In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here, we demonstrate that podoplanin (PDPN) regulated actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor, CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, resulting in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, resulting in an expanded reticular network and enhanced immunity.

Highlights d Increased glial classical complement expression in amyloidosis and tauopathy models d C3 deficiency rescues plaque-proximal synapse loss in PS2APP mice d C3 deficiency mitigates neurodegeneration and neuronal loss in TauP301S mice d C3 protein is increased in brains and cerebrospinal fluid from AD patients

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Blocking dual leucine zipper kinase slows disease progression in animal models of ALS and Alzheimer’s disease.

The usual paradigm for developing kinase inhibitors in oncology is to use a high-affinity proof-of-concept inhibitor with acceptable metabolic properties for key target validation experiments. This approach requires substantial medicinal chemistry and can be confounded by drug toxicity and offtarget activities of the test molecule. As a better alternative, we have developed inducible short-hairpin RNA xenograft models to examine the in vivo efficacy of inhibiting oncogenic BRAF. Our results show that tumor regression resulting from BRAF suppression is inducible, reversible, and tightly regulated in these models. Analysis of regressing tumors showed the primary mechanism of action for BRAF to be increased tumor cell proliferation and survival. In a metastatic melanoma model, conditional BRAF suppression slowed systemic tumor growth as determined by in vivo bioluminescence imaging. Taken together, gain-of-function BRAF signaling is strongly associated with in vivo tumorigenicity, confirming BRAF as an important target for small-molecule and RNA interferencebased therapeutics. (Cancer Res 2006; 66(2): 999-1006)

TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of ␤-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2 ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2 ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/ Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2 ko females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2 ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2 ko brains, and the A␤42:A␤40 ratio was elevated. The amount of soluble, fibrillar A␤ oligomers also increased in PS2APP;Trem2 ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2 ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2 ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of A␤ into dense plaque is an important neuroprotective activity.

Targeting cytotoxic drugs to cancer cells using antibody-drug conjugates (ADCs), particularly those with stable linkers between the drug and the antibody, could be an effective cancer treatment with low toxicity. However, for stable-linker ADCs to be effective, they must be internalized and degraded, limiting potential targets to surface antigens that are trafficked to lysosomes. CD79a and CD79b

Objective-To quantitatively compare aortic curvature and motion with resulting aneurysm location, direction of expansion, and pathophysiological features in experimental abdominal aortic aneurysms (AAAs). Methods and Results-MRI was performed at 4.7 T with the following parameters: (1) 3D acquisition for vessel geometry and (2) 2D cardiac-gated acquisition to quantify luminal motion. Male 24-week-old mice were imaged before and after AAA formation induced by angiotensin II (AngII)-filled osmotic pump implantation or infusion of elastase. AngII-induced AAAs formed near the location of maximum abdominal aortic curvature, and the leftward direction of expansion was correlated with the direction of suprarenal aortic motion. Elastase-induced AAAs formed in a region of low vessel curvature and had no repeatable direction of expansion. AngII significantly increased mean blood pressure (22.7 mm Hg, PϽ0.05), whereas both models showed a significant 2-fold decrease in aortic cyclic strain (PϽ0.05). Differences in patterns of elastin degradation and localization of fluorescent signal from protease-activated probes were also observed. Conclusion-The direction of AngII aneurysm expansion correlated with the direction of motion, medial elastin dissection, and adventitial remodeling. Anterior infrarenal aortic motion correlated with medial elastin degradation in elastaseinduced aneurysms. Results from both models suggest a relationship between aneurysm pathological features and aortic geometry and motion. Key Words: aneurysms Ⅲ angiotensin II Ⅲ magnetic resonance imaging Ⅲ elastase Ⅲ near-infrared fluorescence A bdominal aortic aneurysm (AAA) is a complex disease that leads to significant morbidity and mortality in the United States. 1 AAAs are commonly defined as a 1.5-fold or larger increase in vessel diameter due to a pathological dilation. 2 Diagnosis and monitoring are usually performed using noninvasive ultrasonography, but only surgical options exist to prevent continued vessel growth and reduce the risk of rupture. This "wait-and-see" approach is partially because of a lack of understanding of the mechanisms that lead to AAA development and expansion.As a way to better study disease etiology and progression, murine AAA models have been created that mimic aspects of the human disease. 3,4 In particular, 2 chemically induced murine models have become commonly used. The first model is initiated by subcutaneous systemic delivery of angiotensin II (AngII) into hyperlipidemic apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice, leading to suprarenal AAAs. 3 The predictable formation of these aneurysms above the renal arteries in this model is of particular interest because most human AAAs are infrarenal. The rationale for the development of the second model, induced by intraluminal infusion of elastase into the murine infrarenal aorta, 4 was based on the disrupted nature of elastin in human AAAs. [5][6][7][8] Although both of these models produce AAAs, there are significant differences. The AngII apoE Ϫ/Ϫ model is associated with ...