Local bulk S-matrix elements and CFT singularities

We give a procedure for deriving certain bulk S-matrix elements from corresponding boundary correlators. These are computed in the plane wave limit, via an explicit construction of certain boundary sources that give bulk wavepackets. A critical role is played by a specific singular behavior of the lorentzian boundary correlators. It is shown in examples how correlators derived from the bulk supergravity exhibit the appropriate singular structure, and reproduce the corresponding S-matrix elements. This construction thus provides a nontrivial test for whether a given boundary conformal field theory can reproduce bulk physics, and where it does, supplies a prescription to extract bulk S-matrix elements in the plane wave limit.Comment: 24 pages, 3 fig

Nuclear receptor agonist-driven modification of inflammation and amyloid pathology enhances and sustains cognitive improvements in a mouse model of Alzheimer's disease

BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disorder characterized by pathological hallmarks of beta-amyloid plaque deposits, tau pathology, inflammation, and cognitive decline. Treatment remains a clinical obstacle due to lack of effective therapeutics. Agonists targeting nuclear receptors, such as bexarotene, reversed cognitive deficits regardless of treatment duration and age in murine models of AD. While bexarotene demonstrated marked efficacy in decreasing plaque levels following short-term treatment, prolonged treatment did not modulate plaque burden. This suggested that plaques might reform in mice treated chronically with bexarotene and that cessation of bexarotene treatment before plaques reform might alter amyloid pathology, inflammation, and cognition in AD mice. METHODS: We utilized one-year-old APP/PS1 mice that were divided into two groups. We treated one group of mice for 2 weeks with bexarotene. The other group of mice was treated for 2 weeks with bexarotene followed by withdrawal of drug treatment for an additional 2 weeks. Cognition was evaluated using the novel-object recognition test either at the end of bexarotene treatment or the end of the withdrawal period. We then analyzed amyloid pathology and microgliosis at the conclusion of the study in both groups. RESULTS: Bexarotene treatment enhanced cognition in APP/PS1 mice similar to previous findings. Strikingly, we observed sustained cognitive improvements in mice in which bexarotene treatment was discontinued for 2 weeks. We observed a sustained reduction in microgliosis and plaque burden following drug withdrawal exclusively in the hippocampus. CONCLUSIONS: Our findings demonstrate that bexarotene selectively modifies aspects of neuroinflammation in a region-specific manner to reverse hippocampal-dependent cognitive deficits in AD mice and may provide insight to inform future studies with nuclear receptor agonists

The in-flight calibration of the Hubble Space Telescope fine guidance sensors, 2 (a success story)

The Hubble Space Telescope's fine guidance sensors (FGS's) are unique in the performance levels being attempted; spacecraft control and astrometric research with accuracies better than 3 milli-arcseconds (mas) are the ultimate goals. This paper presents a review of the in-flight calibration of the sensors, describing both the algorithms used and the results achieved to date. The work was done primarily in support of engineering operations related to spacecraft pointing and control and secondarily in support of the astrometric science calibration effort led by the Space Telescope Astrometry Team. Calibration items of principal interest are distortion, sensor magnification, and relative alignment. An initial in-flight calibration of the FGS's was performed in December 1990; this calibration has been used operationally over the past few years. Followup work demonstrated that significant, unexpected temporal variations in the calibration parameters are occurring; provided good characterization of the variation; and set the stage for a distortion calibration designed to achieve the full design accuracy for one of the FGS's. This full distortion calibration, using data acquired in January 1993, resulted in a solution having single-axis residuals with a standard deviation of 2.5 mas. Scale and alignment calibration results for all of the FGS's have been achieved commensurate with the best ground-based astrometric catalogs (root-mean-square error approximately 25 mas). A calibration monitoring program has been established to allow regular updates of the calibration parameters as needed

Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies

Alzheimer's disease (AD) is a prominent neurodegenerative disorder characterized by deposition of β-amyloid (Aβ)-containing extracellular plaques, accompanied by a microglial-mediated inflammatory response, that leads to cognitive decline. Microglia perform many disease-modifying functions such as phagocytosis of plaques, plaque compaction, and modulation of inflammation through the secretion of cytokines. Microglia are reliant upon colony-stimulating factor receptor-1 (CSF1R) activation for survival. In AD mouse models, chronic targeted depletion of microglia via CSF1R antagonism attenuates plaque formation in early disease but fails to alter plaque burden in late disease. It is unclear if acute depletion of microglia during the peak period of plaque deposition will alter disease pathogenesis, and if so, whether these effects are reversible upon microglial repopulation. To test this, we administered the CSF1R antagonist PLX5622 to the 5XFAD mouse model of AD at four months of age for approximately one month. In a subset of mice, the drug treatment was discontinued, and the mice were fed a control diet for an additional month. We evaluated plaque burden and composition, microgliosis, inflammatory marker expression, and neuritic dystrophy. In 5XFAD animals, CSF1R blockade for 28 days depleted microglia across brain regions by over 50%, suppressed microgliosis, and reduced plaque burden. In microglial-depleted AD animals, neuritic dystrophy was enhanced, and increased diffuse-like plaques and fewer compact-like plaques were observed. Removal of PLX5622 elicited microglial repopulation and subsequent plaque remodeling, resulting in more compact plaques predominating microglia-repopulated regions. We found that microglia limit diffuse plaques by maintaining compact-like plaque properties, thereby blocking the progression of neuritic dystrophy. Microglial repopulation reverses these effects. Collectively, we show that microglia are neuroprotective through maintenance of plaque compaction and morphologies during peak disease progression

Holographic Description of AdS Cosmologies

To gain insight in the quantum nature of the big bang, we study the dual field theory description of asymptotically anti-de Sitter solutions of supergravity that have cosmological singularities. The dual theories do not appear to have a stable ground state. One regularization of the theory causes the cosmological singularities in the bulk to turn into giant black holes with scalar hair. We interpret these hairy black holes in the dual field theory and use them to compute a finite temperature effective potential. In our study of the field theory evolution, we find no evidence for a "bounce" from a big crunch to a big bang. Instead, it appears that the big bang is a rare fluctuation from a generic equilibrium quantum gravity state.Comment: 34 pages, 8 figures, v2: minor changes, references adde

Is string theory a theory of quantum gravity?

Some problems in finding a complete quantum theory incorporating gravity are discussed. One is that of giving a consistent unitary description of high-energy scattering. Another is that of giving a consistent quantum description of cosmology, with appropriate observables. While string theory addresses some problems of quantum gravity, its ability to resolve these remains unclear. Answers may require new mechanisms and constructs, whether within string theory, or in another framework.Comment: Invited contribution for "Forty Years of String Theory: Reflecting on the Foundations," a special issue of Found. Phys., ed. by G 't Hooft, E. Verlinde, D. Dieks, S. de Haro. 32 pages, 5 figs., harvmac. v2: final version to appear in journal (small revisions

The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease

BACKGROUND: The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. METHODS: In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2. TREM2 expression, myeloid cell responses to amyloid deposition, plaque burden, and neuritic dystrophy were assessed at 4 months of age. RESULTS: AD mice heterozygous for the Trem2 R47H allele exhibited reduced total Trem2 mRNA expression, reduced TREM2 expression around plaques, and reduced association of myeloid cells with plaques. These results were comparable to AD mice lacking one copy of Trem2. AD mice heterozygous for the Trem2 R47H allele also showed reduced myeloid cell responses to amyloid deposition, including a reduction in proliferation and a reduction in CD45 expression around plaques. Expression of the Trem2 R47H variant also reduced dense core plaque number but increased plaque-associated neuritic dystrophy. CONCLUSIONS: These data suggest that the AD-associated TREM2 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques

Exploratory Case‐Control Analysis of Psychosocial Factors and Adult Periodontitis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141163/1/jper1060.pd

Multiparametric MRI-Based Radiomic Models for Early Prediction of Response to Neoadjuvant Systemic Therapy in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is often treated with neoadjuvant systemic therapy (NAST). We investigated if radiomic models based on multiparametric Magnetic Resonance Imaging (MRI) obtained early during NAST predict pathologic complete response (pCR). We included 163 patients with stage I-III TNBC with multiparametric MRI at baseline and after 2 (C2) and 4 cycles of NAST. Seventy-eight patients (48%) had pCR, and 85 (52%) had non-pCR. Thirty-six multivariate models combining radiomic features from dynamic contrast-enhanced MRI and diffusion-weighted imaging had an area under the receiver operating characteristics curve (AUC) \u3e 0.7. The top-performing model combined 35 radiomic features of relative difference between C2 and baseline; had an AUC = 0.905 in the training and AUC = 0.802 in the testing set. There was high inter-reader agreement and very similar AUC values of the pCR prediction models for the 2 readers. Our data supports multiparametric MRI-based radiomic models for early prediction of NAST response in TNBC