Peut-on être blâmé pour ses croyances? : le déontologisme épistémique face au problème de l'involontarisme doxastique

Peut-on parfois être blâmé pour ses croyances ? Selon les partisans du déontologisme épistémique, la pratique ordinaire consistant à blâmer et critiquer les gens pour leurs croyances est tout à fait légitime. Toutefois, d’autres philosophes soutiennent que malgré son omniprésence dans la vie de tous les jours, le blâme doxastique n’est jamais approprié. En effet, selon l’argument à partir de l’involontarisme doxastique, nous ne pouvons jamais être blâmés pour nos croyances puisque (1) nous pouvons être blâmés pour une croyance seulement si elle est sous notre contrôle volontaire et (2) nos croyances ne sont jamais sous notre contrôle volontaire. Le but de ce mémoire est de déterminer si les déontologistes peuvent répondre de manière convaincante à cet argument. Autrement dit, pouvons-nous parfois être blâmés pour nos croyances malgré ce qu’en disent les anti-déontologistes, ou faut-il leur donner raison et rejeter la pratique du blâme doxastique ? Pour répondre à cette question, je commence par clarifier l’argument anti-déontologiste en précisant la teneur de sa thèse centrale : l’involontarisme doxastique. Par la suite, je passe en revue différentes stratégies qui ont été proposées par des représentants du déontologisme pour défendre le blâme doxastique contre cet argument. Devant l’échec de ces réponses, je suggère une défense alternative du déontologisme selon laquelle l’involontarisme doxastique n’est pas incompatible avec le blâme doxastique. Si cette réponse est concluante, alors nous n’avons pas à donner raison aux anti-déontologistes : nous pouvons parfois être blâmés pour nos croyances.

Topo IIIalpha and BLM act within the Fanconi anemia pathway in response to DNA-crosslinking agents

The Bloom protein (BLM) and Topoisomerase IIIalpha are found in association with proteins of the Fanconi anemia (FA) pathway, a disorder manifesting increased cellular sensitivity to DNA crosslinking agents. In order to determine if the association reflects a functional interaction for the maintenance of genome stability, we have analyzed the effects of siRNA-mediated depletion of the proteins in human cells. Depletion of Topoisomerase IIIalpha or BLM leads to increased radial formation, as is seen in FA. BLM and Topoisomerase IIIalpha are epistatic to the FA pathway for suppression of radial formation in response to DNA interstrand crosslinks since depletion of either of them in FA cells does not increase radial formation. Depletion of Topoisomerase IIIalpha or BLM also causes an increase in sister chromatid exchanges, as is seen in Bloom syndrome cells. Human Fanconi anemia cells, however, do not demonstrate increased sister chromatid exchanges, separating this response from radial formation. Primary cell lines from mice defective in both Blm and Fancd2 have the same interstrand crosslink-induced genome instability as cells from mice deficient in the Fancd2 protein alone. These observations demonstrate that the association of BLM and Topoisomerase IIIalpha with Fanconi proteins is a functional one, delineating a BLM-Topoisomerase IIIalpha-Fanconi pathway that is critical for suppression of chromosome radial formation.

Functional analysis of BLAP75, a BLM-associated protein

Bloom syndrome (BS) is an autosomal recessive disorder characterized by dwarfism, immunodeficiency, impaired fertility, and most importantly, early development of a broad range of cancers. The hallmark of BS cells is hyper-recombination, characterized by a drastically elevated frequency of sister chromatid exchange (SCE). BLM, the gene mutated in BS, encodes a DNA helicase of the RecQ protein family. BLM is thought to participate in several DNA transactions and to interact with many proteins involved in DNA replication, recombination, and repair. However, the precise function of BLM and the BLM-dependent anti-tumor mechanism remain obscure. ^ A novel protein, BLAP75 (BLM-associated polypeptide, 75KD), was identified to form an evolutionarily conserved complex with BLM and DNA topoisomerase IIIα (Topo IIIα). Our work demonstrates that loss of BLAP75 destabilized BLM and Topo IIIα proteins. BLAP75 colocalized with BLM in subnuclear foci in response to DNA damage and the recruitment of BLM to these foci was BLAP75-dependent. Moreover, depletion of BLAP75 by siRNA resulted in an elevated SCE rate similar to cells depleted of BLM by siRNA. In addition, RNAi-mediated silencing of BLAP75 greatly diminished cell viability. This cellular deficiency was rescued by expression of wild type BLAP75 but not BLAP75 with mutated conserved domain III, which abrogated the interaction between BLAP75, BLM and Topo IIIα, suggesting that the integrity of BLM-Topo IIIα-BLAP75 complex might be critical for cell survival. Finally, I found that BLAP75 was phosphorylated during mitosis and upon various DNA-damaging agents, implying that BLAP75 might also function in mitosis and DNA damage response. ^ Taken together, this study has defined BLAP75 as an integral component of the BLM complex to maintain genome stability. Our findings provide insights into the molecular mechanisms of the BLM helicase pathway and tumorigenesis process associated with these mechanisms. ^

