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Supplementary Figures 1-4 and Legends from Insulin-Like Growth Factor Binding Protein-5 Is a Target of Matrix Metalloproteinase-7: Implications for Epithelial-Mesenchymal Signaling

Matrix metalloproteinase-7 (MMP-7) is localized to epithelial cells and is up-regulated in many cancers and in inflammation. We now report that MMP-7 targets a key mesenchymal cell type, the myofibroblast. Recombinant MMP-7 stimulated the proliferation and migration of human colonic myofibroblasts. These responses were partly attributable to activation of other MMPs, notably MMP-3 and MMP-8, and to stimulation of the mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. Using a proteomic approach, we identified insulin-like growth factor binding protein-5 (IGFBP-5) as a previously unsuspected target of MMP-7 produced by colonic myofibroblasts. We present evidence that the MMP-7 cleavage of IGFBP-5 liberates IGF-II that functions as an autocrine myofibroblast growth factor. Thus, MMP-7 may act as a signal from epithelial cells for local recruitment of myofibroblasts and stimulation of their proliferation. Similar effects of MMP-7 produced in epithelial tumors might account for the expansion of stroma through activation of myofibroblasts.

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Data plane programmability is greatly improving network monitoring. Most new proposals rely on controllers pulling information (e.g., sketches or packets) from the data plane. This architecture is not a good fit for tasks requiring high reactivity, such as failure recovery, attack mitigation, and so on. Focusing on these tasks, we argue for a different architecture, where the data plane autonomously detects anomalies and pushes alerts to the controller. As a first step, we demonstrate that statistical checks can be implemented in P4 by revisiting definition and online computation of statistical measures. We collect our techniques in a P4 library, and showcase how they enable in-switch anomaly detection.

As part of the commemoration of the 50th anniversary of SIGCOMM, a panel discussion on "Past and Future Directions in Networking Research" was held during the SIGCOMM conference on August 21, 2019. The panelists were Dah Ming Chiu (Chinese University of Hong Kong), Manya Ghobadi (Massachusetts Institute of Technology), Mark Handley (University College London), Jennifer Rexford (Princeton University), and Lixia Zhang (University of California, Los Angeles). The discussion was moderated by Bruce Maggs (Duke University and Akamai Technologies).

This document specifies tcpcrypt, a TCP encryption protocol designed for use in conjunction with the TCP Encryption Negotiation Option (TCP-ENO). Tcpcrypt coexists with middleboxes by tolerating resegmentation, NATs, and other manipulations of the TCP header. The protocol is self-contained and specifically tailored to TCP implementations, which often reside in kernels or other environments in which large external software dependencies can be undesirable. Because the size of TCP options is limited, the protocol requires one additional one-way message latency to perform key exchange before application data can be transmitted. However, the extra latency can be avoided between two hosts that have recently established a previous tcpcrypt connection.

Despite growing adoption of TLS, a significant fraction of TCP traffic on the Internet remains unencrypted. The persistence of unencrypted traffic can be attributed to at least two factors. First, some legacy protocols lack a signaling mechanism (such as a "STARTTLS" command) by which to convey support for encryption, making incremental deployment impossible. Second, legacy applications themselves cannot always be upgraded, requiring a way to implement encryption transparently entirely within the transport layer. The TCP Encryption Negotiation Option (TCP-ENO) addresses both of these problems through a new TCP option-kind providing out-of-band, fully backward-compatible negotiation of encryption.

SpaceX has filed plans with the US Federal Communications Committee (FCC) to build a constellation of 4,425 low Earth orbit communication satellites. It will use phased array antennas for up and downlinks and laser communication between satellites to provide global low-latency high bandwidth coverage. To understand the latency propertes of such a network, we built a simulator based on public details from the FCC filings. We evaluate how to use the laser links to provide a network, and look at the problem of routing on this network. We provide a preliminary evaluation of how well such a network can provide low-latency communications, and examine its multipath properties. We conclude that a network built in this manner can provide lower latency communications than any possible terrestrial optical fiber network for communications over distances greater than about 3000 km.

