Susceptibility to Crohn's disease (CD), a complex inflammatory disease involving the small intestine, is controlled by up to 32 loci1. One CD risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG162. It is not known how Atg16L1 or autophagy contributes to intestinal biology or CD pathogenesis. To address these questions we generated and characterized mice that are hypomorphic for Atg16L1 protein expression, and validated conclusions based on studies in these mice by analyzing intestinal tissues that we collected from CD patients carrying the CD risk allele of ATG16L1. We show that Atg16L1 is a bona fide autophagy protein. Within the ileal epithelium, both Atg16L1 and a second essential autophagy protein Atg5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell which functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment3. Atg16L1 and Atg5-deficient Paneth cells exhibited striking abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to Atg16L1-deficient Paneth cells including increased expression of genes involved in PPAR signaling and lipid metabolism, acute phase reactants, as well as two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, CD patients homozygous for the ATG16L1 CD risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy protein-deficient mice and expressed increased levels of leptin protein. Thus, Atg16L1, and likely the process of autophagy, play their role within the intestinal epithelium of mice and CD patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.

The colonic epithelial lining undergoes constant replacement, driven by epithelial stem cells in crypts of Lieberkü hn. Stem cells lost because of damage or disease can be replaced by adjacent crypts that undergo fission. The close proximity of an extraordinary number of luminal microbes creates a challenge for this repair process; infection must be prevented while immune system activation and epithelial stem cell genetic damage must be minimized. To understand the factors that modulate crypt/stem cell replacement in the mouse colon, we developed an in vivo acute injury system analogous to punch biopsy of the skin. In contrast to epidermal stem cells, colonic epithelial progenitors did not migrate over the wound bed. Instead, their proliferative expansion was confined to crypts adjacent to wound beds and was delayed to the latter phase of healing. This increased epithelial proliferation was coincident with the infiltration of Trem2 expressing macrophages and increased expression of IL-4 and IL-13 in the wound bed. Interestingly, Trem2 ؊/؊ mice displayed slow and incomplete wound healing of colonic mucosal injuries. We found the latter phase of healing in Trem2 ؊/؊ mice showed a diminished burst of epithelial proliferation, increased expression of IFN-␥ and TNF-␣, diminished expression of IL-4 and IL-13, and increased markers of classical macrophage activation. Ablation of these cytokines in injured WT and Trem2 ؊/؊ mice demonstrated that their expression ultimately determined the rate and nature of wound healing. These studies show that Trem2 signaling is an important pathway to promote healing of wounds in the colon where stem cell replacement is necessary.biopsy injury ͉ epithelium ͉ macrophage ͉ stem cell ͉ wound healing

We identified cellular and molecular mechanisms within the stem cell niche that control the activity of colonic epithelial progenitors (ColEPs) during injury. Here, we show that while WT mice maintained ColEP proliferation in the rectum following injury with dextran sodium sulfate, similarly treated Myd88 -/-(TLR signaling-deficient) and prostaglandin-endoperoxide synthase 2 -/-(Ptgs2 -/-) mice exhibited a profound inhibition of epithelial proliferation and cellular organization within rectal crypts. Exogenous addition of 16,16-dimethyl PGE 2 (dmPGE 2 ) rescued the effects of this injury in both knockout mouse strains, indicating that Myd88 signaling is upstream of Ptgs2 and PGE 2 . In WT and Myd88 -/-mice, Ptgs2 was expressed in scattered mesenchymal cells. Surprisingly, Ptgs2 expression was not regulated by injury. Rather, in WT mice, the combination of injury and Myd88 signaling led to the repositioning of a subset of the Ptgs2-expressing stromal cells from the mesenchyme surrounding the middle and upper crypts to an area surrounding the crypt base adjacent to ColEPs. These findings demonstrate that Myd88 and prostaglandin signaling pathways interact to preserve epithelial proliferation during injury using what we believe to be a previously undescribed mechanism requiring proper cellular mobilization within the crypt niche.

This study examined differences between children with autism and control children in the ability to follow another person's direction of gaze. In Expt 1, children with autism, Down syndrome and normally developing children were given two tasks. The gaze monitoring task (GMT) measured the child's spontaneous tendency to follow gaze direction in response to another person's change of head and eye movement. The visual perspective taking task (VPT) measured the child's ability to compute and report what the other person was looking at, when instructed to do so. Results showed that the majority of Down syndrome and normal children passed both tasks. In contrast, children with autism failed the GMT. This failure could not have been due to a lack of the relevant geometric skill, as they passed the VPT. This geometric skill was examined further in Expt 2, using a fine discrimination task which tested children's ability to discriminate degrees of change in the orientation of gaze. Children with autism were well within their developmental age level on this task. These results indicate a dissociation between (impaired) spontaneous monitoring and (intact) geometric analysis of gaze‐direction.

The 15-item Interpersonal Needs Questionnaire (an assessment of thwarted belongingness and perceived burdensomeness) should be incorporated into suicide risk assessment. Among psychiatric inpatients, greater thwarted belongingness and perceived burdensomeness, as separate predictors, were associated with increased levels of distress due to suicide ideation, desire for death, and desire for suicide. The highest scores on thwarted belongingness and perceived burdensomeness indicated a 79% to 95% chance of experiencing an elevated level of distress due to suicide ideation, desire for death, or desire for suicide. Recommended clinical cutoff scores were provided. For example, thwarted belongingness cutoff score of 31 and perceived burdensomeness cutoff score of 22 maximized the sensitivity and specificity of the INQ to detect some level of desire for suicide.