BMAL1-HIF2α heterodimers contribute to ccRCC.

Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene is higher in ccRCC than in healthy kidneys, unlike in other tumor types.

Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA.

Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal DNA to gain access or employ alternative DNA-binding modes with smaller footprints, they preferentially access solvent-exposed motifs near the entry/exit sites, and frequently interact with histones. The extent of TF-histone interactions, in turn, depends on the motif location on the nucleosome, the type of DNA-binding fold, and adjacent domains present.

BMAL1-HIF2α heterodimers contribute to ccRCC.

Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene is higher in ccRCC than in healthy kidneys, unlike in other tumor types.

DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD.

Design principles for cyclin K molecular glue degraders.

Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928.

From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation.

Thalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates.

Analysis of transmission-related third-generation cephalosporin-resistant Enterobacterales by electronic data mining and core genome multi-locus sequence typing.

Background: To contain intra-hospital transmission of third-generation cephalosporin-resistant Enterobacterales (3GCR-E), contact isolation precautions are recommended.

Aim: To quantify transmissions of 3GCR Escherichia coli and 3GCR Klebsiella pneumoniae within a hospital.

Methods: An automated outbreak detection system (AODS) was used to identify clusters (N≥2) of 3GCR Enterobacterales for the years 2016, 2018 and 2020.

Orphan quality control shapes network dynamics and gene expression.

All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb interactions between network components often result in disease, but how the composition and dynamics of complex networks are established remains poorly understood. Here, we identify the E3 ligase UBR5 as a signaling hub that helps degrade unpaired subunits of multiple transcriptional regulators that act within a network centered on the c-Myc oncoprotein.

Cooperation between bHLH transcription factors and histones for DNA access.

The basic helix-loop-helix (bHLH) family of transcription factors recognizes DNA motifs known as E-boxes (CANNTG) and includes 108 members. Here we investigate how chromatinized E-boxes are engaged by two structurally diverse bHLH proteins: the proto-oncogene MYC-MAX and the circadian transcription factor CLOCK-BMAL1 (refs. ).

Readout of histone methylation by Trim24 locally restricts chromatin opening by p53.

The genomic binding sites of the transcription factor (TF) and tumor suppressor p53 are unusually diverse with regard to their chromatin features, including histone modifications, raising the possibility that the local chromatin environment can contextualize p53 regulation. Here, we show that epigenetic characteristics of closed chromatin, such as DNA methylation, do not influence the binding of p53 across the genome. Instead, the ability of p53 to open chromatin and activate its target genes is locally restricted by its cofactor Trim24.

Enhancing emotion regulation.

Emotion regulation (ER) refers to the process of modulating an affective experience or response. Objectives: This is a systematic review of the research on therapist methods to facilitate patient ER, including affect-focused, experiential methods that aim to enhance immediate patient emotion regulation, and structured psychoeducation, skills training in ER. A total of 10 studies of immediate and intermediate outcomes of emotion regulation methods were examined.

A deep dive into degrader-induced protein-protein interfaces.

Targeted protein degradation (TPD) relies on a comprehensive understanding of interfaces between hijacked E3 ligases and their substrates. In vitro techniques often do not capture the interaction dynamics. Recently, Hanzl et al.

Recognition of the CCT5 di-Glu degron by CRL4 is dependent on TRiC assembly.

Assembly Quality Control (AQC) E3 ubiquitin ligases target incomplete or incorrectly assembled protein complexes for degradation. The CUL4-RBX1-DDB1-DCAF12 (CRL4 ) E3 ligase preferentially ubiquitinates proteins that carry a C-terminal double glutamate (di-Glu) motif. Reported CRL4 di-Glu-containing substrates include CCT5, a subunit of the TRiC chaperonin.

Enhancing working alliance through positive emotional experience: A cross-lag analysis.

Although psychotherapy research has traditionally focused on decrease in distress, emotion research suggests the important role of positive emotional experience in healing and growing. The present study investigates the relationship between positive emotional experiences and working alliance. We chose to investigate this relationship in accelerated experiential dynamic psychotherapy (AEDP), taking advantage of the modality's focus on both negative and positive emotional experiences.

The long-term outcome of accelerated experiential dynamic psychotherapy: 6- and 12-month follow-up results.

Accelerated experiential dynamic psychotherapy (AEDP; Fosha, 2000, 2021b) is an integrative, healing-oriented, mind-body, affect-focused therapy. A posttreatment outcome study demonstrated AEDP's effectiveness (Iwakabe et al., 2020) on a variety of measures of psychological functioning.

Quality control of protein complex assembly by the ubiquitin-proteasome system.

The majority of human proteins operate as multimeric complexes with defined compositions and distinct architectures. How the assembly of these complexes is surveyed and how defective complexes are recognized is just beginning to emerge. In eukaryotes, over 600 E3 ubiquitin ligases form part of the ubiquitin-proteasome system (UPS) which detects structural characteristics in its target proteins and selectively induces their degradation.

RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1.

The chromatin-binding protein 53BP1 promotes DNA repair by orchestrating the recruitment of downstream effectors including PTIP, RIF1, and shieldin to DNA double-strand break sites. While we know how PTIP recognizes 53BP1, the molecular details of RIF1 recruitment to DNA-damage sites remains undefined. Here, we report that RIF1 is a phosphopeptide-binding protein that directly interacts with three phosphorylated 53BP1 epitopes.

Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report.

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms.