Functional Morphology of the Olfactory Mucosa and Olfactory Bulb in Fossorial Rodents: The East African Root Rat (Tachyoryctes splendens) and the Naked Mole Rat (Heterocephalus glaber)

Optimal functioning of the olfactory system is critical for survival of fossorial rodents in their subterranean lifestyle. This study examines the structure of the olfactory mucosa and olfactory bulb of two fossorial rodents exhibiting distinct social behaviors, the East African root rat and the naked mole rat. The social naked mole rat displayed simpler ethmoturbinates consisting of dorsomedial and broad discoid/flaplike parts that projected rostrally from the ethmoid bone. In the solitary root rat however, the ethmoturbinates were highly complex and exhibited elaborate branching which greatly increased the olfactory surface area. In addition, when correlated with the whole brain, the volume of the olfactory bulbs was greater in the root rat (4.24 × 10^?2) than in the naked mole rat (3.92 × 10^?2). Results of this study suggest that the olfactory system of the root rat is better specialized than that of the naked mole rat indicating a higher level of dependence on this system since it leads a solitary life. The naked mole rat to the contrary may have compensated for its relatively inferior olfactory system by living in groups in a social system. These findings demonstrate that structure of the olfactory system of fossorial mammals is dictated by both behavior and habitat.     

Structural insight into dynamic bypass of the major cisplatin‐DNA adduct by Y‐family polymerase Dpo4

Y‐family DNA polymerases bypass Pt‐GG, the cisplatin‐DNA double‐base lesion, contributing to the cisplatin resistance in tumour cells. To reveal the mechanism, we determined three structures of the Y‐family DNA polymerase, Dpo4, in complex with Pt‐GG DNA. The crystallographic snapshots show three stages of lesion bypass: the nucleotide insertions opposite the 3′G (first insertion) and 5′G (second insertion) of Pt‐GG, and the primer extension beyond the lesion site. We observed a dynamic process, in which the lesion was converted from an open and angular conformation at the first insertion to a depressed and nearly parallel conformation at the subsequent reaction stages to fit into the active site of Dpo4. The DNA translocation‐coupled conformational change may account for additional inhibition on the second insertion reaction. The structures illustrate that Pt‐GG disturbs the replicating base pair in the active site, which reduces the catalytic efficiency and fidelity. The in vivo relevance of Dpo4‐mediated Pt‐GG bypass was addressed by a dpo‐4 knockout strain of Sulfolobus solfataricus, which exhibits enhanced sensitivity to cisplatin and proteomic alterations consistent with genomic stress.     

Factors influencing the distribution of the mole rat, Cryptomys zechi (Rodentia, Bathyergidae) in Ghana

Factors influencing the distribution of the Ghana mole rat Cryptomys zechi were investigated in a small part of the middle Volta basin of Ghana where it is endemic. Soil type appeared to be the most important factor controlling mole rat distribution in the area; the mole rats preferred areas where the soil was silt loam. In areas where mole rats were found, local distribution was influenced by food availability and land preparation methods for farming. The highest concentrations of mole rat colonies were found in farmlands where traditional hoe ploughing is used for land preparation and where plants with underground storage organs were more diverse; the lowest concentration was in farms where mechanized ploughing is used for land preparation.     

Characterization of 20 microsatellite loci in the long‐tailed tit Aegithalos caudatus (Aegithalidae,AVES)

We characterized 20 microsatellite loci in the long‐tailed tit, Aegithalos caudatus. Polymorphic loci were identified by testing 114 loci that had been originally isolated in other avian species. The loci were characterized in 23–163 unrelated long‐tailed tits from a British population and displayed between two and 42 alleles, with observed heterozygosity ranging between 0.09 and 0.97.     

Sustained high levels of neuregulin-1 in the longest-lived rodents; a key determinant of rodent longevity

Naked mole-rats (Heterocephalus glaber), the longest-lived rodents, live 7-10 times longer than similarly sized mice and exhibit normal activities for approximately 75% of their lives. Little is known about the mechanisms that allow them to delay the aging process and live so long. Neuregulin-1 (NRG-1) signaling is critical for normal brain function during both development and adulthood. We hypothesized that long-lived species will maintain higher levels of NRG-1 and that this contributes to their sustained brain function and concomitant maintenance of normal activity. We monitored the levels of NRG-1 and its receptor ErbB4 in H. glaber at different ages ranging from 1 day to 26 years and found that levels of NRG-1 and ErbB4 were sustained throughout development and adulthood. In addition, we compared seven rodent species with widely divergent (4-32 year) maximum lifespan potential (MLSP) and found that at a physiologically equivalent age, the longer-lived rodents had higher levels of NRG-1 and ErbB4. Moreover, phylogenetic independent contrast analyses revealed that this significant strong correlation between MLSP and NRG-1 levels was independent of phylogeny. These results suggest that NRG-1 is an important factor contributing to divergent species MLSP through its role in maintaining neuronal integrity.     

