Transcription factors of the nuclear factor–κB/rel (NF-κB) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by Fas or tumor necrosis factor type α (TNF), IEX- 1L, is described here. Its transcription induced by TNF was decreased in cells with defective NF-κB activation, rendering them sensitive to TNF-induced apoptosis, which was abolished by transfection with IEX- 1L. In support, overexpression of antisense IEX- 1L partially blocked TNF-induced expression of IEX -1L and sensitized normal cells to killing. This study demonstrates a key role of IEX- 1L in cellular resistance to TNF-induced apoptosis.

Members of the tumor necrosis factor receptor (TNFR) superfamily are important for cell growth and survival. In addition to providing costimulatory signals for cell proliferation, ligation of both TNFR1 and Fas can result in programmed cell death or apoptosis. The underlying mechanism requires an intact 80-aa stretch present in the cytoplasmic tails of both TNFR1 and Fas, termed the death domain (DD). Here we show that CD27, a member of the TNFR family, expressed on discrete subpopulations of T and B cells and known to provide costimulatory signals for T and B cell proliferation and B cell Ig production, can also induce apoptosis. Co-crosslinking of surface Ig receptors along with ligation of CD27 augments CD27-mediated apoptosis. Unlike TNFR1 and Fas, the cytoplasmic tail of CD27 is relatively short and lacks the DD. Using the yeast two-hybrid system, we have cloned a novel protein (Siva) that binds to the CD27 cytoplasmic tail. It has a DD homology region, a box-B-like ring finger, and a zinc finger-like domain. Overexpression of Siva in various cell lines induces apoptosis, suggesting an important role for Siva in the CD27-transduced apoptotic pathway.

Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)–biomimetic liposomes encapsulating 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine–induced humoral and CD8+ T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP–adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8+ T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP–mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.

Objective To characterize the functional neuroanatomy of late-life depression (LLD) by probing for both episodic and persistent alterations in the executive-control circuit of elderly adults. Design Event-related fMRI data were collected while participants performed an executive-control task. Setting Participants were recruited through a depression-treatment study within the Pittsburgh Intervention Research Center for Late-Life Mood Disorders. Participants 13 non-depressed elderly comparison participants and 13 LLD patients. Intervention The depressed patients underwent imaging before initiating and after completing 12 weeks of paroxetine. Measurements Regional fMRI activity was assessed in the dorsolateral prefrontal cortex (dLPFC: BA9 and BA46 bilaterally) and the dorsal anterior cingulate cortex (dACC). Functional connectivity was assessed by correlating the fMRI time-series in the dLPFC and dACC. Results Both depressed and comparison participants performed the task as expected, with greater response latency during high versus low-load trials. The response-latency load-effect did not differ between groups. In contrast to the null findings for behavioral data, pre-treatment, depressed patients showed diminished activity in the dLPFC (BA46 left, t(25)=1.9, p=.035) and diminished functional connectivity between the dLPFC and dACC. Moreover, right dLPFC (BA46 right, t(25)=2.17, p<.02) showed increased activity after treatment. Conclusions These results support a model of both episodic and persistent neurobiologic components of LLD. The altered functional connectivity, perhaps due to vascular damage to frontal white matter, appears to be persistent. Further, at least some of the pre-frontal hypoactivity (in the right dLPFC) appears to be an episodic characteristic of acute depression amenable to treatment.

No abstract

White matter hyperintensities (WMH), commonly found on T2-weighted FLAIR brain MR images in the elderly, are associated with a number of neuropsychiatric disorders, including vascular dementia, Alzheimer's disease, and late-life depression. Previous MRI studies of WMHs have primarily relied on the subjective and global (i.e., full-brain) ratings of WMH grade. In the current study we implement and validate an automated method for quantifying and localizing WMHs. We adapt a fuzzy connected algorithm to automate the segmentation of WMHs and use a demons-based image registration to automate the anatomic localization of the WMHs using the Johns Hopkins University White Matter Atlas. The method is validated using the brain MR images acquired from eleven elderly subjects with late-onset late-life depression (LLD) and eight elderly controls. This dataset was chosen because LLD subjects are known to have significant WMH burden. The volumes of WMH identified in our automated method are compared with the accepted gold standard (manual ratings). A significant correlation of the automated method and the manual ratings is found (P<0.0001), thus demonstrating similar WMH quantifications of both methods. As has been shown in other studies e.g. (Taylor, et al. 2003)), we found there was a significantly greater WMH burden in the LLD subjects versus the controls for both the manual and automated method. The effect size was greater for the automated method, suggesting that it is a more specific measure. Additionally, we describe the anatomic localization of the WMHs in LLD subjects as well as in the control subjects, and detect the regions of interest (ROIs) specific for the WMH burden of LLD patients. Given the emergence of large neuroimage databases, techniques, such as that described here, will allow for a better understanding of the relationship between WMHs and neuropsychiatric disorders.

No abstract

Diffusion weighted images (DWIs) are commonly acquired with Echo-planar imaging (EPI). B0 inhomogeneities affect EPI by producing spatially nonlinear image distortions. Several strategies have been proposed to correct EPI distortions including B 0 field mapping (B 0 M) and image registration. In this study, an experimental framework is proposed to evaluation the performance of different EPI distortion correction methods in improving DTderived quantities. A deformable registration based method with mutual information metric and cubic B-spline modeled constrained deformation field (BSP) is proposed as an alternative when B 0 mapping data are not available. BSP method is qualitatively and quantitatively compared to B 0 M method using the framework. Both methods can successful reduce EPI distortions and significantly improve the quality of DT-derived quantities. Overall, B 0 M was clearly superior in infratentorial regions including brainstem and cerebellum, as well as in the ventral areas of the temporal lobes while BSP was better in all rostral brain regions.