Structure-function analysis reveals that the Pseudomonas aeruginosa Tps4 two-partner secretion system is involved in CupB5 translocation

Pseudomonas aeruginosa is a Gram-negative opportunistic bacterium, synonymous with cystic fibrosis patients, which can cause chronic infection of the lungs. This pathogen is a model organism to study biofilms: a bacterial population embedded in an extracellular matrix that provide protection from environmental pressures and lead to persistence. A number of Chaperone-Usher Pathways, namely CupA-CupE, play key roles in these processes by assembling adhesive pili on the bacterial surface. One of these, encoded by the cupB operon, is unique as it contains a nonchaperone-usher gene product, CupB5. Two-partner secretion (TPS) systems are comprised of a C-terminal integral membrane β-barrel pore with tandem N-terminal POTRA (POlypeptide TRansport Associated) domains located in the periplasm (TpsB) and a secreted substrate (TpsA). Using NMR we show that TpsB4 (LepB) interacts with CupB5 and its predicted cognate partner TpsA4 (LepA), an extracellular protease. Moreover, using cellular studies we confirm that TpsB4 can translocate CupB5 across the P. aeruginosa outer membrane, which contrasts a previous observation that suggested the CupB3 P-usher secretes CupB5. In support of our findings we also demonstrate that tps4/cupB operons are coregulated by the RocS1 sensor suggesting P. aeruginosa has developed synergy between these systems. Furthermore, we have determined the solution-structure of the TpsB4-POTRA1 domain and together with restraints from NMR chemical shift mapping and in vivo mutational analysis we have calculated models for the entire TpsB4 periplasmic region in complex with both TpsA4 and CupB5 secretion motifs. The data highlight specific residues for TpsA4/CupB5 recognition by TpsB4 in the periplasm and suggest distinct roles for each POTRA domain

Sustained safety and performance of the second-generation drug-eluting absorbable metal scaffold in patients with de novo coronary lesions: 12-month clinical results and angiographic findings of the BIOSOLVE-II first-in-man trial.

Metal absorbable scaffolds constitute a conceptually attractive alternative to polymeric scaffolds. Promising 6-month outcomes of a second-generation drug-eluting absorbable metal scaffold (DREAMS 2G), consisting of an absorbable magnesium scaffold backbone, have been reported. We assessed the 12-month safety and performance of this novel device. The prospective, international, multi-centre, first-in-man BIOSOLVE-II trial enrolled 123 patients with up to two de novo lesions with a reference diameter between 2.2 and 3.7 mm. All patients were scheduled for angiographic follow-up at 6 months, and-if subjects consented-at 12 months. Dual antiplatelet therapy was recommended for 6 months. Quantitative coronary angiography (QCA) parameters remained stable from 6 to 12 months [paired data of 42 patients: in-segment late lumen loss 0.20 ± 0.21 mm vs. 0.25 ± 0.22 mm, P = 0.117, Δ 0.05 ± 0.21 mm (95% CI: -0.01;0.12); in-scaffold late lumen loss 0.37 ± 0.25 mm vs. 0.39 ± 0.27 mm, P = 0.446, Δ 0.03 ± 0.22 (95% CI: -0.04;0.10), respectively]. Intravascular ultrasound and optical coherence tomography findings corroborated the QCA results. Target lesion failure occurred in four patients (3.4%), consisting of one death of unknown cause, one target-vessel myocardial infarction, and two clinically driven target lesion revascularization. No additional event occurred beyond the 6-month follow-up. During the entire follow-up of 12 months, none of the patients experienced a definite or probable scaffold thrombosis. The novel drug-eluting metal absorbable scaffold DREAMS 2G showed a continuous favourable safety profile up to 12 months and stable angiographic parameters between 6 and 12 months. NCT01960504

BASILICA Trial: One-Year Outcomes of Transcatheter Electrosurgical Leaflet Laceration to Prevent TAVR Coronary Obstruction

Background: Coronary artery obstruction is a rare, devastating complication of transcatheter aortic valve replacement. Transcatheter electrosurgical aortic leaflet laceration (Bioprosthetic or Native Aortic Scallop Intentional Laceration to Prevent Iatrogenic Coronary Artery Obstruction [BASILICA]) is a novel technique to prevent coronary artery obstruction. We report the 1-year outcomes of the BASILICA trial. Primary end points of 30-day success and safety have been reported previously. Methods: The BASILICA trial was a prospective, multicenter, single-arm safety and feasibility study. Subjects with severe native or bioprosthetic aortic valve disease at high or extreme risk for surgery, and high risk of coronary artery obstruction, were included. End points at 1 year included death, stroke, and myocardial infarction. Source data was independently verified and end points independently adjudicated. Results: Thirty subjects were enrolled between February 2018 and July 2018. At 30 days, BASILICA was successful in 28 subjects (93.3%), there were 3 strokes (10%), including 1 disabling stroke (3.3%), 1 death (3.3%), and 1 periprocedural myocardial infarction (3.3%). Between 30 days and 1 year, there were no additional strokes, no myocardial infarction, and 2 deaths (10% 1-year mortality). No subject needed repeat intervention for aortic valve or coronary disease. Two subjects had infective endocarditis (6.7%), but neither was isolated to the aortic valve. There were no hospital admissions for heart failure. Fourteen (46.7%) subjects required repeat hospital admission for other causes. Aortic valve gradients on echocardiography, New York Heart Association functional class, and Kansas City Cardiomyopathy Questionnaire scores improved from baseline to 30 days and were maintained at 1 year. Conclusions: In these subjects with multiple comorbidities and restrictive anatomy that underwent transcatheter aortic valve replacement, there was no late stroke, myocardial infarction, or death related to BASILICA. Mitigation of coronary obstruction remained intact at 1 year and was not related to recurrent readmission. These results are reassuring for patients and physicians who wish to avoid the long-term complications related to snorkel stenting

