Size breeds success: multiple paternity, multivariate selection and male semelparity in a small marsupial, Antechinus stuartii

Mating in the marsupial genus Antechinus is a synchronous annual event that is characterized by monoestry in females and abrupt postmating mortality in males. Male semelparity (multiple copulations during a single breeding season per lifetime) is often assumed to occur as a consequence of the intense mating effort expended by males in the rut, but the forces selecting for this remain elusive. Here, we investigate selection in male brown antechinus, Antechinus stuartii, and test two hypotheses for the evolution of semelparity: intermale competition and sperm competition. If intermale competition drives semelparity, we predicted that males would be under strong selection for large body size. If sperm competition is important, we predicted that selection would be strongest on scrotal size, a surrogate for testes volume. Using microsatellite markers, we found that 92% of females in free-living conditions mated with multiple males, producing litters of eight that had up to four fathers. These observations confirm the potential for sperm competition. Using selection analysis, we then found paternity success in 119 males to be related most strongly to body mass and scrotal size, thus providing support for both hypotheses. Large males presumably experience increased paternity success by gaining more matings or prolonged copulations via mate guarding, while large testes may allow increased sperm investment per copulation. Increased levels of free corticosteroid hormones in males facilitate the extreme mating effort during the short period of rut, but lead to immune suppression and consequently to the phenomenon of postmating mortality.     

Poly(vinyl alcohol) hydrogel as a biocompatible viscoelastic mimetic for articular cartilage

The prevalence of suboptimal outcome for surgical interventions in the treatment of full-thickness articular cartilage damage suggests that there is scope for a materials-based strategy to deliver a more durable repair. Given that the superficial layer of articular cartilage creates and sustains the tribological function of synovial joints, it is logical that candidate materials should have surface viscoelastic properties that mimic native articular cartilage. The present paper describes force spectroscopy analysis by nano-indentation to measure the elastic modulus of the surface of a novel poly(vinyl alcohol) hydrogel with therapeutic potential as a joint implant. More than 1 order of magnitude decrease in the elastic modulus was detected after adsorption of a hyaluronic acid layer onto the hydrogel, bringing it very close to previously reported values for articular cartilage. Covalent derivatization of the hydrogel surface with fibronectin facilitated the adhesion and growth of cultured rat tibial condyle chondrocytes as evidenced morphologically and by the observance of metachromatic staining with toluidine blue dye. The present results indicate that hydrogel materials with potential therapeutic benefit for injured and diseased joints can be engineered with surfaces with biomechanical properties similar to those of native tissue and are accepted as such by their constituent cell type.     

Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein

Missense mutations (A30P and A53T) in alpha-synuclein and the overproduction of the wild-type protein cause familial forms of Parkinson's disease and dementia with Lewy bodies. Alpha-synuclein is the major component of the filamentous Lewy bodies and Lewy neurites that define these diseases at a neuropathological level. Recently, a third missense mutation (E46K) in alpha-synuclein was described in an inherited form of dementia with Lewy bodies. Here, we have investigated the functional effects of this novel mutation on phospholipid binding and filament assembly of alpha-synuclein. When compared to the wild-type protein, the E46K mutation caused a significantly increased ability of alpha-synuclein to bind to negatively charged liposomes, unlike the previously described mutations. The E46K mutation increased the rate of filament assembly to the same extent as the A53T mutation. Filaments formed from E46K alpha-synuclein often had a twisted morphology with a cross-over spacing of 43 nm. The observed effects on lipid binding and filament assembly may explain the pathogenic nature of the E46K mutation in alpha-synuclein.     

Low-dose oral vitamin K therapy for the management of asymptomatic patients with elevated international normalized ratios: a brief review

