Socially Optimal Mining Pools

Mining for Bitcoins is a high-risk high-reward activity. Miners, seeking to reduce their variance and earn steadier rewards, collaborate in pooling strategies where they jointly mine for Bitcoins. Whenever some pool participant is successful, the earned rewards are appropriately split among all pool participants. Currently a dozen of different pooling strategies (i.e., methods for distributing the rewards) are in use for Bitcoin mining. We here propose a formal model of utility and social welfare for Bitcoin mining (and analogous mining systems) based on the theory of discounted expected utility, and next study pooling strategies that maximize the social welfare of miners. Our main result shows that one of the pooling strategies actually employed in practice--the so-called geometric pay pool--achieves the optimal steady-state utility for miners when its parameters are set appropriately. Our results apply not only to Bitcoin mining pools, but any other form of pooled mining or crowdsourcing computations where the participants engage in repeated random trials towards a common goal, and where "partial" solutions can be efficiently verified

Secret-Sharing for NP

A computational secret-sharing scheme is a method that enables a dealer, that has a secret, to distribute this secret among a set of parties such that a "qualified" subset of parties can efficiently reconstruct the secret while any "unqualified" subset of parties cannot efficiently learn anything about the secret. The collection of "qualified" subsets is defined by a Boolean function. It has been a major open problem to understand which (monotone) functions can be realized by a computational secret-sharing schemes. Yao suggested a method for secret-sharing for any function that has a polynomial-size monotone circuit (a class which is strictly smaller than the class of monotone functions in P). Around 1990 Rudich raised the possibility of obtaining secret-sharing for all monotone functions in NP: In order to reconstruct the secret a set of parties must be "qualified" and provide a witness attesting to this fact. Recently, Garg et al. (STOC 2013) put forward the concept of witness encryption, where the goal is to encrypt a message relative to a statement "x in L" for a language L in NP such that anyone holding a witness to the statement can decrypt the message, however, if x is not in L, then it is computationally hard to decrypt. Garg et al. showed how to construct several cryptographic primitives from witness encryption and gave a candidate construction. One can show that computational secret-sharing implies witness encryption for the same language. Our main result is the converse: we give a construction of a computational secret-sharing scheme for any monotone function in NP assuming witness encryption for NP and one-way functions. As a consequence we get a completeness theorem for secret-sharing: computational secret-sharing scheme for any single monotone NP-complete function implies a computational secret-sharing scheme for every monotone function in NP

Cost effectiveness of adherence to IDSA/ATS guidelines in elderly patients hospitalized for Community-Aquired Pneumonia

A copy of the survey questionnaire given to the expert panel regarding patient utilities. (PDF 8.28 kb

Genome-wide chromatin mapping with size resolution reveals a dynamic sub-nucleosomal landscape in Arabidopsis

All eukaryotic genomes are packaged as chromatin, with DNA interlaced with both regularly patterned nucleosomes and sub-nucleosomal-sized protein structures such as mobile and labile transcription factors (TF) and initiation complexes, together forming a dynamic chromatin landscape. Whilst details of nucleosome position in Arabidopsis have been previously analysed, there is less understanding of their relationship to more dynamic sub-nucleosomal particles (subNSPs) defined as protected regions shorter than the ~150bp typical of nucleosomes. The genome-wide profile of these subNSPs has not been previously analysed in plants and this study investigates the relationship of dynamic bound particles with transcriptional control. Here we combine differential micrococcal nuclease (MNase) digestion and a modified paired-end sequencing protocol to reveal the chromatin structure landscape of Arabidopsis cells across a wide particle size range. Linking this data to RNAseq expression analysis provides detailed insight into the relationship of identified DNA-bound particles with transcriptional activity. The use of differential digestion reveals sensitive positions, including a labile -1 nucleosome positioned upstream of the transcription start site (TSS) of active genes. We investigated the response of the chromatin landscape to changes in environmental conditions using light and dark growth, given the large transcriptional changes resulting from this simple alteration. The resulting shifts in the suites of expressed and repressed genes show little correspondence to changes in nucleosome positioning, but led to significant alterations in the profile of subNSPs upstream of TSS both globally and locally. We examined previously mapped positions for the TFs PIF3, PIF4 and CCA1, which regulate light responses, and found that changes in subNSPs co-localized with these binding sites. This small particle structure is detected only under low levels of MNase digestion and is lost on more complete digestion of chromatin to nucleosomes. We conclude that wide-spectrum analysis of the Arabidopsis genome by differential MNase digestion allows detection of sensitive features hereto obscured, and the comparisons between genome-wide subNSP profiles reveals dynamic changes in their distribution, particularly at distinct genomic locations (i.e. 5’UTRs). The method here employed allows insight into the complex influence of genetic and extrinsic factors in modifying the sub-nucleosomal landscape in association with transcriptional changes

The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation.