International Expert Consensus on Switching Platelet P2Y(12) Receptor-Inhibiting Therapies

Dual antiplatelet therapy with aspirin and a P2Y(12) inhibitor is the treatment of choice for the prevention of atherothrombotic events in patients with acute coronary syndromes and for those undergoing percutaneous coronary interventions. The availability of different oral P2Y(12) inhibitors (clopidogrel, prasugrel, ticagrelor) has enabled physicians to contemplate switching among therapies because of specific clinical scenarios. The recent introduction of an intravenous P2Y(12) inhibitor (cangrelor) further adds to the multitude of modalities and settings in which switching therapies may occur. In clinical practice, it is not uncommon to switch P2Y(12) inhibitor, and switching may be attributed to a variety of factors. However, concerns about the safety of switching between these agents have emerged. Practice guidelines have not fully elaborated on how to switch therapies, leaving clinicians with limited guidance on when and how to switch therapies when needed. This prompted the development of this expert consensus document by key leaders from North America and Europe with expertise in basic, translational, and clinical sciences in the field of antiplatelet therapy. This expert consensus provides an overview of the pharmacology of P2Y(12) inhibitors, different modalities and definitions of switching, and available literature and recommendations for switching between P2Y(12) inhibitors

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS

Non-Interactive Secure 2PC in the Offline/Online and Batch Settings

In cut-and-choose protocols for two-party secure computation (2PC) the main overhead is the number of garbled circuits that must be sent. Recent work (Lindell, Riva; Huang et al., Crypto 2014) has shown that in a batched setting, when the parties plan to evaluate the same function $N$ times, the number of garbled circuits per execution can be reduced by a $O(\log N)$ factor compared to the single-execution setting. This improvement is significant in practice: an order of magnitude for $N$ as low as one thousand. % Besides the number of garbled circuits, communication round trips are another significant performance bottleneck. Afshar et al. (Eurocrypt 2014) proposed an efficient cut-and-choose 2PC that is round-optimal (one message from each party), but in the single-execution setting. In this work we present new malicious-secure 2PC protocols that are round-optimal and also take advantage of batching to reduce cost. Our contributions include: \begin{itemize} \item A 2-message protocol for batch secure computation ($N$ instances of the same function). The number of garbled circuits is reduced by a $O(\log N)$ factor over the single-execution case. However, other aspects of the protocol that depend on the input/output size of the function do not benefit from the same $O(\log N)$-factor savings. \item A 2-message protocol for batch secure computation, in the random oracle model. All aspects of this protocol benefit from the $O(\log N)$-factor improvement, except for small terms that do not depend on the function being evaluated. \item A protocol in the offline/online setting. After an offline preprocessing phase that depends only on the function $f$ and $N$, the parties can securely evaluate $f$, $N$ times (not necessarily all at once). Our protocol\u27s online phase is only 2 messages, and the total online communication is only $\ell + O(\kappa)$ bits, where $\ell$ is the input length of $f$ and $\kappa$ is a computational security parameter. This is only $O(\kappa)$ bits more than the information-theoretic lower bound for malicious 2PC

Solution Structure of Tensin2 SH2 Domain and Its Phosphotyrosine-Independent Interaction with DLC-1

Background: Src homology 2 (SH2) domain is a conserved module involved in various biological processes. Tensin family member was reported to be involved in tumor suppression by interacting with DLC-1 (deleted-in-liver-cancer-1) via its SH2 domain. We explore here the important questions that what the structure of tensin2 SH2 domain is, and how it binds to DLC-1, which might reveal a novel binding mode. Principal Findings: Tensin2 SH2 domain adopts a conserved SH2 fold that mainly consists of five b-strands flanked by two a-helices. Most SH2 domains recognize phosphorylated ligands specifically. However, tensin2 SH2 domain was identified to interact with nonphosphorylated ligand (DLC-1) as well as phosphorylated ligand. Conclusions: We determined the solution structure of tensin2 SH2 domain using NMR spectroscopy, and revealed the interactions between tensin2 SH2 domain and its ligands in a phosphotyrosine-independent manner