Degrading the key component of the inflammasome: development of an NLRP3 PROTAC.

This study explores PROTACs for NLRP3, the key player in innate immunity. We utilised a thiophene analogue of the NLRP3 inhibitor MCC950 and employed CuAAC chemistry for the assembly of PROTACs bearing various linkers and recruiting three different E3 ligases. Compounds were evaluated in bidirectional thermal stability studies with NLRP3 and E3 ligases.

Initial Multicenter Experience With a Novel Self-Expanding TAVR System in Patients With Aortic Valve Stenosis.

Background: As transcatheter aortic valve replacement is performed increasingly in younger, low-risk patients, the need for commissural alignment and coronary access has increased. Design elements of the JenaValve Trilogy (JVT) transcatheter heart valve (THV) ensure both.

Objectives: This study sought to evaluate the outcome of patients with aortic stenosis (AS) treated with this novel transfemoral, self-expanding THV.

Defining 2 Biologically and Clinically Distinct Groups in Acute Leukemia with a Mixed Phenotype.

A mixed phenotype is characteristic of de novo Mixed Phenotype Acute Leukemia (MPAL) but can also be seen in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with a mixed phenotype and define Acute Myeloid Leukemia with Mixed Phenotype (AML-MP) and MPAL as two distinct groups by characterizing the clinical, genetic, and transcriptomic features.

Femoral or Radial Secondary Access in TAVR: A Subanalysis From the Multicenter PULSE Registry.

Background: Transradial secondary access (TR-SA) may serve as an alternative to the traditional femoral secondary access (TF-SA) for pigtail placement in transcatheter aortic valve replacement (TAVR).

Objectives: The aim of this study was to assess the incidence of secondary access-related vascular complications after TR-SA or TF-SA in TAVR.

Methods: The PULSE (Plug or sUture based vascuLar cloSurE after TAVR) registry retrospectively evaluated data of 10,120 patients who underwent transfemoral TAVR at 10 heart centers from 2016 to 2021.

RNA-binding proteins hnRNPM and ELAVL1 promote type-I interferon induction downstream of the nucleic acid sensors cGAS and RIG-I.

The cytosolic nucleic acid sensors RIG-I and cGAS induce type-I interferon (IFN)-mediated immune responses to RNA and DNA viruses, respectively. So far no connection between the two cytosolic pathways upstream of IKK-like kinase activation has been investigated. Here, we identify heterogeneous nuclear ribonucleoprotein M (hnRNPM) as a positive regulator of IRF3 phosphorylation and type-I IFN induction downstream of both cGAS and RIG-I.

Role of ZFHX4 in orofacial clefting based on human genetic data and zebrafish models.

Orofacial clefting (OFC) is a frequent congenital anomaly and can occur either in the context of underlying syndromes or in isolation (nonsyndromic). The two common OFC phenotypes are cleft lip with/without cleft palate (CL/P) and cleft palate only (CPO). In this study, we searched for penetrant CL/P genes, by evaluating de novo copy number variants (CNV) from an exome sequencing dataset of 50 nonsyndromic patient-parent trios.

Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K.

The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K.

Cryo-EM structure of the human native plasma coagulation factor XIII complex.

The structure of human coagulation factor XIII (FXIII), a heterotetrameric plasma protransglutaminase that covalently cross-links preformed fibrin polymers, remains elusive until today. The heterotetrameric complex is composed of 2 catalytic FXIII-A and 2 protective FXIII-B subunits. Structural etiology underlying FXIII deficiency has so far been derived from crystallographic structures, all of which are currently available for the FXIII-A2 homodimer only.

HMA/VEN treatment modifications and associated outcomes in -mutant AML.

Hypomethylating agents (HMA) and venetoclax (VEN) are commonly used in patients with -mutated (m) acute myeloid leukemia (AML) ineligible for induction chemotherapy. While prior studies demonstrated high response and survival rates with HMA/VEN in m AML, the impact of treatment modifications in real-world settings is unclear. We retrospectively reviewed 89 m AML patients treated with HMA/VEN from January 2018 to June 2023.

