome divergence in the establishment of young polyploid populations. Here we investigate synthetic lines and natural populations of two recently and recurrently formed allotetraploids Tragopogon mirus and T. miscellus (formed within the past 80 years) to assess the role of aberrant meiosis in generating chromosomal/genomic diversity. That diversity is likely important in the formation, establishment and survival of polyploid populations and species.Applications of fluorescence in situ hybridisation (FISH) to natural populations of T. mirus and T. miscellus suggest that chromosomal rearrangements and other chromosomal changes are common in both allotetraploids. We detected extensive chromosomal polymorphism between individuals and populations, including (i) plants monosomic and trisomic for particular chromosomes (perhaps indicating compensatory trisomy), (ii) intergenomic translocations and (iii) variable sizes and expression patterns of individual ribosomal DNA (rDNA) loci. We even observed karyotypic variation among sibling plants. Significantly, translocations, chromosome loss, and meiotic irregularities, including quadrivalent formation, were observed in synthetic (S(0) and S(1) generations) polyploid lines. Our results not only provide a mechanism for chromosomal variation in natural populations, but also indicate that chromosomal changes occur rapidly following polyploidisation.These data shed new light on previous analyses of genome and transcriptome structures in de novo and establishing polyploid species. Crucially our results highlight the necessity of studying karyotypes in young (<150 years old) polyploid species and synthetic polyploids that resemble natural species. The data also provide insight into the mechanisms that perturb inheritance patterns of genetic markers in synthetic polyploids and populations of young natural polyploid species

Independent, Rapid and Targeted Loss of Highly Repetitive DNA in Natural and Synthetic Allopolyploids of Nicotiana tabacum

Allopolyploidy (interspecific hybridisation and polyploidy) has played a significant role in the evolutionary history of angiosperms and can result in genomic, epigenetic and transcriptomic perturbations. We examine the immediate effects of allopolyploidy on repetitive DNA by comparing the genomes of synthetic and natural Nicotiana tabacum with diploid progenitors N. tomentosiformis (paternal progenitor) and N. sylvestris (maternal progenitor). Using next generation sequencing, a recently developed graph-based repeat identification pipeline, Southern blot and fluorescence in situ hybridisation (FISH) we characterise two highly repetitive DNA sequences (NicCL3 and NicCL7/30). Analysis of two independent high-throughput DNA sequencing datasets indicates NicCL3 forms 1.6–1.9% of the genome in N. tomentosiformis, sequences that occur in multiple, discontinuous tandem arrays scattered over several chromosomes. Abundance estimates, based on sequencing depth, indicate NicCL3 is almost absent in N. sylvestris and has been dramatically reduced in copy number in the allopolyploid N. tabacum. Surprisingly elimination of NicCL3 is repeated in some synthetic lines of N. tabacum in their forth generation. The retroelement NicCL7/30, which occurs interspersed with NicCL3, is also under-represented but to a much lesser degree, revealing targeted elimination of the latter. Analysis of paired-end sequencing data indicates the tandem component of NicCL3 has been preferentially removed in natural N. tabacum, increasing the proportion of the dispersed component. This occurs across multiple blocks of discontinuous repeats and based on the distribution of nucleotide similarity among NicCL3 units, was concurrent with rounds of sequence homogenisation

Targeting resistance to radiation-immunotherapy in cold HNSCCs by modulating the Treg-dendritic cell axis.

BACKGROUND: Numerous trials combining radiation therapy (RT) and immunotherapy in head and neck squamous cell carcinoma (HNSCC) are failing. Using preclinical immune cold models of HNSCC resistant to RT-immune checkpoint inhibitors, we investigate therapeutic approaches of overcoming such resistance by examining the differential microenvironmental response to RT. METHODS: We subjected two HPV-negative orthotopic mouse models of HNSCC to combination RT, regulatory T cells (Treg) depletion, and/or CD137 agonism. Tumor growth was measured and intratumorous and lymph node immune populations were compared among treatment groups. Human gene sets, genetically engineered mouse models DEREG and BATF3-/-, flow and time-of-flight cytometry, RNA-Seq, Treg adoptive transfer studies, and in vitro experiments were used to further evaluate the role of dendritic cells (DCs) and Tregs in these treatments. RESULTS: In MOC2 orthotopic tumors, we find no therapeutic benefit to targeting classically defined immunosuppressive myeloids, which increase with RT. In these radioresistant tumors, supplementing combination RT and Treg depletion with anti-CD137 agonism stimulates CD103+ DC activation in tumor-draining lymph nodes as characterized by increases in CD80+ and CCR7+ DCs, resulting in a CD8 T cell-dependent response. Simultaneously, Tregs are reprogrammed to an effector phenotype demonstrated by increases in interferonγ+, tumor necrosis factorα+, PI3K+, pAKT+ and Eomes+ populations as well as decreases in CTLA4+ and NRP-1+ populations. Tumor eradication is observed when RT is increased to an 8 Gy x 5 hypofractionated regimen and combined with anti-CD25+ anti-CD137 treatment. In a human gene set from oral squamous cell carcinoma tumors, high Treg number is associated with earlier recurrence. CONCLUSIONS: Regulating Treg functionality and DC activation status within the lymph node is critical for generating a T cell effector response in these highly radioresistant tumors. These findings underscore the plasticity of Tregs and represent a new therapeutic opportunity for reprogramming the tumor microenvironment in HNSCCs resistant to conventional radioimmunotherapy approaches