2-µm double-pulse single-frequency Tm:fiber laser pumped Ho:YLF laser for a space-borne CO2 lidar.

In the framework of space-borne CO2 lidar development, the transmitter is a critical unit. We report on the development and the assessment of performances of a 2-µm single-frequency thulium fiber laser pumped Q-switched Ho:YLF laser. To fulfill the requirements of space-based operation, a master oscillator power amplifier architecture has been chosen, and the oscillator works in double-pulse operation. The transmitter can generate a single-mode dual wavelength emission "ON" and "OFF" around the R30e line of the 20013←00001 band of CO212. It delivers a pair of OFF-ON pulses with 12 mJ and 42 mJ energy, respectively, at a pulse repetition frequency of 303.5 Hz. The pulse energy and central frequency stabilities are especially documented as well as pulse duration, polarization, overall efficiency, beam quality, pointing stability, and spectral purity. The possible limitations by light-induced damage or radiation-induced attenuation on the laser performances are also evaluated.

Evaluation of a HgCdTe e-APD based detector for 2 µm CO2 DIAL application.

Benefiting from close to ideal amplification properties (high gain, low dark current, and low excess noise factor), HgCdTe electron initiated avalanche photodiode (e-APD) technology exhibits state of the art sensitivity, thus being especially relevant for applications relying on low light level detection, such as LIDAR (Light Detection And Ranging). In addition, the tunable gap of the Hg1-xCdxTe alloy enables coverage of the short wavelength infrared (SWIR) and especially the 2 µm spectral range. For these two reasons, a HgCdTe e-APD based detector is a promising candidate for future differential absorption LIDAR missions targeting greenhouse gas absorption bands in SWIR. In this study, we report on the design and evaluation of such a HgCdTe e-APD based detector. The first part focuses on detector architecture and performance. Key figures of merit are: 2.8 µm cutoff wavelength, 200 µm diameter almost circular sensitive area, 185 K operating temperature (thermo-electric cooling), 22 APD gain (at 12 V reverse bias), 360 kΩ transimpedance gain, and 60 fWHz-0.5 noise equivalent power (at 12 V reverse bias). The second part presents an analysis of atmospheric LIDAR signals obtained by mounting the HgCdTe e-APD based detector on the 2 µm differential absorption LIDAR developed at the Laboratoire de Météorologie Dynamique and dedicated to CO2 monitoring. Discussion emphasizes random and systematic errors in LIDAR measurements regarding breadboard detector characterization. In particular, we investigate the influence of parasitic tails in detector impulse response on short range DIAL measurements.

Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.

Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.

Chromatin associated Sin3A is essential for male germ cell lineage in the mouse.

Spermatogenesis is a complex process that requires coordinated proliferation and differentiation of male germ cells. The molecular events that dictate this process are largely unknown, but are likely to involve highly regulated transcriptional control. In this study, we investigate the contribution of chromatin associated Sin3A in mouse germ cell lineage development. Genetic inactivation of Sin3A in the male germline leads to sterility that results from the early and penetrant apoptotic death observed in Sin3A-deleted germ cells, coincident with the reentry in mitosis. Sin3A-deleted testes exhibit a Sertoli-cell only phenotype, consistent with the absolute requirement for Sin3A in germ cells' development and/or viability. Interestingly, transcripts analysis revealed that the expression program of Sertoli cells is altered upon inactivation of Sin3A in germ cells. These studies identified a central role for the mammalian Sin3-HDAC complex in the germ cell lineage, and point to an exquisite transcriptional crosstalk between germ cells and their niche to support fertility in mammals.

A novel mammalian complex containing Sin3B mitigates histone acetylation and RNA polymerase II progression within transcribed loci.

