Implications of the differing roles of the beta 1 and beta 3 transmembrane and cytosplasmic domains for integrin function

Integrins are transmembrane receptors composed of alpha and beta subunits. Although most integrins contain beta 1, canonical activation mechanisms are based on studies of the platelet integrin, allb beta 3. Its inactive conformation is characterized by the association of the alpha llb transmembrane and cytosolic domain (TM/CT) with a tilted beta 3 TM/CT that leads to activation when disrupted. We show significant structural differences between beta 1 and beta 3 TM/CT in bicelles. Moreover, the 'snorkeling' lysine at the TM/CT interface of beta subunits, previously proposed to regulate alpha llb beta 3 activation by ion pairing with nearby lipids, plays opposite roles in beta 1 and beta 3 integrin function and in neither case is responsible for TM tilt. A range of affinities from almost no interaction to the relatively high avidity that characterizes alpha llb beta 3 is seen between various alpha subunits and beta 1 TM/CTs. The alpha llb beta 3-based canonical model for the roles of the TM/CT in integrin activation and function clearly does not extend to all mammalian integrins

Evaluating end-to-end optimization for data analytics applications in weld

Modern analytics applications use a diverse mix of libraries and functions. Unfortunately, there is no optimization across these libraries, resulting in performance penalties as high as an order of magnitude in many applications. To address this problem, we proposed Weld, a common runtime for existing data analytics libraries that performs key physical optimizations such as pipelining under existing, imperative library APIs. In this work, we further develop the Weld vision by designing an automatic adaptive optimizer for Weld applications, and evaluating its impact on realistic data science workloads. Our optimizer eliminates multiple forms of overhead that arise when composing imperative libraries like Pandas and NumPy, and uses lightweight measurements to make data-dependent decisions at run-time in ad-hoc workloads where no statistics are available, with sub-second overhead. We also evaluate which optimizations have the largest impact in practice and whether Weld can be integrated into libraries incrementally. Our results are promising: using our optimizer, Weld accelerates data science workloads by up to 23X on one thread and 80X on eight threads, and its adaptive optimizations provide up to a 3.75X speedup over rule-based optimization. Moreover, Weld provides benefits if even just 4--5 operators in a library are ported to use it. Our results show that common runtime designs like Weld may be a viable approach to accelerate analytics

Weld: Rethinking the interface between data-intensive applications

Data analytics applications combine multiple functions from different libraries and frameworks. Even when each function is optimized in isolation, the performance of the combined application can be an order of magnitude below hardware limits due to extensive data movement across these functions. To address this problem, we propose Weld, a new interface between data-intensive libraries that can optimize across disjoint libraries and functions. Weld exposes a lazily-evaluated API where diverse functions can submit their computations in a simple but general intermediate representation that captures their data-parallel structure. It then optimizes data movement across these functions and emits efficient code for diverse hardware. Weld can be integrated into existing frameworks such as Spark, TensorFlow, Pandas and NumPy without changing their user-facing APIs. We demonstrate that Weld can speed up applications using these frameworks by up to 29x

Talin regulates integrin beta 1-dependent and -independent cell functions in ureteric bud development

Kidney collecting system development requires integrin-dependent cell-extracellular matrix interactions. Integrins are heterodimeric transmembrane receptors consisting of alpha and beta subunits; crucial integrins in the kidney collecting systemexpress the beta 1 subunit. The beta 1 cytoplasmic tail has two NPxYmotifs that mediate functions by binding to cytoplasmic signaling and scaffolding molecules. Talins, scaffolding proteins that bind to the membrane proximal NPxY motif, are proposed to activate integrins and to link them to the actin cytoskeleton. We have defined the role of talin binding to the beta 1 proximal NPxY motif in the developing kidney collecting system in mice that selectively express a Y-to-A mutation in this motif. The mice developed a hypoplastic dysplastic collecting system. Collecting duct cells expressing this mutation had moderate abnormalities in cell adhesion, migration, proliferation and growth factor-dependent signaling. In contrast, mice lacking talins in the developing ureteric bud developed kidney agenesis and collecting duct cells had severe cytoskeletal, adhesion and polarity defects. Thus, talins are essential for kidney collecting duct development through mechanisms that extend beyond those requiring binding to the beta 1 integrin subunit NPxY motif

β1 Integrin NPXY motifs regulate kidney collecting-duct development and maintenance by induced-fit interactions with cytosolic proteins

Loss of β1 integrin expression inhibits renal collecting-system development. Two highly conserved NPXY motifs in the distal β1 tail regulate integrin function by associating with phosphtyrosine binding (PTB) proteins, such as talin and kindlin. Here, we define the roles of these two tyrosines in collecting-system development and delineate the structural determinants of the distal β1 tail using nuclear magnetic resonance (NMR). Mice carrying alanine mutations have moderate renal collecting-system developmental abnormalities relative to β1-null mice. Phenylalanine mutations did not affect renal collecting-system development but increased susceptibility to renal injury. NMR spectra in bicelles showed the distal β1 tail is disordered and does not interact with the model membrane surface. Alanine or phenylalanine mutations did not alter β1 structure or interactions between α and β1 subunit transmembrane/cytoplasmic domains; however, they did decrease talin and kindlin binding. Thus, these studies highlight the fact that the functional roles of the NPXY motifs are organ dependent. Moreover, the β1 cytoplasmic tail, in the context of the adjacent transmembrane domain in bicelles, is significantly different from the more ordered, membrane-associated β3 integrin tail. Finally, tyrosine mutations of β1 NPXY motifs induce phenotypes by disrupting their interactions with critical integrin binding proteins like talins and kindlins

Talin regulates integrin β1-dependent and -independent cell functions in ureteric bud development.

Kidney collecting system development requires integrin-dependent cell-extracellular matrix interactions. Integrins are heterodimeric transmembrane receptors consisting of α and β subunits; crucial integrins in the kidney collecting system express the β1 subunit. The β1 cytoplasmic tail has two NPxY motifs that mediate functions by binding to cytoplasmic signaling and scaffolding molecules. Talins, scaffolding proteins that bind to the membrane proximal NPxY motif, are proposed to activate integrins and to link them to the actin cytoskeleton. We have defined the role of talin binding to the β1 proximal NPxY motif in the developing kidney collecting system in mice that selectively express a Y-to-A mutation in this motif. The mice developed a hypoplastic dysplastic collecting system. Collecting duct cells expressing this mutation had moderate abnormalities in cell adhesion, migration, proliferation and growth factor-dependent signaling. In contrast, mice lacking talins in the developing ureteric bud developed kidney agenesis and collecting duct cells had severe cytoskeletal, adhesion and polarity defects. Thus, talins are essential for kidney collecting duct development through mechanisms that extend beyond those requiring binding to the β1 integrin subunit NPxY motif