Deconstructing fibrin(ogen) structure.

Fibrinogen and its insoluble degradation product fibrin are pivotal plasma proteins that play important roles in blood coagulation, wound healing, and immune responses. This review highlights research from the last 24 months connecting our progressing view of fibrin(ogen)'s structure, and in particular its conformational flexibility and posttranslational modifications, to its (patho)physiologic roles, molecular interactions, mechanical properties, use as a biomaterial, and potential as a therapeutic target. Recent work suggests that fibrinogen structure is highly dynamic, sampling multiple conformations, which may explain its myriad physiologic functions and the presence of cryptic binding sites.

The impact of von Willebrand factor on fibrin formation and structure unveiled with type 3 von Willebrand disease plasma.

Normally, von Willebrand factor (VWF) remains inactive unless its A1A2 domains undergo a shear stress-triggered conformational change. We demonstrated the capacity of a recombinant A2 domain of VWF to bind and to affect fibrin formation, altering the fibrin clot structure. The data indicated that VWF contains an additional binding site for fibrin in the A2 domain that plays a role in the incorporation of VWF to the polymerizing fibrin.

Full-length αIIbβ3 cryo-EM structure reveals intact integrin initiate-activation intrinsic architecture.

Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryo-EM structures of the full-length αIIbβ3, which covers three distinct states along the activation pathway. Firstly, we obtain the αIIbβ3 structure at 3 Å resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region.

CompARE: study protocol for a phase III randomised controlled platform trial comparing alternative regimens for escalating treatment of intermediate and high-risk oropharyngeal cancer.

Background: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival.

Methods: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention.

Interplay between intrinsic flexibility and sugar coating in Contactin-2 homodimerization.

In this issue of Structure, Chataigner et al. reveal that Contactin-2's homotypic interaction, a glycosylation-dependent process, generates a broad conformational landscape. This structural plasticity, driven by conformational equilibria and sugar coating, facilitates adaptation to diverse ligands and environmental conditions, highlighting its dynamic role in neuronal function.

Randomized Phase 3 Trial of the Hypoxia Modifier Nimorazole Added to Radiation Therapy With Benefit Assessed in Hypoxic Head and Neck Cancers Determined Using a Gene Signature (NIMRAD).

Purpose: Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT).

Methods And Materials: NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689).

Rational design and synthesis of lumican stapled peptides for promoting corneal wound healing.

Purpose: Lumican is a major extracellular matrix (ECM) component in the cornea that is upregulated after injury and promotes corneal wound healing. We have recently shown that peptides designed based on the 13 C-terminal amino acids of lumican (LumC13 and LumC13) are able to recapitulate the effects of lumican on promoting corneal wound healing. Herein we used computational chemistry to develop peptide mimetics derived from LumC13 with increased stability and half-life that are biologically active and non-toxic, thereby promoting corneal wound healing with increased pharmacological potential.

Full-length αIIbβ3 CryoEM structure reveals intact integrin initiate-activation intrinsic architecture.

Integrin αIIbβ3 is the key receptor regulating platelet retraction and accumulation, thus pivotal for hemostasis, and arterial thrombosis as well as a proven drug-target for antithrombotic therapies. Here we resolve the cryoEM structures of the intact full-length αIIbβ3, which covers three distinct states along the activation pathway. Here, we resolve intact αIIbβ3 structure at 3Å resolution, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the head region ligand-binding domain tucked in a specific angle proximity to the TM region.

Systematic mapping of the conformational landscape and dynamism of soluble fibrinogen.

Background: Fibrinogen is a soluble, multisubunit, and multidomain dimeric protein, which, upon its proteolytic cleavage by thrombin, is converted to insoluble fibrin, initiating polymerization that substantially contributes to clot growth. Fibrinogen contains numerous, transiently accessible "cryptic" epitopes for hemostatic and immunologic proteins, suggesting that fibrinogen exhibits conformational flexibility, which may play functional roles in its temporal and spatial interactions. Hitherto, there have been limited integrative approaches characterizing the solution structure and internal flexibility of fibrinogen.

