Meckel's diverticulum: A rare and missed cause of adult gastrointestinal bleed.

Our report details a rare case of gastrointestinal bleeding in an adult male from Meckel's diverticulum. Diagnostic tests were negative except for technetium-99m pertechnetate scintigraphy with SPECT/CT, highlighting importance of diverse modalities.

An epilepsy-associated CILK1 variant compromises KATNIP regulation and impairs primary cilia and Hedgehog signaling.

Mutations in human CILK1 (ciliogenesis associated kinase 1) are linked to ciliopathies and epilepsy. Homozygous point and nonsense mutations that extinguish kinase activity impair primary cilia function, whereas mutations outside the kinase domain are not well understood. Here, we produced a knock-in mouse equivalent of the human CILK1 A615T variant identified in juvenile myoclonic epilepsy (JME). This residue is in the C-terminal region of CILK1 separate from the kinase domain. Mouse embryo fibroblasts (MEF) with either heterozygous or homozygous A612T mutant alleles exhibited a higher ciliation rate, shorter individual cilia and up-regulation of ciliary Hedgehog signaling. Thus, a single A612T mutant allele was sufficient to impair primary cilia and ciliary signaling in MEFs. Gene expression profiles of wild type versus mutant MEFs revealed profound changes in cilia-related molecular functions and biological processes. CILK1 A615T mutant protein was not increased to the same level as the wild type protein when co-expressed with scaffold protein KATNIP (katanin-interacting protein). Our data show that KATNIP regulation of a JME-associated single residue variant of CILK1 is compromised and this impairs the maintenance of primary cilia and Hedgehog signaling.

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma.

Virtually all patients with BRAF-mutant melanoma develop resistance to MAPK inhibitors largely through nonmutational events. Although the epigenetic landscape is shown to be altered in therapy-resistant melanomas and other cancers, a specific targetable epigenetic mechanism has not been validated. Here, we evaluated the corepressor for element 1-silencing transcription factor (CoREST) epigenetic repressor complex and the recently developed bivalent inhibitor corin within the context of melanoma phenotype plasticity and therapeutic resistance. We found that CoREST was a critical mediator of the major distinct melanoma phenotypes and that corin treatment of melanoma cells led to phenotype reprogramming. Global assessment of transcript and chromatin changes conferred by corin revealed specific effects on histone marks connected to epithelial-mesenchymal transition-associated (EMT-associated) transcription factors and the dual-specificity phosphatases (DUSPs). Remarkably, treatment of BRAF inhibitor-resistant (BRAFi-R) melanomas with corin promoted resensitization to BRAFi therapy. DUSP1 was consistently downregulated in BRAFi-R melanomas, which was reversed by corin treatment and associated with inhibition of p38 MAPK activity and resensitization to BRAFi therapies. Moreover, this activity was recapitulated by the p38 MAPK inhibitor BIRB 796. These findings identify the CoREST repressor complex as a central mediator of melanoma phenotype plasticity and resistance to targeted therapy and suggest that CoREST inhibitors may prove beneficial for patients with BRAFi-resistant melanoma.

The Scaffold Protein KATNIP Enhances CILK1 Control of Primary Cilia.

The primary cilium functions as a cellular sensory organelle and signaling antenna that detects and transduces extracellular signals. Mutations in the human gene CILK1 (ciliogenesis associated kinase 1) cause abnormal cilia elongation and faulty Hedgehog signaling, associated with developmental disorders and epilepsy. CILK1 is a protein kinase that requires dual phosphorylation of its TDY motif for activation and its extended C-terminal intrinsically disordered region (IDR) mediates targeting to the basal body and substrate recognition. Proteomics previously identified katanin-interacting protein (KATNIP), also known as KIAA0556, as a CILK1 interacting partner. In this study we discovered that CILK1 colocalizes with KATNIP at the basal body and the CILK1 IDR is sufficient to mediate binding to KATNIP. Deletion analysis of KATNIP shows one of three domains of unknown function (DUF) is required for association with CILK1. KATNIP binding with CILK1 drastically elevated CILK1 protein levels and TDY phosphorylation in cells. This resulted in a profound increase in phosphorylation of known CILK1 substrates and suppression of cilia length. Thus, KATNIP functions as a regulatory subunit of CILK1 that potentiates its actions. This advances our understanding of the molecular basis of control of primary cilia.

Is it the unexpected experience that keeps them coming back? Group climate and session attendance examined between groups, between members, and between sessions.

Attending group therapy sessions is necessary for a group member to have a chance at receiving benefit from the intervention. Group members' perceptions of their group's climate has been linked with important group member outcomes, including session attendance. On the basis of the writings of Curran and Bauer (2011), the current study examined group members' longitudinal ratings of session engagement and decomposed them into between-groups, between-members, and between-sessions components. These components were then used to examine the relationship between group members' ratings of an engaged group climate in the previous session and their attendance the following session. Session attendance in 573 group sessions for 91 group members in 14 Taiwanese counseling groups was modeled in a 3-level hierarchical model (sessions within group members, within groups). Contrary to our hypotheses, between-groups, between-members, and between-sessions components of engagement were not related to session attendance. However, there was a significant interaction between the between-members and between-sessions components of session engagement and group size in predicting session attendance. The likelihood of attendance increased when group members who, on average, rated sessions as being low in engagement uncharacteristically rated a previous session as high in engagement. The likelihood of attendance also increased when group members who, on average, rated sessions as high in engagement uncharacteristically rated the previous session as low in engagement. Larger group sizes amplified these effects. Expectancy (dis)confirmation theory is used to explain these results. Theoretical, research, and clinical implications are discussed.