ASSET FIXITY, ASSET SPECIFICITY AND REGIONAL ECONOMIC CHANGE: HYPOTHESIS AND IMPLICATIONS

That asset specificity and asset fixity are impediments to economic adjustment is well understood in the literatures of industrial organization and agricultural economics. In this paper, we show that spatial factors can plausible be expected to be arguments in functions that define asset fixity and specificity and, hence, asset fixity may be systematically related to space. The implications with regard to differences across space in rates of adjustment to market signals suggest that the short run is longer in remote than in less remote places, which may prove useful in explaining the behavior of a spatial economic system during times of rapid technological change.Industrial Organization,

The Effect of Wetwood on Lumber Drying Times and Rates: An Exploratory Evaluation with Longitudinal Gas Permeability

Lumber containing wetwood, or sinker heartwood, cannot be dried as rapidly as lumber with normal wood. To determine why wetwood dries more slowly, measurements of longitudinal gas permeability (LGP) were made in sapwood, heartwood, and wetwood from white fir (Abies concolor) and aspen (Populus tremuloides and P. grandidentata). The LGP values were then compared with drying times, drying rates, and anatomical characteristics of matched wood samples. Sapwood had highest average LGP values (11 to 38 Darcys) and fastest drying rates. Heartwood had lowest average LGP values (0.2 to 0.8 Darcys) and slow drying rates, but short drying times because of low green moisture content. Wetwood had longest drying times and slowest drying rates, but higher average LGP values (0.2 to 2.5 Darcys) than heartwood.Scanning electron micrographs (SEM) show that low LGP values and slow drying rates for heartwood and wetwood are due largely to aspiration of bordered pits in white fir tracheids and to tyloses formation in aspen vessels. Scanning electron microscopy suggests that wetwood drying rates may be further reduced by deposits of bacteria and extraneous material that block transverse moisture diffusion and increase moisture holding capacity of the wood. Concurrently, wetwood bacteria may increase LGP by destroying tori in aspirated pits of white fir and by aborting tyloses development in aspen

Quantitative Footprinting Analysis Using a DNA-Cleaving Metalloporphyrin Complex+

The results of quantitative footprinting studies involving the antiviral agent netropsin and a DNA-cleaving cationic metalloporphyrin complex are presented. An analysis of the footprinting autoradiographic spot intensities using a model previously applied to footprinting studies involving the enzyme DNase I [Ward, B., Rehfuss, R., Goodisman, J., & Dabrowiak, J. C. (1988) Biochemistry 27, 1198-12051 led to very low values for netropsin binding constants on a restriction fragment from pBR-322 DNA. In this work, we show that, because the porphyrin binds with high specificity to DNA, it does not report site loading information in the same manner as does DNase I. We elucidate a model involving binding equilibria for individual sites and include competitive binding of drug and porphyrin for the same site. The free porphyrin and free drug concentrations are determined by binding equilibria with the carrier (calf thymus DNA) which is present in excess and acts as a buffer for both. Given free porphyrin and free netropsin concentrations for each total drug concentration in a series of footprinting experiments, one can calculate autoradiographic spot intensities in terms of the binding constants of netropsin to the various sites on the 139 base pair restriction fragment. The best values of these binding constants are determined by minimizing the sum of the squared differences between calculated and experimental footprinting autoradiographic spot intensities. Although the determined netropsin binding constants are insensitive to the value assumed for the porphyrin binding constant toward its highest affinity sites, the best mean-square deviation between observed and calculated values, D, depends on the choice of (average) drug binding constant to carrier DNA, Kd. Since D as a function of Kd passes through a clear minimum, we were able to determine this parameter as well. The study demonstrates that the specificity of probe binding to DNA is an important factor influencing the reporting of site occupancy by drug in the quantitative footprinting experiment

IDO1 is an Integral Mediator of Inflammatory Neovascularization.

The immune tolerogenic effects of IDO1 (indoleamine 2,3-dioxygenase 1) have been well documented and genetic studies in mice have clearly established the significance of IDO1 in tumor promotion. Dichotomously, the primary inducer of IDO1, the inflammatory cytokine IFNγ (interferon-γ), is a key mediator of immune-based tumor suppression. One means by which IFNγ can exert an anti-cancer effect is by decreasing tumor neovascularization. We speculated that IDO1 might contribute to cancer promotion by countering this anti-neovascular effect of IFNγ, possibly through IDO1-potentiated elevation of the pro-tumorigenic inflammatory cytokine IL6 (interleukin-6). In this study, we investigated how genetic loss of IDO1 affects neovascularization in mouse models of oxygen-induced retinopathy and lung metastasis. Neovascularization in both models was significantly reduced in mice lacking IDO1, was similarly reduced with loss of IL6, and was restored in both cases by concomitant loss of IFNγ. Likewise, the lack of IDO1 or IL6 resulted in reduced metastatic tumor burden and increased survival, which the concomitant loss of IFNγ abrogated. This insight into IDO1\u27s involvement in pro-tumorigenic inflammatory neovascularization may have important ramifications for IDO1 inhibitor development, not only in cancer where clinical trials are currently ongoing, but in other disease indications associated with neovascularization as well

Site-Specific Binding Constants for Actinomycin D on DNA Determined from Footprinting Studies

