Assisted protein folding at low temperature: evolutionaryadaptation of the Antarctic fish chaperonin CCT and its clientproteins

Eukaryotic ectotherms of the Southern Ocean face energetic challenges to protein folding assisted by the cytosolic chaperonin CCT. We hypothesize that CCT and its client proteins (CPs) have co-evolved molecular adaptations that facilitate CCT–CP interaction and the ATP-driven folding cycle at low temperature. To test this hypothesis, we compared the functional and structural properties of CCT–CP systems from testis tissues of an Antarctic fish, Gobionotothen gibberifrons (Lo¨nnberg) (habitat/body T=-1.9 to +2˚C), and of the cow (body T=37˚C). We examined the temperature dependence of the binding of denatured CPs (bactin, b-tubulin) by fish and bovine CCTs, both in homologous and heterologous combinations and at temperatures between 24˚C and 20˚C, in a buffer conducive to binding of the denatured CP to the open conformation of CCT. In homologous combination, the percentage of G. gibberifrons CCT bound to CP declined linearly with increasing temperature, whereas the converse was true for bovine CCT. Binding of CCT to heterologous CPs was low, irrespective of temperature. When reactions were supplemented with ATP, G. gibberifrons CCT catalyzed the folding and release of actin at 2˚C. The ATPase activity of apo-CCT from G. gibberifrons at 4˚C was, 2.5-fold greater than that of apo-bovine CCT, whereas equivalent activities were observed at 20˚C. Based on these results, we conclude that the catalytic folding cycle of CCT from Antarctic fishes is partially compensated at their habitat temperature, probably by means of enhanced CP-binding affinity and increased flexibility of the CCT subunits

The reproducibility of interventional radiology randomized controlled trials and external validation of a classification system

PURPOSEThe fragility index (FI) measures the robustness of randomized controlled trials (RCTs). It complements the P value by taking into account the number of outcome events. In this study, the authors measured the FI for major interventional radiology RCTs.METHODSInterventional radiology RCTs published between January 2010 and December 2022 relating to trans-jugular intrahepatic portosystemic shunt, trans-arterial chemoembolization, needle biopsy, angiography, angioplasty, thrombolysis, and nephrostomy tube insertion were analyzed to measure the FI and robustness of the studies.RESULTSA total of 34 RCTs were included. The median FI of those studies was 4.5 (range 1–68). Seven trials (20.6%) had a number of patients lost to follow-up that was higher than their FI, and 15 (44.1%) had a FI of 1–3.CONCLUSIONThe median FI, and hence the reproducibility of interventional radiology RCTs, is low compared to other medical fields, with some having a FI of 1, which should be interrupted cautiously

Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation

Background: Ischemia reperfusion injury (I/RI) is a common complication of cardiovascular diseases. Resolution of detrimental I/RI-generated prothrombotic and proinflammatory responses is essential to restore homeostasis. Platelets play a crucial part in the integration of thrombosis and inflammation. Their role as participants in the resolution of thromboinflammation is underappreciated; therefore we used pharmacological and genetic approaches, coupled with murine and clinical samples, to uncover key concepts underlying this role. Methods: Middle cerebral artery occlusion with reperfusion was performed in wild-type or annexin A1 (AnxA1) knockout (AnxA1-/-) mice. Fluorescence intravital microscopy was used to visualize cellular trafficking and to monitor light/dye-induced thrombosis. The mice were treated with vehicle, AnxA1 (3.3 mg/kg), WRW4 (1.8 mg/kg), or all 3, and the effect of AnxA1 was determined in vivo and in vitro. Results: Intravital microscopy revealed heightened platelet adherence and aggregate formation post I/RI, which were further exacerbated in AnxA1-/- mice. AnxA1 administration regulated platelet function directly (eg, via reducing thromboxane B2 and modulating phosphatidylserine expression) to promote cerebral protection post-I/RI and act as an effective preventative strategy for stroke by reducing platelet activation, aggregate formation, and cerebral thrombosis, a prerequisite for ischemic stroke. To translate these findings into a clinical setting, we show that AnxA1 plasma levels are reduced in human and murine stroke and that AnxA1 is able to act on human platelets, suppressing classic thrombin-induced inside-out signaling events (eg, Akt activation, intracellular calcium release, and Ras-associated protein 1 [Rap1] expression) to decrease IIbβ3 activation without altering its surface expression. AnxA1 also selectively modifies cell surface determinants (eg, phosphatidylserine) to promote platelet phagocytosis by neutrophils, thereby driving active resolution. (n=5-13 mice/group or 7-10 humans/group.) Conclusions: AnxA1 affords protection by altering the platelet phenotype in cerebral I/RI from propathogenic to regulatory and reducing the propensity for platelets to aggregate and cause thrombosis by affecting integrin (IIbβ3) activation, a previously unknown phenomenon. Thus, our data reveal a novel multifaceted role for AnxA1 to act both as a therapeutic and a prophylactic drug via its ability to promote endogenous proresolving, antithromboinflammatory circuits in cerebral I/RI. Collectively, these results further advance our knowledge and understanding in the field of platelet and resolution biology.Fil: Senchenkova, Elena Y.. State University of Louisiana; Estados UnidosFil: Ansari, Junaid. State University of Louisiana; Estados UnidosFil: Becker, Felix. University Hospital Muenster; AlemaniaFil: Vital, Shantel A.. State University of Louisiana; Estados UnidosFil: Al-Yafeai, Zaki. State University of Louisiana; Estados UnidosFil: Sparkenbaugh, Erica M.. University North Carolina Chapel Hill; Estados UnidosFil: Pawlinski, Rafal. University North Carolina Chapel Hill; Estados UnidosFil: Stokes, Karen Y.. State University of Louisiana; Estados UnidosFil: Carroll, Jennifer L.. State University of Louisiana; Estados UnidosFil: Dragoi, Ana-Maria. State University of Louisiana; Estados UnidosFil: Qin, Cheng Xue. Baker Heart And Diabetes Institute; AustraliaFil: Ritchie, Rebecca H.. Baker Heart And Diabetes Institute; AustraliaFil: Sun, Hai. University Hospital Muenster; AlemaniaFil: Cuellar-Saenz, Hugo H.. State University of Louisiana; Estados UnidosFil: Rubinstein Guichon, Mara Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. Columbia University; Estados UnidosFil: Han, Yiping W.. Columbia University; Estados UnidosFil: Orr, A. Wayne. University Hospital Muenster; AlemaniaFil: Perretti, Mauro. Queen Mary University Of London; Reino UnidoFil: Granger, D. Neil. State University of Louisiana; Estados UnidosFil: Gavins, Felicity N.E.. State University of Louisiana; Estados Unido

Carotid-cavernous fistula caused by laceration of persistent fetal trigeminal artery treated with single catheter coil embolization

We present the endovascular treatment of traumatic carotid-cavernous fistula from persistent fetal trigeminal artery (PFTA) laceration. To date, there are six such cases of traumatic PFTA-cavernous fistulas reported in the literature. These injuries can pose a unique challenge in that rupture of a PFTA in its course through the cavernous sinus may produce a fistula feeding from both anterior and posterior circulations. Previously, these have been treated with dual catheter coil embolization from the carotid and basilar systems. We utilize a single catheter technique accessing the cavernous sinus through the origin of the PFTA on the internal carotid. Both anterior and posterior fistula components may be embolized through this single access. This represents a simple yet safe treatment option

Endovascular Management of Hemorrhagic Stroke

Significant advances in endovascular neurosurgery tools, devices, and techniques are changing the approach to the management of acute hemorrhagic stroke. The endovascular treatment of intracranial aneurysms emerged in the early 1990s with Guglielmi detachable coils, and since then, it gained rapid popularity that surpassed open surgery. Stent-assisted coiling and balloon remodeling techniques have made the treatment of wide-necked aneurysms more durable. With the introduction of flow diverters and flow disrupters, many aneurysms with complex geometrics can now be reliably managed. Arteriovenous malformations and fistulae can also benefit from endovascular therapy by embolization using n-butyl cyanoacrylate (NBCA), Onyx, polyvinyl alcohol (PVA), and coils. In this article, we describe the role of endovascular treatment for the most common causes of intracerebral and subarachnoid hemorrhages, particularly ruptured aneurysms and vascular malformations

Multicenter Study for the Treatment of Sidewall versus Bifurcation Intracranial Aneurysms with Use of Woven EndoBridge (WEB)

