NF-κB Inducing Kinase Attenuates Colorectal Cancer by Regulating Noncanonical NF-κB Mediated Colonic Epithelial Cell Regeneration.

BACKGROUND & AIMS: Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-κB-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/differentiation via noncanonical NF-κB signaling that is unique from canonical NF-kB signaling. METHODS: Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis were initiated in whole-body NIK knockout mice (Nik-/-) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium. RESULTS: Human transcriptomic data revealed dysregulated noncanonical NF-kB signaling. In vitro studies evaluating Nik-/- crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of Nik-/- cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, Nik-/- mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammation-induced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (NikΔCEC). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (NikΔMYE). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (RelAΔMYE) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (RelAΔCEC). CONCLUSIONS: Dysregulated noncanonical NF-κB signaling is associated with the development of colorectal cancer in a tissue-dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.

Interspecific differences in the effects of masking and distraction on anti-predator behavior in suburban anthropogenic noise.

Predation is a common threat to animal survival. The detection of predators or anti-predator communication signals can be disrupted by anthropogenic noise; however, the mechanism by which responses are affected is unclear. Masking and distraction are the two hypotheses that have emerged as likely explanations for changes in behavior in noise. Masking occurs when the signal and noise fall within the same sensory domain; noise overlapping the energy in the signal reduces signal detection. Distraction can occur when noise in any sensory domain contributes to a greater cognitive load, thereby reducing signal detection. Here, we used a repeated measures field experiment to determine the relative contributions of masking and distraction in mediating reduced anti-predator responses in noise. We recorded the approaches and vocalizations of black-capped chickadees (Poecile atricapillus), tufted titmice (Baeolophus bicolor), and white-breasted nuthatches (Sitta carolinensis) to both visual and acoustic cues of predator presence, either with or without simultaneous exposure to anthropogenic noise. Titmice increased their calling to both visual and acoustic cues of predator presence. However, there was no significant effect of noise on the calling responses of titmice regardless of stimulus modality. Noise appeared to produce a distraction effect in chickadees; however, this effect was small, suggesting that chickadees may be relatively unaffected by low levels of anthropogenic noise in suburban environments. White-breasted nuthatch calling behavior was affected by the interaction of the modality of the predator stimulus and the noise condition. Nuthatches had a delayed response to the predator presentations, with a greater calling rate following the presentation of the acoustic stimulus in quiet compared to the presentation of the acoustic stimulus in noise. However, there was no difference in calling rate between the quiet and noise conditions for the visual stimulus. Together this suggests that even moderate levels of noise have some masking effect for white-breasted nuthatches. We suggest that the mechanisms through which noise influences anti-predator behavior may depend on the social roles, foraging ecology and auditory capabilities of each species.

The developmental roots of neurodegeneration.

Neurodegenerative disorders can alter neural circuitry long before symptoms appear, but the path from early changes to later pathologies is obscure. In this issue of Neuron, Capizzi et al. (2021) show how early axonal growth defects in Huntington's disease create vulnerability to later degeneration.

Comparison of Fontan Surgical Options for Patients with Apicocaval Juxtaposition.

Apicocaval juxtaposition (ACJ) is a rare form of viscerocardiac malpositions in association with single-ventricle congenital heart defects. The Fontan surgery is the common palliation, and possible surgical options include ipsilateral, contralateral, and intra-atrial conduits. Concerns include lower hemodynamic performances or risks of conduit compression by the cardiac mass. This study investigates the hemodynamics and clinical outcomes of ACJ patients and potential surgical improvements. Ten consecutive ACJ patients were included, along with a reference cohort of ten non-ACJ patients. Magnetic resonance images were acquired at 6 ± 0.6 year follow-up for anatomical analysis and hemodynamic assessments using computational fluid dynamics. Metrics of interest are deformation index (DI), indexed power loss (iPL), and hepatic flow distribution (HFDoff). A "virtual" surgery was performed to explore potential hemodynamic improvements using a straightened conduit. DI for ACJ patients fell within the DI range of non-ACJ patients. Contralateral conduits had insignificantly higher iPL (0.070 [0.032,0.137]) than ipsilateral conduits (0.041 [0.013,0.095]) and non-ACJ conduits (0.034 [0.011,0.061]). HFDoff was similar for the ipsilateral (21 [12,35]), contralateral (26 [7,41]), and non-ACJ Fontan conduits (17 [0,48]). Virtual surgery demonstrated that a straightened conduit reduced HFDoff and iPL for the contralateral and ipsilateral conduits, potentially leading to improved clinical outcomes. In this limited sample, the hemodynamic performance of ACJ patients was not significantly different from their non-ACJ counterparts. The use of a straightened conduit option could potentially improve patient outcomes. Additionally, the fear of significant compression of conduits for ACJ patients was unsupported.