Induction of systemic disease resistance in Nicotiana benthamiana by the cyclodipeptides cyclo (l‐Pro‐l‐Pro) and cyclo (d‐Pro‐d‐Pro)

Cyclodipeptides, formed from two amino acids by cyclodehydration, are produced naturally by many organisms, and are known to possess a large number of biological activities. In this study, we found that cyclo (l ‐Pro‐l ‐Pro) and cyclo (d ‐Pro‐d ‐Pro) (where Pro is proline) could induce defence responses and systemic resistance in Nicotiana benthamiana. Treatment with the two cyclodipeptides led to a reduction in disease severity by Phytophthora nicotianae and Tobacco mosaic virus (TMV) infections compared with controls. Both cyclopeptides triggered stomatal closure, induced reactive oxygen species production and stimulated cytosolic calcium ion and nitric oxide production in guard cells. In addition, the application of cyclodipeptides significantly up‐regulated the expression of the plant defence gene PR‐1a and the PR‐1a protein, and increased cellular salicylic acid (SA) levels. These results suggest that the SA‐dependent defence pathway is involved in cyclodipeptide‐mediated pathogen resistance in N. benthamiana. We report the systemic resistance induced by cyclodipeptides, which sheds light on the potential of cyclodipeptides for the control of plant diseases.     

Critical role of poly(ADP‐ribose) polymerase‐1 in modulating the mode of cell death caused by continuous oxidative stress

Continuously generated hydrogen peroxide (H₂O₂) inhibits typical apoptosis and instead initiates a caspase‐independent, apoptosis‐inducing factor (AIF)‐mediated pyknotic cell death. This may be related to H₂O₂‐mediated DNA damage and subsequent ATP depletion, although the exact mechanisms by which the mode of cell death is decided after H₂O₂ exposure are still unclear. Accumulated evidence and our previous data led us to hypothesize that continuously generated H₂O₂, not an H₂O₂ bolus, induces severe DNA damage, signaling poly(ADP‐ribose) polymerase‐1 (PARP‐1) activation, ATP depletion, and eventually caspase‐independent cell death. Results from the present study support that H₂O₂ generated continuously by glucose oxidase causes excessive DNA damage and PARP‐1 activation. Blockage of PARP‐1 by a siRNA transfection or by pharmacological inhibitor resulted in the significant inhibition of ATP depletion, loss of mitochondrial membrane potential, nuclear translocation of AIF and endonuclease G, and eventually conversion to caspase‐dependent apoptosis. Overall, the current study demonstrates the different roles of PARP‐1 inhibition in modulation of cell death according to the method of H₂O₂ exposure, that is, continuous generation versus a direct addition. J. Cell. Biochem. 108: 989–997, 2009. © 2009 Wiley‐Liss, Inc.     

LH responses to single doses of exogenous GnRH in the Cape mole rat (Georychus capensis): the pituitary potential for opportunistic breeding

The Cape mole rat Georychus capensis is a solitary mole rat that inhabits the winter rainfall region of the Western Cape Province of South Africa. Circulating basal concentrations of luteinizing hormone (LH) were found to be significantly higher in the breeding season in both sexes. During both the breeding and non-breeding season, administration of exogenous gonadotropin-releasing hormone (GnRH) increased circulatory LH levels. The magnitude of the LH response to an overdose of exogenous GnRH both in and out of the breeding season in males and females was not significantly different. Typically, seasonally breeding species exhibit a down-regulation of the pituitary and reproductive functions out of the breeding season. It appears that there is no down-regulation of GnRH receptors at the level of the pituitary out of the breeding season, because the pituitary responds to an exogenous GnRH challenge equally both in and out of the breeding period. The Cape mole rat exhibits the potential for opportunistic breeding out of the breeding period, provided that environmental factors are favourable. This finding questions whether this mole rat is actually a seasonal breeder or whether reproduction is hindered by the ecological constraint of the lack of opportunities to burrow and find mates at certain times of the year.     