Metastatic cancer cells have the ability to both degrade and migrate through the extracellular matrix (ECM). Invasiveness can be correlated with the presence of dynamic actin-rich membrane structures called podosomes or invadopodia. We showed previously that the adaptor protein tyrosine kinase substrate with five Src homology 3 domains (Tks5)/Fish is required for podosome/invadopodia formation, degradation of ECM, and cancer cell invasion in vivo and in vitro. Here, we describe Tks4, a novel protein that is closely related to Tks5. This protein contains an amino-terminal Phox homology domain, four SH3 domains, and several proline-rich motifs. In Src-transformed fibroblasts, Tks4 is tyrosine phosphorylated and predominantly localized to rosettes of podosomes. We used both short hairpin RNA knockdown and mouse embryo fibroblasts lacking Tks4 to investigate its role in podosome formation. We found that lack of Tks4 resulted in incomplete podosome formation and inhibited ECM degradation. Both phenotypes were rescued by reintroduction of Tks4, whereas only podosome formation, but not ECM degradation, was rescued by overexpression of Tks5. The tyrosine phosphorylation sites of Tks4 were required for efficient rescue. Furthermore, in the absence of Tks4, membrane type-1 matrix metalloproteinase (MT1-MMP) was not recruited to the incomplete podosomes. These findings suggest that Tks4 and Tks5 have overlapping, but not identical, functions, and implicate Tks4 in MT1-MMP recruitment and ECM degradation.Peer reviewe

Tsc1-Tp53 loss induces mesothelioma in mice, and evidence for this mechanism in human mesothelioma

Mesothelioma is diagnosed in approximately 2,500 patients in the United States every year, most often arising in the pleural space, but also occurring as primary peritoneal mesothelioma. The vast majority of patients with mesothelioma die from their disease within 3 years. We developed a new mouse model of mesothelioma by bladder or intra-peritoneal injection of adenovirus Cre into mice with conditional alleles of each of Tp53 and Tsc1. Such mice began to develop malignant ascites about 6 months after injection, which was due to peritoneal mesothelioma, based on tumor morphology and immunohistochemical staining. Mesothelioma cell lines were established which showed loss of both Tsc1 and Tp53, with mTORC1 activation. Treatment of mice with malignant ascites due to mesothelioma with rapamycin led to a marked reduction in ascites, extended survival, and a 95–99% reduction in mesothelioma tumor volume, in comparison to vehicle-treated mice. To see if TSC1/TSC2 loss was a common genetic event in human mesothelioma, we examined 9 human mesothelioma cell lines, and found that 4 of 9 showed persistent activation of mTORC1 though none had loss of TSC1 or TSC2. A tissue microarray analysis of 198 human mesothelioma specimens showed that 33% of cases had reduced TSC2 expression and 60% showed activation of mTOR, indicating that mTOR activation is common in human mesothelioma and suggesting that it is a potential therapeutic target

NASA's Current Evidence and Hypothesis for the Visual Impairment and Intracranial Pressure Risk

While 40 years of human spaceflight exploration has reported visual decrement to a certain extent in a subgroup of astronauts, recent data suggests that there is indeed a subset of crewmembers that experience refraction changes (hyperoptic shift), cotton wool spot formation, choroidal fold development, papilledema, optic nerve sheath distention and/or posterior globe flattening with varying degrees of severity and permanence. Pre and postflight ocular measures have identified a potential risk of permanent visual changes as a result of microgravity exposure, which has been defined as the Visual Impairment and Intracranial Pressure risk (VIIP). The combination of symptoms are referred to as the VIIP syndrome. It is thought that the ocular structural and optic nerve changes are caused by events precipitated by the cephalad fluid shift crewmembers experience during long-duration spaceflight. Three important systems, ocular, cardiovascular, and central nervous, seem to be involved in the development of symptoms, but the etiology is still under speculation. It is believed that some crewmembers are more susceptible to these changes due to genetic/anatomical predisposition or lifestyle (fitness) related factors. Future research will focus on determining the etiology of the VIIP syndrome and development of mechanisms to mitigate the spaceflight risk

The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation.

Metastatic cancer cells have the ability to both degrade and migrate through the extracellular matrix (ECM). Invasiveness can be correlated with the presence of dynamic actin-rich membrane structures called podosomes or invadopodia. We showed previously that the adaptor protein tyrosine kinase substrate with five Src homology 3 domains (Tks5)/Fish is required for podosome/invadopodia formation, degradation of ECM, and cancer cell invasion in vivo and in vitro. Here, we describe Tks4, a novel protein that is closely related to Tks5. This protein contains an amino-terminal Phox homology domain, four SH3 domains, and several proline-rich motifs. In Src-transformed fibroblasts, Tks4 is tyrosine phosphorylated and predominantly localized to rosettes of podosomes. We used both short hairpin RNA knockdown and mouse embryo fibroblasts lacking Tks4 to investigate its role in podosome formation. We found that lack of Tks4 resulted in incomplete podosome formation and inhibited ECM degradation. Both phenotypes were rescued by reintroduction of Tks4, whereas only podosome formation, but not ECM degradation, was rescued by overexpression of Tks5. The tyrosine phosphorylation sites of Tks4 were required for efficient rescue. Furthermore, in the absence of Tks4, membrane type-1 matrix metalloproteinase (MT1-MMP) was not recruited to the incomplete podosomes. These findings suggest that Tks4 and Tks5 have overlapping, but not identical, functions, and implicate Tks4 in MT1-MMP recruitment and ECM degradation.Peer reviewe