Mechanisms of progression of chronic renal diseases, a major healthcare burden, are poorly understood. Angiotensin II (AngII), the major renin-angiotensin system effector, is known to be involved in renal deterioration, but the molecular pathways are still unknown. Here, we show that mice overexpressing a dominant negative isoform of epidermal growth factor receptor (EGFR) were protected from renal lesions during chronic AngII infusion. Transforming growth factor-alpha (TGF-alpha) and its sheddase, TACE (also known as ADAM17), were induced by AngII treatment, TACE was redistributed to apical membranes and EGFR was phosphorylated. AngII-induced lesions were substantially reduced in mice lacking TGF-alpha or in mice given a specific TACE inhibitor. Pharmacologic inhibition of AngII prevented TGF-alpha and TACE accumulation as well as renal lesions after nephron reduction. These findings indicate a crucial role for AngII-dependent EGFR transactivation in renal deterioration and identify in TACE inhibitors a new therapeutic strategy for preventing progression of chronic renal diseases.

We study the problem of generating plausible interpretations of a scene from a collection of line segments automatically extracted from a single indoor image. We show that we can recognize the three dimensional structure of the interior of a building, even in the presence of occluding objects. Several physically valid structure hypotheses are proposed by geometric reasoning and verified to find the best fitting model to line segments, which is then converted to a full 3D model. Our experiments demonstrate that our structure recovery from line segments is comparable with methods using full image appearance. Our approach shows how a set of rules describing geometric constraints between groups of segments can be used to prune scene interpretation hypotheses and to generate the most plausible interpretation.

Cerebral and myocardial ischemia, two of the leading causes of morbidity and mortality worldwide, are associated with inflammation that can lead to multiple organ failure and death. High-mobility group box 1(HMGB1), a recently described mediator of lethal systemic inflammation, has been detected in individuals with severe sepsis and hemorrhagic shock, but its role during ischemic injury in humans is unknown. To determine whether systemic HMGB1 levels are elevated after ischemic injury, a prospective observational study was performed in subjects with a diagnosis of either Acute Coronary Syndrome (ACS) or cerebral vascular ischemia (transient ischemic attack or cerebral vascular accident). Subjects (n, 16; age [mean], 67+/-16.3 years) were enrolled in the North Shore-LIJ emergency department within 24 h of symptom onset. Blood samples were collected, and HMGB1 levels analyzed by Western blot analysis using previously described methods (Wang et al. Science. 1999). Control samples were obtained from healthy age- and sex-matched volunteers (n, 16; age [mean], 68+/-15.8 years). Here, we report that serum HMGB1 levels were significantly elevated in both myocardial ischemia subjects (myocardial control serum HMGB1, 1.94+/-2.05 ng/mL, vs. myocardial ischemia serum HMGB1, 159+/-54.3 ng/mL; P<0.001); and in cerebral ischemia subjects (cerebral control serum HMGB1, 16.8+/-10.9 ng/mL, vs. cerebral ischemia serum HMGB1, 218+/-18.8 ng/mL; P<0.001). These results suggest that systemic HMGB1 levels are elevated in human ischemic disease.

EGF family growth factors, including transforming growth factor-alpha (TGFalpha), amphiregulin (AR), and heparin-binding EGF (HB-EGF), are invariably expressed as transmembrane precursors that are cleaved at one or more sites in the extracellular domain to release soluble growth factor. Considerable attention has focused on the identification of proteases responsible for these processing events. We previously implicated tumor necrosis factor-alpha converting enzyme (TACE/ADAM17) in the generation of soluble TGFalpha from its transmembrane precursor, proTGFalpha. Here, we review our findings that primary keratinocytes from Tace(deltaZn/deltaZn) mice, which express a nonfunctional TACE, released dramatically lower levels of soluble TGFalpha compared to their normal counterparts, even though TGFalpha mRNA and cell-associated protein levels were similar in the two cell populations. Restoration of TACE activity in Tace(deltaZn/deltaZn) cells increased shedding of TGFalpha species, including the mature, 6-kDa protein. Further, exogenous TACE enzyme accurately cleaved the N-terminal processing site of proTGFalpha in cell lysates, as well as both physiologic sites of a soluble proTGFalpha ectodomain. TACE also accurately cleaved peptide substrates corresponding to the processing sites of several additional EGF family members, and restoration of TACE activity enhanced the shedding of soluble AR and HB-EGF proteins from Tace(deltaZn/deltaZn) cells. Finally, reduction of functional TACE gene dosage greatly exacerbated the open-eye defect of Egfr(wa-2/wa-2) newborns, which is regulated by redundant actions of several EGF family ligands. The implications of these results for the biology of the EGF family and TACE are discussed.

