Genes,agents and the institution of responsible action

The concern of this paper is with how the accounts of human beings and their behaviour now emerging from genetics, genomics and the new human biotechnology should be related to traditional accounts in which we identify ourselves as responsible agents, capable of choice, who normally act freely and voluntarily. The paper addresses these apparently competing accounts in terms of their functions and modes of use, and thereby arrives at a general solution to this current version of the ancient problem of free will and determinism. The causal scientific discourse of genetics and the everyday discourse of responsibility and choice do different things for us, it suggests, and should not be regarded as articulating conflicting theories. Whilst the former is oriented to the task of naturalistic explanation, the latter is predominantly, if not entirely, a medium of communication through which we affect each other and thereby mutually regulate our conduct. If this is indeed the case, then interesting implications follow concerning the proper relationship of the two kinds of account, which need no longer be regarded as incompatible with each other. And insights emerge into both the limitations and the profound importance of the contribution that genetics and genomics seem destined to make to the understanding of human behaviour.     

Deoxyuridine triphosphatase: A potential site of interaction with pyrimidine nucleotide analogues

Deoxyuridine triphosphatase has been purified from cultured human lymphoid cells in high yield and stable form by a relatively simple procedure. The properties differed somewhat from those reported previously, e.g. apparent K_m, molecular weight, and effects of divalent metals. No other naturally occurring dNTP or NTP serves as substrate, however, the enzyme may be an important site of interaction with intracellular derivatives of analogues of dUrd. It is shown here that deoxyuridine triphosphatase acts on araUTP, 6-azadUTP, 2′-FdUTP, and 2′,3′-dideoxyUTP, but the enzyme has no effect on 5-C1dUTP, 5-BrdUTP, 5-HgdUTP and dUrd-5′[α-thio]triphosphate. For the preparation of one of the analogues, the enzyme, trans-N-deoxyribosylase, from Lactobacillus, was used to prepare the deoxynucleoside from the base, a procedure that may have general usefulness.     

How reliable are dung counts for estimating elephant numbers?

Dung counts are the most commonly used techniques for estimating elephant numbers in forests, yet there is considerable scepticism concerning their accuracy. Published accounts of dung counts show that they give estimates similar to those from other methods for vertebrates ranging in size from lizards to elephants. For ungulates, macropods and elephants there are strong correlations between estimates from dung counts and other methods. Thus, dung counts are as accurate or inaccurate as other methods for estimating vertebrate numbers, including elephants. Dung counts for elephants give estimates that are as precise as, and sometimes more precise than, those from aerial surveys of elephants. This is because the variance in dung density is usually low and results in a lower than expected variance for the final elephant estimate when combined with the variances of defecation and decay rates. Dung counts may be more appropriate than aerial surveys for monitoring small or declining elephant populations.     

Hip fractures in healthy patients: operative delay versus prognosis.

One hundred and forty five women who had undergone hemiarthroplasty for a subcapital fracture of the femoral neck but who were otherwise fit were studied to determine whether undue delay between injury and operation influenced their social circumstances three months after surgery. The median delay for those patients who showed good rehabilitation at three months was 29 hours, but for those who showed poor rehabilitation it was 57 hours. This difference was significant. It is suggested that a subcapital fracture in an otherwise fit elderly patient should therefore be regarded as a surgical emergency.     

Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis.