Evolution of genital masculinization: why do female hyaenas have such a large 'penis'?

In place of a 'normal' external vagina, female spotted hyaenas bear a fully erectile, penis-sized clitoris through which they mate and give birth. Early hypotheses on the evolution of this organ have focused on its signal function, because the erect phallus is used by both sexes as part of submission or appeasement displays. However, a quite different hypothesis is suggested by recent data on the ecological function of female aggressiveness, and on the role of androgens in the development of aggressiveness and male genital development. In this view, the female phallus may have originated as an unselected side effect of selection for androgen-mediated bellicosity, a major advantage in the extraordinarily competitive hyaena social system.     

Pushing cancer cells to commit suicide: Is 072RB,the new BH3 mimetic,up to the job?

It has been known since the early 90s that apoptosis is the mode of death of cancer cells during chemotherapy.1 Propensity of cells to undergo apoptosis is modulated by the balance of pro-apoptotic versus anti-apoptotic members of Bcl-2 family proteins.2 Mitochondrial outer membrane permeabilization (MOMP) which leads to release of cytochrome c and other apoptogenic factors triggering apoptosis occurs as a result of shift of this balance towards pro-apoptotic Bcl-2 proteins. Furthermore, constitutive prevalence of the anti-apoptotic Bcl-2 family proteins is considered to promote cancer development; the classic example is B-cell lymphoma. Anticancer strategies therefore, were designed that rely on promoting apoptosis of cancer cells via altering the balance among the interacting Bcl-2 proteins. One strategy involves the use of antisense oligonucleotides targeting anti-apoptotic Bcl-2 proteins. Preclinical and clinical investigations on the drugs developed along this strategy [e.g. Oblimersen (Genasense®)] are already well advanced. Another, attractive approach is to use agents that mimic the Bcl-2 homology 3 (BH3) domains of the pro-apoptotic Bcl-2 family proteins (BH3 mimetics). Their mode of action involves competitive binding to surface hydrophobic grooves of anti-apoptotic Bcl-2 members thereby releasing the pro-apoptotic Bcl-2 molecules otherwise sequestered in complexes with the anti-apoptotic ones.2-4 The most investigated BH3 mimetic ABT-737 demonstrated distinct antitumor activity in vitro and in vivo against some leukemia types and solid tumors.3,5

In the article published in this issue of Cell Cycle6 Ponassi and her collaborators describe a novel BH3 mimetic, named 072RB, constructed by replacing specific moieties of Bim-BH3 with natural and non-natural aminoacids and adding an internalizing sequence. In elegant studies the authors convincingly demonstrate internalization and mitochondrial localization of 072RB followed by suppression of growth and apoptotic death of cells of leukemia cell lines. They also observed lethal ex vivo effects of 072RB on AML leukemic cells as well as remarkable inhibition of growth of xenografted human AML cells in NOD/SCID mice with no evidence of toxicity to normal tissue. Normal human lymphocytes, whether quiescent or mitogenically stimulated, were resistant to this BH3 mimetic. An important virtue of 072RB is resistance to proteolysis conferring its stability when used in vivo.

The interplay between the pro-apoptotic and anti-apoptotic Bcl-2 family members is rather complex because depending on cell type and the agent that induces apoptosis different members interact with each other. The mechanism of these interactions is still not fully understood. According to the “different affinity” model the BH3-only proteins Bad and Bmf target Bcl-2, Bcl-w and Bcl-xL, Noxa targets Mcl-1 and A1 whereas Bim and Puma target all the above pro-survival Bcl-2 proteins with comparable affinities.3 In the “direct activator” model Bim, tBid and Puma are the most downstream molecules, directly binding to Bax/Bak and thereby preventing their release, oligomerization and MOMP. In either of these models therefore, the Bim-activating BH-3 mimetic, such as 072RB, is expected to have wider spectrum of activity towards different cell types and different inducers of apoptosis than for instance ABT-737, as the latter, because of its Bad-like structure, does not target Mcl-1.

