Requirements of SLP76 tyrosines in ITAM and integrin receptor signaling and in platelet function in vivo

Src homology 2 domain–containing leukocyte phosphoprotein of 76 kD (SLP76), an adaptor that plays a critical role in platelet activation in vitro, contains three N-terminal tyrosine residues that are essential for its function. We demonstrate that mice containing complementary tyrosine to phenylalanine mutations in Y145 (Y145F) and Y112 and Y128 (Y112/128F) differentially regulate integrin and collagen receptor signaling. We show that mutation of Y145 leads to severe impairment of glycoprotein VI (GPVI)–mediated responses while preserving outside-in integrin signaling. Platelets from Y112/128F mice, although having mild defects in GPVI signaling, exhibit defective actin reorganization after GPVI or αIIbβ3 engagement. The in vivo consequences of these signaling defects correlate with the mild protection from thrombosis seen in Y112/128F mice and the near complete protection observed in Y145F mice. Using genetic complementation, we further demonstrate that all three phosphorylatable tyrosines are required within the same SLP76 molecule to support platelet activation by GPVI

Determination of the Argon Spectral Function From (e, e\u27p) Data

The E12-14-012 experiment, performed in Jefferson Lab Hall A, has measured the (e,e′p) cross section in parallel kinematics using a natural argon target. Here, we report the full results of the analysis of the data set corresponding to beam energy 2.222 GeV, and spanning the missing momentum and missing energy range 15 ≲ pm ≲ 300  MeV /c and 12 ≲ Em ≲ 80  MeV. The reduced cross section, determined as a function of pm and Em with ≈ 4% accuracy, has been fitted using the results of Monte Carlo simulations involving a model spectral function and including the effects of final state interactions. The overall agreement between data and simulations turns out to be quite satisfactory (χ2/d. o. f. =1.9). The resulting spectral function will provide valuable new information, needed for the interpretation of neutrino interactions in liquid argon detectors

Individual phosphatidylinositol transfer proteins have distinct functions that do not involve lipid transfer activity

Platelets utilize signal transduction pathways facilitated by Class I phosphatidylinositol transfer proteins (PITPs). The two mammalian Class I PITPs, PITPα and PITPβ, are single PITP domain soluble proteins that are encoded by different genes and have 77% sequence identity, though their individual roles in mammalian biology remain uncharacterized. These proteins are believed to shuttle phosphatidylinositol and phosphatidylcholine between separate intracellular membrane compartments, thereby regulating phosphoinositide synthesis and second messenger formation. Previously, we observed that platelet-specific deletion of PITPα, the predominant expressed murine PITP isoform, had no effect on hemostasis, but had impaired tumor metastasis formation and disrupted phosphoinositide signaling. Here, we find that mice lacking the lesser expressed PITPβ in their platelets exhibit a similar phenotype. However, in contrast to PITPα-null platelet lysates that have impaired lipid transfer activity, PITPβ-null platelet lysates have essentially normal lipid transfer activity, although both isoforms contribute to phosphoinositide synthesis in vitro. Moreover, we found that platelet-specific deletion of both PITPs leads to ex vivo platelet aggregation/secretion and spreading defects, impaired tail bleeding, and profound tumor dissemination. Our studies also demonstrate that PITP isoforms are required for maintaining endogenous phosphoinositide PI(4,5)P2 levels and agonist stimulated second messenger formation. The data shown here demonstrate that both class I PITP isoforms contribute to phosphoinositide signaling in platelets, likely through distinct biochemical mechanisms or in different subcellular domains. They are functionally overlapping and either single isoform is able to maintain the homeostasis of platelets

National Athletic Trainers\u27 Association Position Statement: Evaluation, Management, and Outcomes of and Return-to-Play Criteria for Overhead Athletes With Superior Labral Anterior-Posterior Injuries