We report site-specific binding constants for the intercalating anticancer drug actinomycin D (Act-D), binding to a 139-base-pair restriction fragment from pBR 322 DNA. The binding constants are derived from analysis of footprinting experiments, in which the radiolabeled 139-mer is cleaved using DNase I, the cleavage products undergo gel electrophoresis, and, from the gel autoradiogram, spot intensities, proportional to amounts of cleaved fragments, are measured. A bound drug prevents DNase I from cleaving at -7 bonds, leading to decreased amounts of corresponding fragments. With the radiolabel on the 3’ end of the noncoding strand (A-label), we measured relative amounts of 54 cleavage products at 25 Act-D concentrations. For cleavage of the 139-mer with the label on the 3’ end of the coding strand (G-label), relative amounts of 43 cleavage products at 11 Act-D concentrations were measured. These measurements give information about - 120 base pairs of the restriction fragment (- 12 turns of the DNA helix); in this region, 14 strong and weak Act-D binding sites were identified. The model used to interpret the footprinting plots is derived in detail. Binding constants for 14 sites on the fragment are obtained simultaneously. It is important to take into account the effect of drug binding at its various sites on the local concentration of probe elsewhere. It is also necessary to include in the model weak as well as strong Act-D sites on the carrier DNA which is present, since the carrier DNA controls the free-drug concentration. As expected, the strongest sites are those with the sequence (all sequences are 5’ - 3’) GC, with TGCT having the highest binding constant, 6.4 X lo6 M-l. Sites having the sequence GC preceded by G are weak binding sites, having binding constants approximately 1 order of magnitude lower than those of the strong sites. Also, the non-GC-containing sequences CCG and CCC bind Act-D with a binding constant comparable to those of the weak GGC sites. The analysis may reveal drug-induced structural changes on the DNA, which are discussed in terms of the mechanism of Act-D binding

Determination of Netropsin-DNA Binding Constants from Footprinting Data

A theory for deriving drug-DNA site binding constants from footprinting data is presented. Plots of oligonucleotide concentration, as a function of drug concentration, for various cutting positions on DNA are required. It is assumed that the rate of cleavage at each nucleotide position is proportional to the concentration of enzyme at that nucleotide and to the probability that the nucleotide is not blocked by drug. The probability of a nucleotide position not being blocked is calculated by assuming a conventional binding equilibrium for each binding site with exclusions for overlapping sites. The theory has been used to evaluate individual site binding constants for the antiviral agent netropsin toward a 139 base pair restriction fragment of pBR-322 DNA. Drug binding constants, evaluated from footprinting data in the presence of calf thymus DNA and poly(dGdC) as carrier and in the absence of carrier DNA, were determined by obtaining the best fit between calculated and experimental footprinting data. Although the strong sites on the fragment were all of the type (T-A),, the value of the binding constant was strongly sequence dependent. Sites containing the dinucleotide sequence 5\u27-TA-3\u27 were found to have significantly lower binding constants than those without this sequence, suggesting that an adenine-adenine clash produces a DNA structural alteration in the minor groove which discourages netropsin binding to DNA. The errors, scope, and limitations associated with the method are presented and discussed

Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

Background: There is strong evidence that people born in winter and in spring have a small increased risk of schizophrenia. As this ‘season of birth’ effect underpins some of the most influential hypotheses concerning potentially modifiable risk exposures, it is important to exclude other possible explanations for the phenomenon. Methods: Here we sought to determine whether the season of birth effect reflects gene-environment confounding rather than a pathogenic process indexing environmental exposure. We directly measured, in 136 538 participants from the UK Biobank (UKBB), the burdens of common schizophrenia risk alleles and of copy number variants known to increase the risk for the disorder, and tested whether these were correlated with a season of birth. Results: Neither genetic measure was associated with season or month of birth within the UKBB sample. Conclusions: As our study was highly powered to detect small effects, we conclude that the season of birth effect in schizophrenia reflects a true pathogenic effect of environmental exposure

A Ransomware Case for Use in the Classroom

Given the global growth in ransomware attacks, employees need to understand the risks of ransomware and how to protect against it. This paper presents a teaching case based on an actual ransomware attack on a hospital that undergraduate or graduate course can use to teach students. The case introduces students to Wildcat Hospital, a fictitious 450-bed acute-care facility in a suburban location in the Northeastern United States. A ransomware attack hit Wildcat Hospital as the workday began. Malware infected the hospital\u27s computers and demanded one bitcoin, a virtual currency that affords anonymity, as ransom to restore functionality of the information systems. The chief executive officer and the chief information officer led the organizational response to the attack. We include links to two videos, a demo of a Locky ransomware attack in action, and a National Broadcasting Company (NBC) TV network news report about a similar ransomware incident at another hospital (Hollywood Presbyterian Medical Center in California) to engage students

Technology Policy: A Fixture on the National Agenda

In his commentary, Robert Kidd, president of the Maine Science and Technology Foundation, echoes the call by Rycroft, Kash and Adams in their article [this issue] for a new technology policy focused on industrial competitiveness. He defines a partnership role for states in the design and implementation of national technology priorities. James Ward, IV and Richard Hill, raise several questions in their commentary. Can we rely on the federal government to successfully direct this policy area? How would a new technology policy impact the roles and responsibilities of the private and public sectors? What can we learn from partnerships between universities and industry that have led to innovation and enhanced competitiveness and did they result from good policy or practical incentives at the local level

Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition.

Autophagy is a lysosomal degradation pathway that eliminates aggregated proteins and damaged organelles to maintain cellular homeostasis. A major route for activating autophagy involves inhibition of the mTORC1 kinase, but current mTORC1-targeting compounds do not allow complete and selective mTORC1 blockade. Here, we have coupled screening of a covalent ligand library with activity-based protein profiling to discover EN6, a small-molecule in vivo activator of autophagy that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal v-ATPase, which activates mTORC1 via the Rag guanosine triphosphatases. EN6-mediated ATP6V1A modification decouples the v-ATPase from the Rags, leading to inhibition of mTORC1 signaling, increased lysosomal acidification and activation of autophagy. Consistently, EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. Our results provide insight into how the v-ATPase regulates mTORC1, and reveal a unique approach for enhancing cellular clearance based on covalent inhibition of lysosomal mTORC1 signaling