This study investigated the benefits of cultural exposure for transracially adopted (TRA) Korean children's developmental understanding of being Korean. Fifty TRA Korean children living in the United States were interviewed to assess their understanding of the implications of their Korean status for peer relations and personal identities, using a model of perspective-taking ability (PTA). Results showed cultural exposure and chronological age were significant predictors of children's PTA for being Korean. Cultural exposure had a slightly stronger relationship with PTA development for younger children than older ones. Comparison with another sample suggested that nonadopted native Korean children in the United States for an average of 25 months achieved levels of PTA at earlier ages did TRA children but that level of cultural exposure mediated these age differences.

Methods now exist for analyzing previously taken clinical computed tomography (CT) scans to measure a dual-energy X-ray absorptiometry (DXA)-equivalent bone mineral density (BMD) at the hip and a finite element analysis-derived femoral strength. We assessed the efficacy of this "biomechanical CT" (BCT) approach for identifying patients at high risk of incident hip fracture in a large clinical setting. Using a case-cohort design sampled from 111,694 women and men aged 65 or older who had a prior hip CT scan, a DXA within 3 years of the CT, and no prior hip fracture, we compared those with subsequent hip fracture (n = 1959) with randomly selected sex-stratified controls (n = 1979) and analyzed their CT scans blinded to all other data. We found that the age-, race-, and body mass index (BMI)-adjusted hazard ratio (HR; per standard deviation) for femoral strength was significant before (women: HR = 2.8, 95% confidence interval [CI] 2.2-3.5; men: 2.8, 2.1-3.7) and after adjusting also for the (lowest) hip BMD T-score by BCT (women: 2.1, 1.4-3.2; men: 2.7, 1.6-4.6). The hazard ratio for the hip BMD T-score was similar between BCT and DXA for both sexes (women: 2.1, 1.8-2.5 BCT versus 2.1, 1.7-2.5 DXA; men: 2.8, 2.1-3.8 BCT versus 2.5, 2.0-3.2 DXA) and was higher than for the (lowest) spine/hip BMD T-score by DXA (women: 1.6, 1.4-1.9; men: 2.1, 1.6-2.7). Compared with the latter as a clinical-practice reference and using both femoral strength and the hip BMD T-score from BCT, sensitivity for predicting hip fracture was higher for BCT (women: 0.66 versus 0.59; men: 0.56 versus 0.48), with comparable respective specificity (women: 0.66 versus 0.67; men: 0.76 versus 0.78). We conclude that BCT analysis of previously acquired routine abdominal or pelvic CT scans is at least as effective as DXA testing for identifying patients at high risk of hip fracture. © 2018 American Society for Bone and Mineral Research.

Dysregulation of the centrosome duplication cycle has been implicated in tumorigenesis. Our previous work has shown that the human papillomavirus type 16 (HPV-16) E7 oncoprotein rapidly induces aberrant centrosome and centriole duplication in normal human cells. We report here that HPV E7-induced abnormal centriole duplication is specifically abrogated by a small molecule CDK inhibitor, indirubin-3 0 -oxime (IO), but not a kinase-inactive derivative. Importantly, normal centriole duplication was not markedly affected by IO, and the inhibitory effects were observed at concentrations that did not affect the G1/S transition of the cell division cycle. Depletion of CDK2 by siRNA similarly abrogated HPV E7-induced abnormal centrosome duplication and ectopic expression of CDK2 in combination with cyclin E or cyclin A could rescue the inhibitory effect of IO. IO treatment also reduced the steady-state level of aneuploid cells in HPV-16 E7-expressing cell populations. Our results suggest that cyclin/CDK2 activity is critically involved in abnormal centrosome duplication induced by HPV-16 E7 oncoprotein expression, but may be dispensable for normal centrosome duplication and cell cycle progression.

Background: The World Health Organization recommends periodic mass antibiotic distributions to reduce the ocular strains of chlamydia that cause trachoma, the world's leading cause of infectious blindness. Their stated goal is to control infection, not to completely eliminate it. A single mass distribution can dramatically reduce the prevalence of infection. However, if infection is not eliminated in every individual in the community, it may gradually return back into the community, so often repeated treatments are necessary. Since public health groups are reluctant to distribute antibiotics indefinitely, we are still in need of a proven long-term rationale. Here we use mathematical models to demonstrate that repeated antibiotic distributions can eliminate infection in a reasonable time period.