Towards a Theory of CyberPlace: A Proposal for a New Legal Framework

This article discusses whether the existing legal framework for property and places should apply to the electronic medium, or whether the uniqueness of the Internet requires a different characterization. The source of the right of the owner of an Internet site to legally control access to and use of the site and its content is the tort law of trespass and the law of contract. The sources of the right of users to freely access and use Internet content are the policies of free speech and public accommodation. Part I of this paper reviews the common law trespass theories that courts have employed to regulate online activities. Part II considers the de nition of “place” and whether particular uses of the Internet are “places of public accommodation.” Part III proposes a new legal framework that could serve as a basis for legislative action to promote both of these policies in cyberspace. This framework recognizes the unique qualities of the Internet, incorporating both the public policy favoring freedom of expression and the private property interest in controlling unauthorized use of Internet resources

Groundwater-supported evapotranspiration within glaciated watersheds under conditions of climate change

This paper analyzes the effects of geology and geomorphology on surface-water/-groundwater interactions, evapotranspiration, and recharge under conditions of long-term climatic change. Our analysis uses hydrologic data from the glaciated Crow Wing watershed in central Minnesota, USA, combined with a hydrologic model of transient coupled unsaturated/saturated flow (HYDRAT2D). Analysis of historical water-table (1970–1993) and lake-level (1924–2002) records indicates that larger amplitude and longer period fluctuations occur within the upland portions of watersheds due to the response of the aquifer system to relatively short-term climatic fluctuations. Under drought conditions, lake and water-table levels fell by as much as 2–4 m in the uplands but by 1 m in the lowlands. The same pattern can be seen on millennial time scales. Analysis of Holocene lake-core records indicates that Moody Lake, located near the outlet of the Crow Wing watershed, fell by as much as 4 m between about 4400 and 7000 yr BP. During the same time, water levels in Lake Mina, located near the upland watershed divide, fell by about 15 m. Reconstructed Holocene climate as represented by HYDRAT2D gives somewhat larger drops (6 and 24 m for Moody Lake and Lake Mina, respectively). The discrepancy is probably due to the effect of three-dimensional flow. A sensitivity analysis was also carried out to study how aquifer hydraulic conductivity and land-surface topography can influence water-table fluctuations, wetlands formation, and evapotranspiration. The models were run by recycling a wet year (1985, 87 cm annual precipitation) over a 10-year period followed by 20 years of drier and warmer climate (1976, 38 cm precipitation). Model results indicated that groundwater-supported evapotranspiration accounted for as much as 12% (10 cm) of evapotranspiration. The aquifers of highest hydraulic conductivity had the least amount of groundwater-supported evapotranspiration owing to a deep water table. Recharge was even more sensitive to aquifer hydraulic conductivity, especially in the lowland regions. These findings have important implications for paleoclimatic studies, because the hydrologic response of a surface-water body will vary across the watershed to a given climate signal

Dendritic Cell-Derived TSLP Negatively Regulates HIF-1α and IL-1β during Dectin-1 signaling

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Thymic stromal lymphopoietin (TSLP) is a functionally pleotropic cytokine important in immune regulation, and TSLP dysregulation is associated with numerous diseases. TSLP is produced by many cell types, but has predominantly been characterized as a secreted factor from epithelial cells which activates dendritic cells (DC) that subsequently prime T helper (TH) 2 immunity. However, DC themselves make significant amounts of TSLP in response to microbial products, but the functional role of DC-derived TSLP remains unclear. We show that TSLPR signaling negatively regulates IL-1β production during dectin-1 stimulation of human DC. This regulatory mechanism functions by dampening Syk phosphorylation and is mediated via NADPH oxidase-derived ROS, HIF-1α and pro-IL-1β expression. Considering the profound effect TSLPR signaling has on the metabolic status and the secretome of dectin-1 stimulated DC, these data suggest that autocrine TSLPR signaling could have a fundamental role in modulating immunological effector responses at sites removed from epithelial cell production of TSLP

Performance of discrete heat engines and heat pumps in finite time

The performance in finite time of a discrete heat engine with internal friction is analyzed. The working fluid of the engine is composed of an ensemble of noninteracting two level systems. External work is applied by changing the external field and thus the internal energy levels. The friction induces a minimal cycle time. The power output of the engine is optimized with respect to time allocation between the contact time with the hot and cold baths as well as the adiabats. The engine's performance is also optimized with respect to the external fields. By reversing the cycle of operation a heat pump is constructed. The performance of the engine as a heat pump is also optimized. By varying the time allocation between the adiabats and the contact time with the reservoir a universal behavior can be identified. The optimal performance of the engine when the cold bath is approaching absolute zero is studied. It is found that the optimal cooling rate converges linearly to zero when the temperature approaches absolute zero.Comment: 45 pages LaTeX, 25 eps figure

A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors

Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety, pharmacokinetics, and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments. Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): PartA = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W

The Impact of Insulin Pump Therapy on Glycemic Profiles in Patients with Type 2 Diabetes: Data from the OpT2mise Study

Background: The OpT2mise randomized trial was designed to compare the effects of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) on glucose profiles in patients with type 2 diabetes. Research Design and Methods: Patients with glycated hemoglobin (HbA1c) levels of ≥8% (64 mmol/mol) and ≤12% (108 mmol/mol) despite insulin doses of 0.7-1.8 U/kg/day via MDI were randomized to CSII (n=168) or continued MDI (n=163). Changes in glucose profiles were evaluated using continuous glucose monitoring data collected over 6-day periods before and 6 months after randomization. Results: After 6 months, reductions in HbA1c levels were significantly greater with CSII (-1.1±1.2% [-12.0±13.1 mmol/mol]) than with MDI (-0.4±1.1% [-4.4±12.0 mmol/mol]) (P<0.001). Similarly, compared with patients receiving MDI, those receiving CSII showed significantly greater reductions in 24-h mean sensor glucose (SG) (treatment difference, -17.1 mg/dL; P=0.0023), less exposure to SG >180 mg/dL (-12.4%; P=0.0004) and SG >250 mg/dL (-5.5%; P=0.0153), and more time in the SG range of 70-180 mg/dL (12.3%; P=0.0002), with no differences in exposure to SG<70 mg/dL or in glucose variability. Changes in postprandial (4-h) glucose area under the curve >180 mg/dL were significantly greater with CSII than with MDI after breakfast (-775.9±1,441.2 mg/dL/min vs. -160.7±1,074.1 mg/dL/min; P=0.0015) and after dinner (-731.4±1,580.7 mg/dL/min vs. -71.1±1,083.5 mg/dL/min; P=0.0014). Conclusions: In patients with suboptimally controlled type 2 diabetes, CSII significantly improves selected glucometrics, compared with MDI, without increasing the risk of hypoglycemia