Differential Proliferative Characteristics of Alveolar Fibroblasts in Interstitial Lung Diseases: Regulative Role of IL-1 and PGE2

Fibroblasts (Fb) from patients with sarcoidosis (SA) and hypersensitivity pneumonitis (HP) exhibited a lower proliferative capacity compared with Fb obtained from control (CO) and diffuse interstitial fibrosis patients (DIF). Proliferation of Fb from SA or lip patients was suppressed by autologous LPS-stimulated alveolar macrophages (AM) supernatants but not by those from CO patients. Similarly, alveolar macrophages (AM) derived supernatant, obtained from CO, did not suppress the proliferation of SA and HP Fb. AM from SA and HP patients secreted higher amounts of IL-1α and β compared with controls and compared with Fb from SA and HP patients. Steady levels of IL-1α and βmRNA were expressed in unstimulated and stimulated cultures. Fb from SA and HP patients could be stimulated by LPS to secrete significantly higher levels of PGE2 than those detected in supernatants from LPS stimulated Fb of DIF patients. Only the proliferation of Fb from SA and HP patients was sensitive to amounts of IL-1 equivalent to those detected in the lung of these diseases. As SA and HP are two diseases where irreversible deterioration occurs in only 20% of the patients, we hypothesize that mediators in the lung may modulate Fb proliferation. IL-1 of AM origin and PGE2 of Fb origin secreted at high levels, may be candidates for this suppression because it was abrogated by anti IL-1β and indomethacin

VNToR: Network Virtualization at the Top-of-Rack Switch

Cloud providers typically implement abstractions for net- work virtualization on the server, within the operating sys- tem that hosts the tenant virtual machines or containers. Despite being flexible and convenient, this approach has funda- mental problems: incompatibility with bare-metal support, unnecessary performance overhead, and susceptibility to hypervisor breakouts. To solve these, we propose to offload the implementation of network-virtualization abstractions to the top-of-rack switch (ToR). To show that this is feasible and beneficial, we present VNToR, a ToR that takes over the implementation of the security-group abstraction. Our prototype combines commodity switching hardware with a custom software stack and is integrated in OpenStack Neutron. We show that VNToR can store tens of thousands of access rules, adapts to traffic-pattern changes in less than a millisecond, and significantly outperforms the state of the art

Cloud-scale VM Deflation for Running Interactive Applications On Transient Servers

Transient computing has become popular in public cloud environments for running delay-insensitive batch and data processing applications at low cost. Since transient cloud servers can be revoked at any time by the cloud provider, they are considered unsuitable for running interactive application such as web services. In this paper, we present VM deflation as an alternative mechanism to server preemption for reclaiming resources from transient cloud servers under resource pressure. Using real traces from top-tier cloud providers, we show the feasibility of using VM deflation as a resource reclamation mechanism for interactive applications in public clouds. We show how current hypervisor mechanisms can be used to implement VM deflation and present cluster deflation policies for resource management of transient and on-demand cloud VMs. Experimental evaluation of our deflation system on a Linux cluster shows that microservice-based applications can be deflated by up to 50\% with negligible performance overhead. Our cluster-level deflation policies allow overcommitment levels as high as 50\%, with less than a 1\% decrease in application throughput, and can enable cloud platforms to increase revenue by 30\%.Comment: To appear at ACM HPDC 202

A longitudinal study of adult-onset asthma incidence among HMO members

BACKGROUND: HMO databases offer an opportunity for community based epidemiologic studies of asthma incidence, etiology and treatment. The incidence of asthma in HMO populations and the utility of HMO data, including use of computerized algorithms and manual review of medical charts for determining etiologic factors has not been fully explored. METHODS: We identified adult-onset asthma, using computerized record searches in a New England HMO. Monthly, our software applied exclusion and inclusion criteria to identify an "at-risk" population and "potential cases". Electronic and paper medical records from the past year were then reviewed for each potential case. Persons with other respiratory diseases or insignificant treatment for asthma were excluded. Confirmed adult-onset asthma (AOA) cases were defined as those potential cases with either new-onset asthma or reactivated mild intermittent asthma that had been quiescent for at least one year. We validated the methods by reviewing charts of selected subjects rejected by the algorithm. RESULTS: The algorithm was 93 to 99.3% sensitive and 99.6% specific. Sixty-three percent (n = 469) of potential cases were confirmed as AOA. Two thirds of confirmed cases were women with an average age of 34.8 (SD 11.8), and 45% had no evidence of previous asthma diagnosis. The annualized monthly rate of AOA ranged from 4.1 to 11.4 per 1000 at-risk members. Physicians most commonly attribute asthma to infection (59%) and allergy (14%). New-onset cases were more likely attributed to infection, while reactivated cases were more associated with allergies. Medical charts included a discussion of work exposures in relation to asthma in only 32 (7%) cases. Twenty-three of these (72%) indicated there was an association between asthma and workplace exposures for an overall rate of work-related asthma of 4.9%. CONCLUSION: Computerized HMO records can be successfully used to identify AOA. Manual review of these records is important to confirm case status and is useful in evaluation of provider consideration of etiologies. We demonstrated that clinicians attribute most AOA to infection and tend to ignore the contribution of environmental and occupational exposures

Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function

BRCC36 is a Zn²⁺-dependent deubiquitinating enzyme (DUB) that hydrolyzes lysine-63-linked ubiquitin chains as part of distinct macromolecular complexes that participate in either interferon signaling or DNA-damage recognition. The MPN⁺ domain protein BRCC36 associates with pseudo DUB MPN⁻ proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity. To understand the basis for BRCC36 regulation, we have solved the structure of an active BRCC36-KIAA0157 heterodimer and an inactive BRCC36 homodimer. Structural and functional characterizations show how BRCC36 is switched to an active conformation by contacts with KIAA0157. Higher-order association of BRCC36 and KIAA0157 into a dimer of heterodimers (super dimers) was required for DUB activity and interaction with targeting proteins SHMT2 and RAP80. These data provide an explanation of how an inactive pseudo DUB allosterically activates a cognate DUB partner and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity, subcellular localization, and biological function