Transcription requires the progression of RNA polymerase II (RNAP II) through a permissive chromatin structure. Recent studies of Saccharomyces cerevisiae have demonstrated that the yeast Sin3 protein contributes to the restoration of the repressed chromatin structure at actively transcribed loci. Yet, the mechanisms underlying the restoration of the repressive chromatin structure at transcribed loci and its significance in gene expression have not been investigated in mammals. We report here the identification of a mammalian complex containing the corepressor Sin3B, the histone deacetylase HDAC1, Mrg15, and the PHD finger-containing Pf1 and show that this complex plays important roles in regulation of transcription. We demonstrate that this complex localizes at discrete loci approximately 1 kb downstream of the transcription start site of transcribed genes, and this localization requires both Pf1's and Mrg15's interaction with chromatin. Inactivation of this mammalian complex promotes increased RNAP II progression within transcribed regions and subsequent increased transcription. Our results define a novel mammalian complex that contributes to the regulation of transcription and point to divergent uses of the Sin3 protein homologues throughout evolution in the modulation of transcription.

The mammalian Sin3 proteins are required for muscle development and sarcomere specification.

The highly related mammalian Sin3A and Sin3B proteins provide a versatile platform for chromatin-modifying activities. Sin3-containing complexes play a role in gene repression through deacetylation of nucleosomes. Here, we explore a role for Sin3 in myogenesis by examining the phenotypes resulting from acute somatic deletion of both isoforms in vivo and from primary myotubes in vitro. Myotubes ablated for Sin3A alone, but not Sin3B, displayed gross defects in sarcomere structure that were considerably enhanced upon simultaneous ablation of both isoforms. Massively parallel sequencing of Sin3A- and Sin3B-bound genomic loci revealed a subset of target genes directly involved in sarcomere function that are positively regulated by Sin3A and Sin3B proteins. Both proteins were coordinately recruited to a substantial number of genes. Interestingly, depletion of Sin3B led to compensatory increases in Sin3A recruitment at certain target loci, but Sin3B was never found to compensate for Sin3A loss. Thus, our analyses describe a novel transcriptional role for Sin3A and Sin3B proteins associated with maintenance of differentiated muscle cells.

Sin3B expression is required for cellular senescence and is up-regulated upon oncogenic stress.

Serial passage of primary mammalian cells or strong mitogenic signals induce a permanent exit from the cell cycle called senescence. A characteristic of senescent cells is the heterochromatinization of loci encoding pro-proliferative genes, leading to their transcriptional silencing. Senescence is thought to represent a defense mechanism against uncontrolled proliferation and cancer. Consequently, genetic alterations that allow senescence bypass are associated with susceptibility to oncogenic transformation. We show that fibroblasts genetically inactivated for the chromatin-associated Sin3B protein are refractory to replicative and oncogene-induced senescence. Conversely, overexpression of Sin3B triggers senescence and the formation of senescence-associated heterochromatic foci. Although Sin3B is strongly up-regulated upon oncogenic stress, decrease in expression of Sin3B is associated with tumor progression in vivo, suggesting that expression of Sin3B may represent a barrier against transformation. Together, these results underscore the contribution of senescence in tumor suppression and suggest that expression of chromatin modifiers is modulated at specific stages of cellular transformation. Consequently, these findings suggest that modulation of Sin3B-associated activities may represent new therapeutic opportunities for treatment of cancers.

The role of blood cultures in the acute evaluation of postoperative fever in arthroplasty patients.

The use of blood cultures to work up fever in postarthroplasty patients was studied retrospectively. Four hundred fifty-three patients done consecutively with a diagnosis-related group 209 discharge diagnosis were studied. One hundred patients (22%) had blood cultures drawn for fever greater than 101 degrees F. Specifically, there were 240 total knee arthroplasty patients with 40 blood cultures drawn. There were 124 total hip arthroplasty patients with 31 blood cultures drawn. One patient with a total knee arthroplasty had positive cultures as did one patient with a total hip arthroplasty. Both were thought to be contaminants, and neither had any sequelae. Blood cultures are expensive and do not add relevant information in the care of postarthroplasty patients.