It is too early to predict whether BH3 mimetics bestow the breakthrough in cancer therapy. Their unique mechanism of action specifically targeting apoptotic machinery raises hopes that this may be the case.3 The new BH3 mimetic 072RB described by Ponassi et al.6 has all attributes to become the leading member of this new class of anticancer drugs. 072RB definitely deserves further evaluation in clinical trials to reveal its therapeutic capabilities whether used as a single agent or in combinatorial therapy.

ReferencesGorczyca W, at al. Leukemia 1993; 7:659-70.Fletcher JI, et al. Cell Cycle 2008; 7:39-44.Labi V, et al. Cell Death Differ 2008; 15:977-87.Wade et al., Cell Cycle 2008; 7:1973-82.Konoplewa M, et al. Cancer Cell 2006; 10:375-88.Ponassi R, et al. Cell Cycle 2008; In this issue.     

Transdifferentiation: why and how?

Cell therapy is based on the replacement of damaged cells in order to restore injured tissues. The first consideration is that an abundant source of cells is needed; second, these cells should be immunologically compatible with the guest and third, there should be no real threat of these cells undergoing malignant transformation in the future. Given these requirements, already differentiated adult cells or adult stem cells obtained from the body of the patient appear to be the ideal candidates to meet all of these demands. The utilization of somatic cells also avoids numerous ethical and political drawbacks and concerns. Transdifferentiation is the phenomenon by which an adult differentiated cell switches to another differentiated cell. This paper reviews the importance of transdifferentiation, discussing the cells that are suitable for this process and the methods currently employed to induce the change in cell type.     

Iron-sulfur clusters: why iron?

This communication addresses a simple question by means of density functional calculations: Why is iron used as the metal in iron-sulfur clusters? While there may be several answers to this question, it is shown here that one feature - the well-defined inner-sphere reorganization energy of self-exchange electron transfer - is very much favored in iron-sulfur clusters as opposed to metal substituted analogues of Mn, Co, Ni, and Cu. Furthermore, the conclusion holds for both 1Fe and 2Fe type iron-sulfur clusters. The results show that only iron provides a small inner-sphere reorganization energy of 21 kJ/mol in 1Fe (rubredoxin) and 46 kJ/mol in 2Fe (ferredoxin) models, whereas other metal ions exhibit values in the range 57-135 kJ/mol (1Fe) and 94-140 kJ/mol (2Fe). This simple result provides an important, although partial, explanation why iron alone is used in this type of clusters. The results can be explained by simple orbital rules of electron transfer, which state that the occupation of anti-bonding orbitals should not change during the redox reactions. This rule immediately suggests good and poor electron carriers.     

Apoptosis: suicide, execution or murder?

Apoptosis, a controlled form of cell death, appears to be regulated in several ways. Early studies indicated that de novo protein synthesis was required for apoptosis of thymocytes, but more recent studies have found that other cells can undergo apoptosis when protein synthesis is blocked or that inhibition of protein or RNA synthesis can induce apoptosis. Whether these findings reflect distinct forms of apoptosis or variations on a single pathway is not yet known. In this article the case for a single pathway to apoptosis, accessible at multiple points, is discussed.     

Propane-associated autoerotic asphyxiation: accident or suicide?

Autoerotic fatalities refer to a death resulting from the participation in a sex-related activity designed to heighten sexual arousal. The overwhelming majority of these deaths are due to asphyxia, most often by hanging or ligature compression of the neck. Here we report a case of "atypical" autoerotic fatality in which death was not induced by ligature compression. Unusual death of a 24-year-old man, involving propane inhalation and plastic bag suffocation, is described. The special characteristics of propane gas as an asphyxiant agent are discussed, as well as its effect on the human body.     

Phagocyte-derived reactive species: salvation or suicide?

Activated phagocytes produce "reactive oxygen, halogen and nitrogen species" that help to kill some types of microorganism. How these species destroy microorganisms remains, however, an enigma: both direct oxidative damage and indirect damage (whereby reactive species promote the actions of other antibacterial agents) are involved, and no single mechanism is likely to account for the killing of all microorganisms. Phagocyte-derived reactive species are known to injure human tissues and to contribute to inflammation. Recently, however, we have learned that they can also be anti-inflammatory by modulating the immune response. These data have implications for the proposed use of antioxidants to treat inflammation.     