The DNA Helicase Activity of BLM Is Necessary for the Correction of the Genomic Instability of Bloom Syndrome Cells

Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by growth deficiency, immunodeficiency, genomic instability, and the early development of cancers of many types. BLM, the protein encoded by BLM, the gene mutated in BS, is localized in nuclear foci and absent from BS cells. BLM encodes a DNA helicase, and proteins from three missense alleles lack displacement activity. BLM transfected into BS cells reduces the frequency of sister chromatid exchanges and restores BLM in the nucleus. Missense alleles fail to reduce the sister chromatid exchanges in transfected BS cells or restore the normal nuclear pattern. BLM complements a phenotype of a Saccharomyces cerevisiae sgs1 top3 strain, and the missense alleles do not. This work demonstrates the importance of the enzymatic activity of BLM for its function and nuclear localization pattern.

Land management systems : BLM faces risks in completing the Automated Land and Mineral Record System : report to the Chairman and Ranking Minority Member, Subcommittee on Interior and Related Agencies, Committee on Appropriations, House of Representatives /

"B-271929"--P. 1.

Utah BLM statewide wilderness environmental impact statement : draft /

Vol. 1 includes index.

Land management systems : status of BLM's actions to improve information technology management : report to the Subcommittee on Interior and Related Agencies, Committee on Appropriations, House of Representatives /

"B-284472"--P. 3.

BLM intensive wilderness inventory, Utah : final decision on wilderness study areas.

Cover title.

Opportunity and challenge : the story of BLM /

Mode of access: Internet.

Rangeland management : BLM's hot desert grazing program merits reconsideration : report to the Chairman, Subcommittee on National Parks and Public Lands, Committee on Interior and Insular Affairs, House of Representatives /

"B-245031"--P. [1].

Utah BLM statewide wilderness environmental impact statement : final /

"BLM-UT-ES-90-002-4332"--P. [4] of cover.

Utah BLM statewide wilderness environmental impact statement : draft /

"Int. no. DES 86-1"--V. 1, p. i.

Disruption of the BLM gene in ATM-null DT40 cells does not exacerbate either phenotype

Bloom syndrome and ataxia-telangiectasia are autosomal recessive human disorders characterized by immunodeficiency, genome instability and predisposition to develop cancer. Recent data reveal that the products of these two genes, BLM and ATM, interact and function together in recognizing abnormal DNA structures. To investigate the function of these two molecules in DNA damage recognition, we generated double knockouts of ATM(-/-) BLM-/- in the DT40 chicken B-lymphocyte cell line. The double mutant cells were viable and exhibited a variety of characteristics of both ATM(-/-) and BLM-/- cells. There was no evidence for exacerbation of either phenotype; however, the more extreme radiosensitivity seen in ATM(-/-) and the elevated sister chromatid exchange seen in BLM-/- cells were retained in the double mutants. These results suggest that ATM and BLM have largely distinct roles in recognizing different forms of damage in DNA, but are also compatible with partially overlapping functions in recognizing breaks in radiation-damaged DNA.

Annotated record of the detailed examination of Mn deposits from BLM Leg Alpha Cruise, R/V Kana Keoki off the south-western coastal area of the Gulf of Mexico off Texas

The BLM-OCS (Bureau of Land Management-Outer Continental Shelf) program was designed to establish chemical, biological, and geological baseline on the South Texas Continental Shelf. The focus for the geological program was to establish the nature and amount of the suspended sediment in the water column, of the Holocene sediments on the shelf, and to identify and locate regions of geology conditions which may be hazardous to OCS operations. To accomplish these goals three cruises were planned. The report constitutes results of the first cruise. The results of these cruises associated with the subsequent laboratory analysis, enabled to establish a detailed baseline in order to provide significant geologic and biologic data for environmental assessment. Dredges recovered are available at University of Texas (see: BLM/OCS South Texas Outer Continental Shelf (STOCS) Project Sediment Data http://www.ngdc.noaa.gov/docucomp/page?xml=NOAA/NESDIS/NGDC/MGG/Geology/iso/xml/G02888.xml&view=getDataView&header=none).

Annotated record of the detailed examination of Mn deposits from BLM Leg Bravo Cruise, R/V Kana Keoki off the south-western coastal area of the Gulf of Mexico off Texas

The BLM-OCS (Bureau of Land Management-Outer Continental Shelf) program was designed to establish chemical, biological, and geological baseline on the South Texas Continental Shelf. The focus for the geological program was to establish the nature and amount of the suspended sediment in the water column, of the Holocene sediments on the shelf, and to identify and locate regions of geology conditions which may be hazardous to OCS operations. To accomplish these goals three cruises were planned. The report constitutes results of the second cruise. The results of these cruises associated with the subsequent laboratory analysis, enabled to establish a detailed baseline in order to provide significant geologic and biologic data for environmental assessment. Dredges recovered are available at University of Texas (see: BLM/OCS South Texas Outer Continental Shelf (STOCS) Project Sediment Data http://www.ngdc.noaa.gov/docucomp/page?xml=NOAA/NESDIS/NGDC/MGG/Geology/iso/xml/G02888.xml&view=getDataView&header=none).