ASYMPTOMATIC ELEVATION OF THE INTERNATIONAL normalized ratio (INR) is a common problem associated with hemorrhage. Evidence from randomized controlled trials supports the use of low-dose oral vitamin K therapy as a treatment that promptly reduces the INR. Vitamin K given orally is more effective than subcutaneous vitamin K injection, and as effective as intravenous administration when INR values are compared 24 hours after administration. A 1.0-mg vitamin K dose is likely most appropriate for patients with INR values between 4.5 and 10. The fear of over-correction of the INR has limited the widespread use of vitamin K; however, our review suggests that this occurs infrequently when small doses are administered orally.Asymptomatic elevation of the international normalized ratio (INR) is a common and important clinical problem encountered by all health care professionals who supervise patients taking warfarin. Patients in typical outpatient practices have INRs outside the desired range 50% of the time.^1,2 One randomized controlled trial (RCT) suggested that, despite measures to ensure an appropriate level of anticoagulation, 14% of total patient-time was spent with INR values above the therapeutic range.³ There is a strong relation between the degree of INR elevation and the risk of hemorrhage. Serious warfarin-associated bleeding usually occurs from the gastrointestinal or genitourinary system;⁴ the risk of such bleeding may as much as double for each 1-point increase in the INR.⁵ Investigators of a prospective cohort study⁶ followed 114 consecutive patients who presented to an anticoagulation clinic with an INR greater than 6 and found that abnormal bleeding developed in 10 (8.8%) of them and life-threatening hemorrhage in 5 (4.4%; 2 fatal) over the 2-week follow-up period. Therefore, interventions leading to a prompt reduction of the INR may reduce the risk of serious bleeding in patients taking warfarin.Most indications for warfarin anticoagulation have a target therapeutic INR range of 2.0 to 3.0. However, some indications, such as mechanical heart valves, require a higher intensity of anticoagulation. 7^,8 An elevated INR is one that is above the therapeutic range. However, most studies that have evaluated interventions for asymptomatic elevation of the INR have examined INRs several points above the upper limit of the therapeutic range, usually selecting a lower limit for intervention between 4.5 and 6.0. In assessing patients with an elevated INR, one should consider potential causes such as noncompliance, inappropriate dosing, fluctuations in vitamin K intake, hepatic dysfunction, laboratory errors, drug interactions (Box 1) and alcohol intake.Table 1Box 1A common strategy for lowering an elevated INR is simply to withhold warfarin. In some cases parenteral vitamin K therapy may be administered. Recent interest has focused on the use of vitamin K orally as a simple, safe and effective way of normalizing an excessively elevated INR. Although no tablet form of vitamin K is currently available in Canada, the intravenous formulation (see Fig. 1) can be given orally, either undiluted or after mixing with orange juice to mask its unpleasant taste. We reviewed the literature to ascertain whether or not oral vitamin K therapy is effective, to identify the degree of INR abnormality that is best managed with oral therapy, to identify the dose that is most appropriate and to identify the relative risks of hemorrhage and thrombosis with this regimen as compared with other management approaches.Fig. 1: Ampule of vitamin K. Because the tablet form of vitamin K is not currently available in Canada, the parenteral formulation can be given orally. It is dispensed in ampules of 0.5 mL (equivalent to 1.0 mg) and 1.0 mL (equivalent to 10.0 mg). The ...     

T cell immunity to lymphoma following treatment with anti-CD40 monoclonal antibody

In this study we demonstrate that treatment with anti-CD40 mAb eradicates a range of mouse lymphomas (BCL(1), A31, A20, and EL4), but only when used against i.v. tumor doses in excess of 10(7) cells. Only partial protection was seen against smaller tumor loads. We saw no evidence that anti-CD40 mAb changed the phenotype of the lymphomas or inhibited their growth in the initial period following treatment, but it did result in a rapid expansion of cytotoxic CD8(+) cells that was able to clear the neoplastic disease and provide long-term protection against tumor rechallenge. The CTL responses were blocked by mAb against a range of coreceptors and cytokines, including CD8, B7-1, B7-2, LFA-1, and IFN-gamma, but not CD4 or CTLA-4, indicating the presence of a conventional cellular Th1 response. Furthermore, we found evidence of cross-recognition between lymphomas (BCL(1) and A20) as measured by cytotoxicity and IFN-gamma responses in vitro and using tumor rechallenge experiments, suggesting common target Ags. Finally, although anti-CD40 was shown to stimulate NK cell killing, we could find no role for these cells in controlling tumor growth. These data underline the ability of anti-CD40 mAb to potentiate CTL responses and the potency of cellular immunity in eradicating large quantities of syngeneic tumor.     

Microbotanical signatures of kreb: differentiating inflorescence phytoliths from northern African wild grasses

Vegetation History and Archaeobotany - Throughout northern Africa, evidence for an intensification of wild grass gathering is reflected in Holocene archaeological contexts. However, both the...