Brain donation: who and why?

Understanding what influences people to donate, or not donate, body organs and tissues is very important for the future of transplant surgery and medical research (Garrick in J Clin Neurosci 13:524–528, 2006). A previous web-based motivation survey coordinated by the New South Wales Tissue Resource Centre found that most people who participated in brain donation were young, female, educated Australians, not affiliated with any particular religion, and with a higher prevalence of medical illness than the general Australian population. It discussed the main motivating factors for brain donation to be “the benefits of the research to medicine and science”. This study has been replicated in a paper-based version to capture a broader cross-section of the general population, to find out who they are and what motivates them to donate. All consented and registered brain donors (n = 1,323) were sent a questionnaire via the post and recipients were given 3 months to complete the questionnaire and return it in a reply paid envelope. Results were entered into the original web-based survey and analyzed using SPSS version 10. Six hundred and fifty-eight questionnaires were returned completed, a response rate of 53%. The results show that people from all age groups are interested in brain donation. The over 65’s are the largest of the groups (30.7%). The majority of the participants were female (60.6%), married (49.2%) with children (65.8%), employed (52.9%) and have a tertiary education (73.3%). They were either non-religious (48.2%) or Christian (41.6%) and were mostly Australian (65.4%). Most (81%) had pledged to donate other organs and tissues for transplantation. The most commonly cited reasons for the donation were to benefit science (27.6%), to benefit medicine (23.9%), a family illness (17.5%) and to benefit the community (16.6%). This study demonstrates that people across all age groups are interested in brain donation. Recruitment of new brain donors could target the over 65 female Australians, who are not religious or Christian and who have also donated other organs and tissues for transplant purposes. It also indicates the need to make donation for research part of the national transplant donation program.     

Automated species identification: why not?

Where possible, automation has been a common response of humankind to many activities that have to be repeated numerous times. The routine identification of specimens of previously described species has many of the characteristics of other activities that have been automated, and poses a major constraint on studies in many areas of both pure and applied biology. In this paper, we consider some of the reasons why automated species identification has not become widely employed, and whether it is a realistic option, addressing the notions that it is too difficult, too threatening, too different or too costly. Although recognizing that there are some very real technical obstacles yet to be overcome, we argue that progress in the development of automated species identification is extremely encouraging that such an approach has the potential to make a valuable contribution to reducing the burden of routine identifications. Vision and enterprise are perhaps more limiting at present than practical constraints on what might possibly be achieved.     

Recycling expensive medication: why not?

New (and proposed) advances in packaging, preserving, labeling, and verifying product integrity of individual tablets and capsules may allow for the recycling of certain expensive medicines. Previously sold, but unused, medication, if brought back to special pharmacies for resale or donation, may provide a low-cost source of patent-protected medicines. Benefits of such a program go beyond simply providing affordable medication to the poor. This article suggests that medicine recycling may be a possibility (especially if manufacturers are mandated to blister-package and bar-code individual tablets and capsules). This early discussion of medication recycling identifies relevant issues, such as: need, rationale, existing programs, available supplies, expiration dates, new technology for ensuring safety and potency, environmental impact, public health benefits, program focus, program structure, and liability.     

Connecting ORC and heterochromatin: why?

Considerable evidence connects heterochromatin or silenced chromatin with the Origin Recognition Complex (ORC) which is needed for initiation of DNA replication. In this review we consider biological forces that might be served by this connection. The prevailing view in the literature is that ORC recruits heterochromatin. This seems paradoxical because a replication initiator, ORC, would be recruiting factors which seem to oppose replication by forming inaccessible chromatin structures. Here we suggest a different view, that heterochromatin recruits ORC to facilitate replication of hard-to-replicate heterochromatic regions. We consider how existing data can be reconciled with this viewpoint, and we consider the biological predictions that arise from this perspective