Expression and Characterization of Intein-Cyclized Trimer of Protein A Domain Z.

protein A (SpA) is an IgG Fc-binding virulence factor that is widely used in antibody purification and as a scaffold to develop affinity molecules. A cyclized SpA Z domain could offer exopeptidase resistance, reduced chromatographic ligand leaching after single-site endopeptidase cleavage, and enhanced IgG binding properties by preorganization, potentially reducing conformational entropy loss upon binding. In this work, a Z domain trimer (Z3) was cyclized using protein intein splicing.

Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2.

Allosteric activation and silencing of leukocyte β2-integrins transpire through cation-dependent structural changes, which mediate integrin biosynthesis and recycling, and are essential to designing leukocyte-specific drugs. Stepwise addition of Mg reveals two mutually coupled events for the αXβ2 ligand-binding domain-the αX I-domain-corresponding to allostery establishment and affinity maturation. Electrostatic alterations in the Mg-binding site establish long-range couplings, leading to both pH- and Mg-occupancy-dependent biphasic stability change in the αX I-domain fold.

Comparison and ensemble of 2D and 3D approaches for COVID-19 detection in CT images.

Detecting COVID-19 in computed tomography (CT) or radiography images has been proposed as a supplement to the RT-PCR test. We compare slice-based (2D) and volume-based (3D) approaches to this problem and propose a deep learning ensemble, called IST-CovNet, combining the best 2D and 3D systems with novel preprocessing and attention modules and the use of a bidirectional Long Short-Term Memory model for combining slice-level decisions. The proposed ensemble obtains 90.

COVID-19 anxiety and hygiene status in vocational schools of health services students in Turkey: A multicenter study.

Background: While the coronavirus (COVID-19) pandemic creates fear and anxiety on the students' academic achievement, the risk of an infectious disease may negatively affect education by reducing the concentration ability of students. Thus, it is essential to evaluate the knowledge, behaviors, anxiety levels, and hygiene status of students.

Objective: This study aimed to investigate the knowledge, behavior change, anxiety, and hygiene status of university students about COVID-19.

Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

Background: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control.

Methods: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7).

Neutralizing Aptamers Block S/RBD-ACE2 Interactions and Prevent Host Cell Infection.

The receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike (S) protein plays a central role in mediating the first step of virus infection to cause disease: virus binding to angiotensin-converting enzyme 2 (ACE2) receptors on human host cells. Therefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID-19). Using a target-based selection approach, we developed oligonucleotide aptamers containing a conserved sequence motif that specifically targets S/RBD.

Neutralizing Aptamers Block S/RBD-ACE2 Interactions and Prevent Host Cell Infection.

The receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike (S) protein plays a central role in mediating the first step of virus infection to cause disease: virus binding to angiotensin-converting enzyme 2 (ACE2) receptors on human host cells. Therefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID-19). Using a target-based selection approach, we developed oligonucleotide aptamers containing a conserved sequence motif that specifically targets S/RBD.

Radiotherapy for Head and Neck Cancer: Evaluation of Triggered Adaptive Replanning in Routine Practice.

Purpose And Objective: A proportion of patients receiving radiotherapy for head and neck squamous cell carcinoma (HNSCC) require treatment re-planning. The aim of this retrospective study is to analyze the patients who required re-planning and to identify factors, which may predict need for re-planning.

Materials And Methods: A single center evaluation of all patients receiving radical or adjuvant (chemo)radiotherapy (CRT) for HNSCC between January and December 2016 was undertaken.

Influencing Factors on Radiotherapy Outcome in Stage I-II Glottic Larynx Cancer-A Multicenter Study.

Larynx cancer represents one of the most frequently diagnosed head and neck malignancies, which is most often confined to the glottic area. The aim of this study was to report the oncological outcome and identify prognostic factors in early-stage glottic squamous cell carcinoma treated with radiotherapy. Patients ( = 761) diagnosed and treated in 10 centers between 1990 and 2015 were retrospectively analyzed.