Antagonistic nanobodies implicate mechanism of GSDMD pore formation and potential therapeutic application.

Inflammasome activation results in the cleavage of gasdermin D (GSDMD) by pro-inflammatory caspases. The N-terminal domains (GSDMD) oligomerize and assemble pores penetrating the target membrane. As methods to study pore formation in living cells are insufficient, the order of conformational changes, oligomerization, and membrane insertion remained unclear.

Annotated image dataset of fire blight symptoms for object detection in orchards.

The monitoring of plant diseases in nurseries, breeding farms and orchards is essential for maintaining plant health. Fire blight () is still one of the most dangerous diseases in fruit production, as it can spread epidemically and cause enormous economic damage. All measures are therefore aimed at preventing the spread of the pathogen in the orchard and containing an infection at an early stage [1-6].

The SAVED domain of the type III CRISPR protease CalpL is a ring nuclease.

Prokaryotic CRISPR-Cas immune systems detect and cleave foreign nucleic acids. In type III CRISPR-Cas systems, the Cas10 subunit of the activated recognition complex synthesizes cyclic oligoadenylates (cOAs), second messengers that activate downstream ancillary effector proteins. Once the viral attack has been weathered, elimination of extant cOA is essential to limit the antiviral response and to allow cellular recovery.

Structural basis of Cdk7 activation by dual T-loop phosphorylation.

Cyclin-dependent kinase 7 (Cdk7) is required in cell-cycle and transcriptional regulation owing to its function as both a CDK-activating kinase (CAK) and part of transcription factor TFIIH. Cdk7 forms active complexes by associating with Cyclin H and Mat1, and is regulated by two phosphorylations in the activation segment (T loop): the canonical activating modification at T170 and another at S164. Here we report the crystal structure of the human Cdk7/Cyclin H/Mat1 complex containing both T-loop phosphorylations.

Prospective ECG-gated High-Pitch Photon-Counting CT Angiography: Evaluation of measurement accuracy for aortic annulus sizing in TAVR planning.

Purpose: In planning transcatheter aortic valve replacement (TAVR), retrospective cardiac spiral-CT is recommended to measure aortic annulus with subsequent CT-angiography (CTA) to evaluate access routes. Photon-counting detector (PCD)-CT enables to assess the aortic annulus in desired cardiac phases, using prospective ECG-gated high-pitch CTA. The aim of this study was to evaluate the measurement accuracy of aortic annulus using prospective ECG-gated high-pitch CTA against retrospective spiral-CT reference.

Performance of Purpose-Built vs Off-Label Transcatheter Devices for Aortic Regurgitation: The PURPOSE Study.

Background: Severe pure aortic regurgitation (AR) carries a high mortality and morbidity risk, and it is often undertreated because of the inherent surgical risk. Transcatheter heart valves (THVs) have been used off-label in this setting with overall suboptimal results. The dedicated "purpose-built" Jena Valve Trilogy (JVT, JenaValve Technology) showed an encouraging performance, although it has never been compared to other THVs.

CRISPR/Cas9-mediated knock out of ITGB6 in human OSCC cells reduced migration and proliferation ability.

Background: The treatment of oral squamous cell carcinoma (OSCC) remains challenging and survival rates have not been improved significantly over the past decades. Integrins have been recognized driving the cancer progression and high expression levels cause poor outcomes in patients afflicted with OSCC. Integrin αvβ6 and its subunit integrin beta 6 (ITGB6) were discovered to enhance the invasiveness by providing beneficial effects on downstream pathways promoting the cancer progression.

Selective depletion of tumor-infiltrating regulatory T cells with BAY 3375968, a novel Fc-optimized anti-CCR8 antibody.

Regulatory T cells (Tregs) are known to facilitate tumor progression by suppressing CD8+ T cells within the tumor microenvironment (TME), thereby also hampering the effectiveness of immune checkpoint inhibitors (ICIs). While systemic depletion of Tregs can enhance antitumor immunity, it also triggers undesirable autoimmune responses. Therefore, there is a need for therapeutic agents that selectively target Tregs within the TME without affecting systemic Tregs.