Background The Woven EndoBridge (WEB) device was explicitly designed for wide-neck intracranial bifurcation aneurysms. Small-scale reports have evaluated the off-label use of WEB devices for the treatment of sidewall aneurysms, with promising outcomes. Purpose To compare the angiographic and clinical outcomes of the WEB device for the treatment of sidewall aneurysms compared with the treatment of bifurcation aneurysms. Materials and Methods A retrospective review of the WorldWideWEB Consortium, a synthesis of retrospective databases spanning from January 2011 to June 2021 at 22 academic institutions in North America, South America, and Europe, was performed to identify patients with intracranial aneurysms treated with the WEB device. Characteristics and outcomes were compared between bifurcation and sidewall aneurysms. Propensity score matching (PSM) was used to match by age, pretreatment ordinal modified Rankin Scale score, ruptured aneurysms, location of aneurysm, multiple aneurysms, prior treatment, neck, height, dome width, daughter sac, and incorporated branch. Results A total of 683 intracranial aneurysms were treated using the WEB device in 671 patients (median age, 61 years [IQR, 53-68 years]; male-to-female ratio, 1:2.5). Of those, 572 were bifurcation aneurysms and 111 were sidewall aneurysms. PSM was performed, resulting in 91 bifurcation and sidewall aneurysms pairs. No significant difference was observed in occlusion status at last follow-up, deployment success, or complication rates between the two groups. Conclusion No significantly different outcomes were observed following the off-label use of the Woven EndoBridge, or WEB, device for treatment of sidewall aneurysms compared with bifurcation aneurysms. The correct characterization of the sidewall aneurysm location, neck angle, and size is crucial for successful treatment and lower retreatment rate. © RSNA, 2022 See also the editorial by Hetts in this issue

Comparing treatment outcomes of various intracranial bifurcation aneurysms locations using the Woven EndoBridge (WEB) device

BACKGROUND: The Woven EndoBridge (WEB) device has Food and Drug Administration approval for treatment of wide-necked intracranial bifurcation aneurysms. The WEB device has been shown to result in adequate occlusion in bifurcation aneurysms overall, but its usefulness in the individual bifurcation locations has been evaluated separately only in few case series, which were limited by small sample sizes. OBJECTIVE: To compare angiographic and clinical outcomes after treatment of bifurcation aneurysms at various locations, including anterior communicating artery (AComA), anterior cerebral artery (ACA) bifurcation distal to AComA, basilar tip, internal carotid artery (ICA) bifurcation, and middle cerebral artery (MCA) bifurcation aneurysms using the WEB device. METHODS: A retrospective cohort analysis was conducted at 22 academic institutions worldwide to compare treatment outcomes of patients with intracranial bifurcation aneurysms using the WEB device. Data include patient and aneurysm characteristics, procedural details, angiographic and functional outcomes, and complications. RESULTS: A total of 572 aneurysms were included. MCA (36%), AComA (35.7%), and basilar tip (18.9%) aneurysms were most common. The rate of adequate aneurysm occlusion was significantly higher for basilar tip (91.6%) and ICA bifurcation (96.7%) aneurysms and lower for ACA bifurcation (71.4%) and AComA (80.6%) aneurysms (p=0.04). CONCLUSION: To our knowledge, this is the most extensive study to date that compares the treatment of different intracranial bifurcation aneurysms using the WEB device. Basilar tip and ICA bifurcation aneurysms showed significantly higher rates of aneurysm occlusion than other locations

Abstract 153: First Pass Effect in Mechanical Thrombectomy for Anterior Circulation Acute Ischemic Stroke is Modified by Procedure Time: Proposal of a New Measure for Thrombectomy Procedures

Abstract only Objective: To determine whether first pass effect (FPE) after mechanical thrombectomy (MT) for anterior circulation large vessel occlusion acute ischemic stroke (LVO-AIS) is modified by procedural time (PT). Methods: The Stroke Thrombectomy and Aneurysm Registry (STAR), a multi-center international dataset, was retrospectively analyzed for anterior circulation LVO-AIS treated by MT who achieved excellent reperfusion (TICI 2c/3). The primary outcome was good functional outcome as defined by a 90-day modified Rankin Scale (mRS) 0-2. The primary study exposure was first pass success (FPS, 1 pass vs ≥2 passes) and the secondary exposure was PT. Logistic regression models were fit-adjusted and marginal effects used to assess the interaction of PT (≤30 vs >30 minutes) and FPS, adjusting for potential confounders including time from last known well to start of MT. Results: A total of 1,310 patients had excellent reperfusion. These patients were divided into two cohorts based on PT: ≤30 minutes (777 patients, 59.3%) and > 30 minutes (533 patients, 40.7%). Good functional outcome was observed in 658 patients (50.2%). The interaction term between FPS and PT was significant (p=0.018). Individuals with FPS in ≤30 minutes had 11.5% higher adjusted predicted probability of good outcome compared with those who required ≥2 passes (58.2% vs. 46.7%, p=0.001). However, there was no significant difference in the adjusted predicted probability of good outcome based on FPS in individuals with PT >30 minutes (p=0.763). This relationship appeared identical in models with PT treated as a continuous variable. Conclusion: In a large, real-world, multi-national dataset, we find that FPE is importantly modified by PT. The added clinical benefit of FPE is lost in longer procedures (>30 minutes). These data argue for a new metric for MT procedures, namely, FPE 30 , that better represents the ideal of fast, complete reperfusion with a single pass of a thrombectomy device