email terumiks@lbl.gov 2 SUMMARY SATB1 is an important regulator of nuclear architecture that anchors specialized DNA sequences onto its cage-like network and recruits chromatin remodeling/modifying factors to control gene transcription. We studied the role of SATB1 in regulating the coordinated expression of Il5, Il4, and Il13 from the 200kb cytokine gene cluster region of mouse chromosome 11 during T-helper 2 (Th2)-cell activation. We show that upon cell activation, SATB1 is rapidly induced to form a unique transcriptionally-active chromatin structure that includes the cytokine gene region.Chromatin is folded into numerous small loops all anchored by SATB1, is histone H3 acetylated at lysine 9/14, and associated with Th2-specific factors, GATA3, STAT6, c-Maf, the chromatinremodeling enzyme Brg-1, and RNA polymerase II across the 200kb region. Before activation, the chromatin displays some of these features, such as association with GATA3 and STAT6, but these were insufficient for cytokine gene expression. Using RNA interference (RNAi), we show that upon cell activation, SATB1 is not only required for chromatin folding into dense loops, but also for c-Maf induction and subsequently for Il4, Il5, and Il13 transcription. Our results show that SATB1 is an important determinant for chromatin architecture that constitutes a novel higher-order, transcriptionally-active chromatin structure upon Th2-cell activation.

Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly high. Staphylococcus aureus is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including: Staphylococcal abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast, S. aureus intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against S. aureus, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.

Lee CC, Sherman SM. Synaptic properties of thalamic and intracortical inputs to layer 4 of the first-and higher-order cortical areas in the auditory and somatosensory systems. J Neurophysiol 100: 317-326, 2008. First published April 24, 2008 doi:10.1152/jn.90391.2008. The thalamus is an essential structure in the mammalian forebrain conveying information topographically from the sensory periphery to primary neocortical areas. Beyond this initial processing stage, "higherorder" thalamocortical connections have been presumed to serve only a modulatory role, or are otherwise functionally disregarded. Here we demonstrate that these "higher-order" thalamic nuclei share similar synaptic properties with the "first-order" thalamic nuclei. Using whole cell recordings from layer 4 neurons in thalamocortical slice preparations in the mouse somatosensory and auditory systems, we found that electrical stimulation in all thalamic nuclei elicited large, glutamatergic excitatory postsynaptic potentials (EPSPs) that depress in response to repetitive stimulation and that fail to activate a metabotropic glutamate response. In contrast, the intracortical inputs from layer 6 to layer 4 exhibit facilitating EPSPs. These data suggest that higher-order thalamocortical projections may serve a functional role similar to the first-order nuclei, whereas both are physiologically distinct from the intracortical layer 6 inputs. These results suggest an alternate route for information transfer between cortical areas via a corticothalamocortical pathway.

This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.

Despite the functional importance of the medial geniculate body (MGB) in normal hearing, many aspects of its projections to auditory cortex are unknown. We analyzed the MGB projections to thirteen auditory areas in the cat using two retrograde tracers to investigate thalamocortical nuclear origins, topography, convergence, and divergence. MGB divisions and auditory cortex areas were defined independently of the connectional results using architectonic, histochemical, and immunocytochemical criteria. Each auditory cortex area received a unique pattern of input from several MGB nuclei; and these patterns of input identify four groups of cortical areas distinguished by their putative functional affiliations: tonotopic, non-tonotopic, multisensory, and limbic. Each family of areas received projections from a functionally related set of MGB nuclei; some nuclei project to only a few a few areas (e.g., the MGB ventral division to tonotopic areas), and others project to all areas (e.g., the medial division input to every auditory cortical areas and to other regions). Projections to tonotopic areas had fewer nuclear origins than those to multisensory or limbicaffiliated fields. All projections were organized topographically, even those from non-tonotopic nuclei. The few divergent neurons (mean: 2%) are consistent with a model of multiple segregated streams ascending to auditory cortex. The expanded cortical representation of MGB auditory, multisensory, and limbic affiliated streams appears to be a primary facet of forebrain auditory function. The emergence of several auditory cortex representations of characteristic frequency may be a functional multiplication of the more limited maps in the MGB. This expansion suggests emergent cortical roles consistent with the divergence of thalamocortical connections.

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The mammalian auditory cortex (AC) is essential for computing the source and decoding the information contained in sound. Knowledge of AC corticocortical connections is modest other than in the primary auditory regions, nor is there an anatomical framework in the cat for understanding the patterns of connections among the many auditory areas. To address this issue, we investigated cat AC connectivity in thirteen auditory regions. Retrograde tracers were injected in the same area or in different areas to reveal the areal and laminar sources of convergent input to each region. Architectonic borders were established in Nissl and SMI-32 immunostained material. We assessed the topography, convergence, and divergence of the labeling. Intrinsic input constituted >50% of the projection cells in each area, and extrinsic inputs were strongest from functionally related areas. Each area received significant convergent ipsilateral input from several fields (5 to 8; mean 6). These varied in their laminar origin and projection density. Major extrinsic projections were preferentially from areas of the same functional type (tonotopic to tonotopic, non-tonotopic to non-tonotopic, limbic-related to limbic-related, multisensory-to-multisensory), while smaller projections link areas belonging to different groups. Branched projections between areas were <2% with deposits of two tracers in an area or in different areas. All extrinsic projections to each area were highly and equally topographic and clustered. Intrinsic input arose from all layers except layer I, and extrinsic input had unique, area-specific infragranular and supragranular origins. The many areal and laminar sources of input may contribute to the complexity of physiological responses in AC and suggest that many projections of modest size converge within each area rather than a simpler area-to-area serial or hierarchical pattern of corticocortical connectivity.