Objective: To present recommendations for the diagnosis, management, outcomes, and return to play of athletes with superior labral anterior-posterior (SLAP) injuries. Background: In overhead athletes, SLAP tears are common as either acute or chronic injuries. The clinical guidelines presented here were developed based on a systematic review of the current evidence and the consensus of the writing panel. Clinicians can use these guidelines to inform decision making regarding the diagnosis, acute and long-term conservative and surgical treatment, and expected outcomes of and return-to-play guidelines for athletes with SLAP injuries. Recommendations: Physical examination tests may aid diagnosis; 6 tests are recommended for confirming and 1 test is recommended for ruling out a SLAP lesion. Combinations of tests may be helpful to diagnose SLAP lesions. Clinical trials directly comparing outcomes between surgical and nonoperative management are absent; however, in cohort trials, the reports of function and return-to-sport outcomes are similar for each management approach. Nonoperative management that includes rehabilitation, nonsteroidal anti-inflammatory drugs, and corticosteroid injections is recommended as the first line of treatment. Rehabilitation should address deficits in shoulder internal rotation, total arc of motion, and horizontal-adduction motion, as well as periscapular and glenohumeral muscle strength, endurance, and neuromuscular control. Most researchers have examined the outcomes of surgical management and found high levels of satisfaction and return of shoulder function, but the ability to return to sport varied widely, with 20% to 94% of patients returning to their sport after surgical or nonoperative management. On average, 55% of athletes returned to full participation in prior sports, but overhead athletes had a lower average return of 45%. Additional work is needed to define the criteria for diagnosing and guiding clinical decision making to optimize outcomes and return to play

In-situ coating of silicon-rich films on tokamak plasma-facing components with real-time Si material injection

Experiments have been conducted in the DIII-D tokamak to explore the in-situ growth of silicon-rich layers as a potential technique for real-time replenishment of surface coatings on plasma-facing components (PFCs) during steady-state long-pulse reactor operation. Silicon (Si) pellets of 1 mm diameter were injected into low- and high-confinement (L-mode and H-mode) plasma discharges with densities ranging from $3.9-7.5\times10^{19}$ m$^{-3}$ and input powers ranging from 5.5-9 MW. The small Si pellets were delivered with the impurity granule injector (IGI) at frequencies ranging from 4-16 Hz corresponding to mass flow rates of 5-19 mg/s ($1-4.2\times10^{20}$ Si/s) at cumulative amounts of up to 34 mg of Si per five-second discharge. Graphite samples were exposed to the scrape-off layer and private flux region plasmas through the divertor material evaluation system (DiMES) to evaluate the Si deposition on the divertor targets. The Si II emission at the sample correlates with silicon injection and suggests net surface Si-deposition in measurable amounts. Post-mortem analysis showed Si-rich coatings of varying morphology mainly containing silicon oxides, with SiO$_2$ being the dominant component. No evidence of SiC was found, which is attributed to low divertor surface temperatures. The Si-rich coating growth rates were found to be at least $0.4-0.7$ nm/s, and the erosion rate was $0.1-0.3$ nm/s. The technique is estimated to coat a surface area of at least 0.94 m$^2$ on the outer divertor. These results demonstrate the potential of using real-time material injection to grow silicon-rich layers on divertor PFCs during reactor operation

Lost in reviews:Looking for the involvement of stakeholders, patients, public and other non-researcher contributors in realist reviews

The involvement of non‐researcher contributors (eg, stakeholders, patients and the public, decision and policy makers, experts, lay contributors) has taken a variety of forms within evidence syntheses. Realist reviews are a form of evidence synthesis that involves non‐researcher contributors yet this practice has received little attention. In particular, the role of patient and public involvement (PPI) has not been clearly documented. This review of reviews describes the ways in which contributor involvement, including PPI, is documented within healthcare realist reviews published over the last five years. A total of 448 papers published between 2014 and 2019 were screened, yielding 71 full‐text papers included in this review. Statements about contributor involvement were synthesized across each review using framework analysis. Three themes are described in this article including nomenclature, nature of involvement, and reporting impact.Papers indicate that contributor involvement in realist reviews refers to stakeholders, experts, or advisory groups (ie, professionals, clinicians, or academics). Patients and the public are occasionally subsumed into these groups and in doing so, the nature and impact of their involvement become challenging to identify and at times, is lost completely. Our review findings indicate a need for the realist review community to develop guidance to support researchers in their future collaboration with contributors, including patients and the public