Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands

Suppressor of cytokine signaling (SOCS)2 protein is a key negative regulator of the growth hormone (GH) and Janus kinase (JAK)-Signal Transducers and Activators of Transcription (STAT) signaling cascade. The central SOCS2-Src homology 2 (SH2) domain is characteristic of the SOCS family proteins and is an important module that facilitates recognition of targets bearing phosphorylated tyrosine (pTyr) residues. Here we identify an exosite on the SOCS2-SH2 domain which, when bound to a non-phosphorylated peptide (F3), enhances SH2 affinity for canonical phosphorylated ligands. Solution of the SOCS2/F3 crystal structure reveals F3 as an α-helix which binds on the opposite side of the SH2 domain to the phosphopeptide binding site. F3:exosite binding appears to stabilise the SOCS2-SH2 domain, resulting in slower dissociation of phosphorylated ligands and consequently, enhances binding affinity. This biophysical enhancement of SH2:pTyr binding affinity translates to increase SOCS2 inhibition of GH signaling

Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-alpha/beta (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-gamma is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.ANRS Nord-Sud ; CIBSS ; CODI ; Comité para el Desarrollo de la Investigación ; Fulbright Future Scholarshi

Natural killer cells and anti-tumor immunity

Immune checkpoint inhibitors harness the power of the immune system to fight cancer. The clinical success achieved with antibodies against the inhibitory T cell receptors PD-1 and CTLA4 has focused attention on the possibility of manipulating other immune cells, in particular those involved in innate immunity. Here we review the role of innate lymphoid cells (ILCs)and their contribution to tumor immunity. As the prototypical ILC, the natural killer (NK)cell has an intrinsic ability to detect and kill cancer cells. NK cells are dependent on the cytokine interleukin (IL)-15 for their development and effector activity. We discuss the role of the Suppressor of cytokine (SOCS)proteins in negatively regulating IL-15 and NK cell responses and the potential for targeting these small intracellular regulators as new immune checkpoints

Reliability of radiographic measurements for acute distal radius fractures

BACKGROUND: The management of distal radial fractures is guided by the interpretation of radiographic findings. The aim of this investigation was to determine the intra- and inter-observer reliability of eight traditionally reported anatomic radiographic parameters in adults with an acute distal radius fracture. METHODS: Five observers participated. All were routinely involved in making treatment decisions based on distal radius fracture radiographs. Observers performed independent repeated measurements on 30 radiographs for eight anatomical parameters: dorsal shift (mm), intra-articular gap (mm), intra-articular step (mm), palmar tilt (degrees), radial angle (degrees), radial height (mm), radial shift (mm), ulnar variance (mm). Intraclass correlation coefficients (ICCs) and the magnitude of retest errors were calculated. RESULTS: Measurement reliability was summarised as high (ICC > 0.80), moderate (0.60–0.80) or low (<0.60). Intra-observer reliability was high for dorsal shift and palmar tilt; moderate for radial angle, radial height, ulnar variance and radial shift; and low for intra-articular gap and step. Inter-observer reliability was high for palmar tilt; moderate for dorsal shift, ulnar variance, radial angle and radial height; and low for radial shift, intra-articular gap and step. Error magnitude (95 % confidence interval) was within 1–2 mm for intra-articular gap and step, 2–4 mm for ulnar variance, 4–6 mm for radial shift, dorsal shift and radial height, and 6–8° for radial angle and palmar tilt. CONCLUSIONS: Based on previous reports of critical values for palmar tilt, ulnar variance and radial angle, error margins appear small enough for measurements to be useful in guiding treatment decisions. Our findings indicate that clinicians cannot reliably measure values ≤1 mm for intra-articular gap and step when interpreting radiographic parameters using the standardised methods investigated in this study. As a guide for treatment selection, palmar tilt, ulnar variance and radial angle measurements may be useful, but intra-articular gap and step appear unreliable. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12880-016-0147-7) contains supplementary material, which is available to authorized users

'It's the ultimate observer role..you're feeling and seeing what's happening to you' : students' experiences of peer simulation

Introduction: Simulation-based education (SBE) benefits learners, but multiple barriers limit curriculum integration. Peer simulation, where students are formally educated to portray patient roles in simulated interactions with their peers, might maintain the educational benefits of SBE, be cost-effective, and enable additional learning. Our research question was: What are the perspectives and experiences of physiotherapy students who participated in peer simulation?'. Methods: Second-year physiotherapy students (n=16) participated in a blended peer simulation programme that included preparation for patient role portrayal and simulated clinical interactions with peers. Using an interpretivist approach, students' experiences and perspectives were explored in two focus groups. Inductive thematic analysis was completed by two researchers. Results: Three primary themes were identified that characterised the experiences and perspectives of physiotherapy students: peer simulation is a valuable learning experience, specific design features enable effective peer simulation, and portraying a patient provides unique insight. Peer simulation was unexpectedly realistic, revealed knowledge and skill deficits, and improved their clinical skills. Specific design features included consistent engagement, repetitive, individualised practice, multiple forms of feedback, and detailed role preparation. Being the patient in peer simulation gave students unique and valuable insight into patients' experiences of and feelings about health issues and healthcare interactions. Conclusion: Physiotherapy students acquire new insights during peer simulation that may enrich their capabilities for practice through understanding healthcare interactions from patients' perspectives. Physiotherapy students' learning in peer simulation appears to align with the powerful learning experiences of health professional students in other immersive simulation modalities

Additional file 1: of Reliability of radiographic measurements for acute distal radius fractures

Data set- Repeated measurements by five observers for the eight anatomical parameters. File contains the raw values for the repeated measurements recorded by the five observers for the 30 radiographs. (XLS 49 kb