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Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Following repeal of the Don't Ask Don't Tell Policy, nearly one million lesbian, gay, and bisexual veterans and service members may increasingly seek access to Veterans Affairs services (G. Gates, 2004; G. J. Gates, 2010). Limited data exist regarding lesbian, gay, bisexual, transgender (LGBT) military personnel posing a unique challenge to clinicians and healthcare systems serving veterans with evidence-based and culturally relevant practice. In an effort to fill this information void, participatory program evaluation is used to inform recommendations for LGBT-affirmative health care systems change in a post-DADT world.

Harm reduction is fundamentally a movement intended to empower the patient and consumer of health services. This project applied harm reduction theory as a strategy to empower collaborating community partners and researchers to overcome their preconceptions about each other in order to create a successful HIV prevention intervention and evaluation study for injection drug using women. The Women's Options for Risk Reduction through Knowledge of Self (WORKS) intervention program offered a series of four HIV prevention workshops, in conjunction with sexually transmitted infection (STI) and HIV counseling and testing to female injection drug users (IDUs) or the partners of IDUs. This community collaboration was to integrate the strengths of researchers and service providers in a comprehensive approach to prevention evaluation. In this collaborative research context, capacity building meant developing the long-term goal, explicit commitment to and integration of evaluation into the overall operation of a HIV prevention service delivery organization. The WORKS Intervention collaboration's aim was to improve the capacity of community-based organizations (CBOs) to use research-based data on HIV risk taking behavior and prevention strategies to provide effective interventions and services and effectively evaluate their efforts. Barriers to successful planning, implementation, and evaluation are presented with the strategies used to overcome them. Intervention effectiveness results from the process evaluation are presented in the context of prevention and research capacity development in CBOs.

Fanconi anemia (FA) is a hereditary disease of unknown pathogenic mechanisms, although mutations in seven different genes can be causative. Six of these genes have been cloned and sequenced. Only slight homology to the DNA of any other known gene has been found with the exception of FANCG which is identical to XRCC9. The function of these genes, including XRCC9, is presently unknown. Since pADP ribosyl transferase (pADPRT) plays a role in apoptosis, and apoptosis is affected in FA cells, we studied the correlation between pADPRT and FA cells. We reinvestigated the previously reported lack of pADPRT activity in fibroblasts from patients with Fanconi anemia. Here we describe the role of the lower redox potential of FA cells and demonstrate that this is an efficient strategy in the prevention of cell death due to the lack of energy under oxidative stress. This strategy is advantageous for the cells under the nonreplicative condition of confluency in which the risk of mutation is low and the prevention of apoptosis permits cell survival. pADPRT is not diminished to the same extent in all complementation groups of FA. It is prominent in FANCA, FANCG and FANCF cells, indicating that these genes control pADPRT diminution. Our experiments suggest that the pADPRT level is linked with the oxidoreduction reactions seen in FA.

The cause of the molecular defect of Fanconi anemia (FA) remains unknown. Cells from patients with FA exert an elevated spontaneous chromosomal instability which is further triggered by mitomycin C. The induced lability is reduced by overexpression of thioredoxin which is not the case for spontaneous instability. However, both are eliminated by overexpression of thioredoxin cDNA with an added nuclear localization signal. This implies that thioredoxin is lacking in the nuclei of FA cells. The total thioredoxin content in all FA cells tested is reduced. The resultant lack of nuclear thioredoxin can be the explanation for the major symptomatology in FA. Since thioredoxin is known to be the reactive cofactor of ribonucleotid reductase its shortcoming reduces the supply of deoxyribonucleotides thus hindering the DNA and replication repair with resultant chromosomal breaks. Furthermore, depression of tyrosine hydroxylase, the key enzyme of melanine synthesis, could be the basis for the pathognomotic 'café au lait' spots of FA. The observation of thioredoxin reduction in FA cells permits insight into the molecular phathophysiology of FA.

Fanconi anemia (FA) is an autosomal recessive chromosomal breakage disorder characterized by developmental defects, hypersensitivity toward oxygen and DNA crosslinking agents, and susceptibility to cancer. An increased level of reactive oxygen intermediates and an increased level of 8-oxoguanine in FA cells point to a defective oxygen metabolism. Recent investigations showed that FA cells from several complementation groups have a reduced capacity to repair oxidatively damaged DNA. One major enzyme involved in the repair of oxidative DNA lesions is the ribosomal protein S3. Previous reports implied a role for the ribosomal protein S3 in DNA repair in FA cells. However, a more detailed analysis of the ribosomal protein S3 in FA cells from complementation groups A-E could not confirm this. DNA analysis and Western blot analysis did not show significant differences in ribosomal protein S3 between FA cells and cells from healthy individuals. Furthermore, even the overexpression of the ribosomal protein S3 did not reduce the chromosomal instability of FA cells., (Copyright 1999 Academic Press.)

Fanconi anemia (FA) is an autosomal recessive disorder characterized by skeletal abnormalities, pancytopenia and a marked predisposition to cancer. FA cells exhibit chromosomal instability and hypersensitivity towards oxygen and cross-linking agents such as diepoxybutane and mitomycin C. An increased level of reactive oxygen intermediates and an elevation of 8-oxoguanine in FA cells point to a defective oxygen metabolism in FA cells. We investigated the repair activity of oxidatively damaged DNA in lymphoblastoid cells from FA patients of complementation groups A-E. The repair activity for oxidatively damaged DNA was significantly reduced in lymphoblastoid cell lines of complementation groups B-E. Complementation of the FA-C cell line with the wild type FA-C gene restored the repair activity to normal. This indicates that the FA-C protein participates in the repair of oxidatively damaged DNA.

The ERCC2 (excision repair cross-complementing rodent repair group 2) gene product is involved in transcription-coupled repair as an integral member of the basal transcription factor BTF2/TFIIH complex. Defects in this gene can result in three distinct human disorders, namely the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. We report the comparative analysis of 91.6 kb of new sequence including 54.3 kb encompassing the human ERCC2 locus, the syntenic region in the mouse (32.6 kb), and a further 4.7 kb of sequence 3' of the previously reported ERCC2 region in the hamster. In addition to ERCC2, our analysis revealed the presence of two previously undescribed genes in all three species. The first is centromeric (in the human) to ERCC2 and is most similar to the kinesin light chain gene in sea urchin. The second gene is telomeric (in the human) to ERCC2 and contains a motif found in ankyrins, some cell cycle proteins, and transcription factors. Multiple EST matches to this putative new gene indicate that it is expressed in several human tissues, including breast. The identification and description of two new genes provides potential candidate genes for disorders mapping to this region of 19q13.2.