The cohesin complex is required for the DNA damage‐induced G2/M checkpoint in mammalian cells

Cohesin complexes mediate sister chromatid cohesion. Cohesin also becomes enriched at DNA double‐strand break sites and facilitates recombinational DNA repair. Here, we report that cohesin is essential for the DNA damage‐induced G2/M checkpoint. In contrast to cohesin's role in DNA repair, the checkpoint function of cohesin is independent of its ability to mediate cohesion. After RNAi‐mediated depletion of cohesin, cells fail to properly activate the checkpoint kinase Chk2 and have defects in recruiting the mediator protein 53BP1 to DNA damage sites. Earlier work has shown that phosphorylation of the cohesin subunits Smc1 and Smc3 is required for the intra‐S checkpoint, but Smc1/Smc3 are also subunits of a distinct recombination complex, RC‐1. It was, therefore, unknown whether Smc1/Smc3 function in the intra‐S checkpoint as part of cohesin. We show that Smc1/Smc3 are phosphorylated as part of cohesin and that cohesin is required for the intra‐S checkpoint. We propose that accumulation of cohesin at DNA break sites is not only needed to mediate DNA repair, but also facilitates the recruitment of checkpoint proteins, which activate the intra‐S and G2/M checkpoints.     

Pragmatic randomized controlled trial of long‐term psychoanalytic psychotherapy for treatment‐resistant depression: the Tavistock Adult Depression Study (TADS)

This pragmatic randomized controlled trial tested the effectiveness of long‐term psychoanalytic psychotherapy (LTPP) as an adjunct to treatment‐as‐usual according to UK national guidelines (TAU), compared to TAU alone, in patients with long‐standing major depression who had failed at least two different treatments and were considered to have treatment‐resistant depression. Patients (N=129) were recruited from primary care and randomly allocated to the two treatment conditions. They were assessed at 6‐monthly intervals during the 18 months of treatment and at 24, 30 and 42 months during follow‐up. The primary outcome measure was the 17‐item version of the Hamilton Depression Rating Scale (HDRS‐17), with complete remission defined as a HDRS‐17 score ≤8, and partial remission defined as a HDRS‐17 score ≤12. Secondary outcome measures included self‐reported depression as assessed by the Beck Depression Inventory ‐ II, social functioning as evaluated by the Global Assessment of Functioning, subjective wellbeing as rated by the Clinical Outcomes in Routine Evaluation ‐ Outcome Measure, and satisfaction with general activities as assessed by the Quality of Life Enjoyment and Satisfaction Questionnaire. Complete remission was infrequent in both groups at the end of treatment (9.4% in the LTPP group vs. 6.5% in the control group) as well as at 42‐month follow‐up (14.9% vs. 4.4%). Partial remission was not significantly more likely in the LTPP than in the control group at the end of treatment (32.1% vs. 23.9%, p=0.37), but significant differences emerged during follow‐up (24 months: 38.8% vs. 19.2%, p=0.03; 30 months: 34.7% vs. 12.2%, p=0.008; 42 months: 30.0% vs. 4.4%, p=0.001). Both observer‐based and self‐reported depression scores showed steeper declines in the LTPP group, alongside greater improvements on measures of social adjustment. These data suggest that LTPP can be useful in improving the long‐term outcome of treatment‐resistant depression. End‐of‐treatment evaluations or short follow‐ups may miss the emergence of delayed therapeutic benefit.     

Intercolonial encounters and xenophobia in the common mole rat, Cryptomys hottentotus hottentotus (Bathyergidae): the effects of aridity, sex, and reproductive status

The ecological constraints prevalent in arid environments havepromoted the evolution of social groups with a high reproductiveskew in mole rat species occurring there. Outbred social bathyergidsface conflict between maintaining colony integrity to enhancepersonal foraging success and hence survival, and dispersalto maximum individual lifetime reproductive success (LRS). Thisconflict will be a crucial determinant of the response of colonymembers to the presence of foreign conspecifics. We investigatedhow ecological constraints, sex, and reproductive status influencethe outcome of meetings between foreign common mole rats (Cryptomyshottentotus hottentotus) in a series of dyadic encounters. Individualsfrom two localities, at the extremes of an aridity gradient,were used to assess the effects of aridity. The effects of sexand reproductive status were investigated by trials betweenindividuals of differing sex and status. The arid populationrevealed substantially higher levels of rejection than the mesicpopulation. Sex and status played a significant role in moderatingindividual response. For both populations, encounters betweendifferent-sexed individuals produced lower levels of rejectionthan those between same-sexed individuals. For the mesic site,rejection was greatest for encounters between reproductive animals.Conversely, for the arid site, the levels of rejection werecomparatively high and comparable for all combinations of reproductivestatus. Ecological constraints, sex, and reproductive statusare significant factors in interactions between foreign commonmole rats, ultimately influencing individual survival, colonyintegrity and the differential LRS of all colony members. Ourresults provide insight into the evolution and maintenance offamily groups within the bathyergids.