An ISP's customers increasingly demand delivery of their traffic without congestion and with low latency. The ISP's topology, routing, and traffic engineering, often over multiple paths, together determine congestion and latency within its backbone. We first consider how to measure a topology's capacity to route traffic without congestion and with low latency. We introduce low-latency path diversity (LLPD), a metric that captures a topology's flexibility to accommodate traffic on alternative low-latency paths. We explore to what extent 116 real backbone topologies can, regardless of routing system, keep latency low when demand exceeds the shortest path's capacity. We find, perhaps surprisingly, that topologies with good LLPD are precisely those where routing schemes struggle to achieve low latency without congestion. We examine why these schemes perform poorly, and offer an existence proof that a practical routing scheme can achieve a topology's potential for congestion-free, low-delay routing. Finally we examine implications for the design of backbone topologies amenable to achieving high capacity and low delay.

© 2017 ACM. Modern datacenter networks provide very high capacity via redundant Clos topologies and low switch latency, but transport protocols rarely deliver matching performance. We present NDP, a novel datacenter transport architecture that achieves near-optimal completion times for short transfers and high flow throughput in a wide range of scenarios, including incast. NDP switch buffers are very shallow and when they fill the switches trim packets to headers and priority forward the headers. This gives receivers a full view of instantaneous demand from all senders, and is the basis for our novel, high-performance, multipath-aware transport protocol that can deal gracefully with massive incast events and prioritize traffic from different senders on RTT timescales. We implemented NDP in Linux hosts with DPDK, in a software switch, in a NetFPGA-based hardware switch, and in P4. We evaluate NDP's performance in our implementations and in large-scale simulations, simultaneously demonstrating support for very low-latency and high throughput.

Conventional operating systems used for video streaming employ an in-memory disk buffer cache to mask the high latency and low throughput of disks. However, data from Netflix servers show that this cache has a low hit rate, so does little to improve throughput. Latency is not the problem it once was either, due to PCIe-attached flash storage. With memory bandwidth increasingly becoming a bottleneck for video servers, especially when end-to-end encryption is considered, we revisit the interaction between storage and networking for video streaming servers in pursuit of higher performance.We show how to build high-performance userspace network services that saturate existing hardware while serving data directly from disks, with no need for a traditional disk buffer cache. Employing netmap, and developing a new diskmap service, which provides safe high-performance userspace direct I/O access to NVMe devices, we amortize system overheads by utilizing efficient batching of outstanding I/O requests, process-to-completion, and zerocopy operation. We demonstrate how a buffer-cache-free design is not only practical, but required in order to achieve efficient use of memory bandwidth on contemporary microarchitectures. Minimizing latency between DMA and CPU access by integrating storage and TCP control loops allows many operations to access only the last-level cache rather than bottle-necking on memory bandwidth. We illustrate the power of this design by building Atlas, a video streaming web server that outperforms state-of-the-art configurations, and achieves ~72Gbps of plaintext or encrypted network traffic using a fraction of the available CPU cores on commodity hardware.

Purpose: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability. Methods: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein. Results: Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function. Conclusion: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association. Genet Med advance online publication 02 February 2017

As 802.11 wireless networks proliferate, interference becomes increasingly severe, particularly in dense, urban environments. These networks are usually operated by different users (e.g., tenants in apartments). In this paper, we develop techniques for mitigating interference between such loosely cooperating 802.11 MIMO APs and clients, which do not share a high-speed wired backplane or central controller. We propose CoOperative Power Allocation (COPA), an approach to concurrent wireless medium access that combines fine-grained, per-subcarrier power allocation, nulling, and multi-stream transmission to claim capacity that status-quo approaches cannot. Jointly turning these knobs allows COPA to allocate subcarriers to senders partially, rather than all-or-nothing, and to embrace a measure of interference when doing so increases capacity.

The advantages of 802.11 wireless networks have led to their widespread use which in turn has intensified the problem of interference, especially in dense urban settings. Such networks are close to one another but not centrally managed and do not share any high-speed wired backend. We present a system that leverages subcarrier selection, power allocation, nulling and multi-stream transmission but most importantly does so in a loosely cooperative manner between participating hosts, leading to considerable throughput improvements over the status-quo.

We present FUBAR, a system that reduces congestion and maximizes the utility of the entire network by installing new routes and changing the traffic load on existing ones. FUBAR works offline to periodically adjust the distribution of traffic on paths. It requires neither changes to end hosts nor precise prior knowledge of the traffic matrix. We demonstrate that even in the presence of traffic from all network devices to all other devices, FUBAR can optimize a real-world core-level network in a matter of minutes.