Semi‐supervised determination of pseudocryptic morphotypes using observer‐free characterizations of anatomical alignment and shape

Accurate, quantitative characterization of complex shapes is recognized as a key methodological challenge in biology. Recent development of automated three‐dimensional geometric morphometric protocols (auto3dgm) provides a promising set of tools to help address this challenge. While auto3dgm has been shown to be useful in characterizing variation across clades of morphologically very distinct mammals, it has not been adequately tested in more problematic cases where pseudolandmark placement error potentially confounds interpretation of true shape variation. Here, we tested the sensitivity of auto3dgm to the degree of variation and various parameterization settings using a simulation and three microCT datasets that characterize mammal tooth crown morphology as biological examples. The microCT datasets vary in degree of apparent morphological differentiation, with two that include grossly similar morphospecies and one that includes two laboratory strains of a single species. Resulting alignments are highly sensitive to the number of pseudolandmarks used to quantify shapes. The degree to which the surfaces were downsampled and the apparent degree of morphological differentiation across the dataset also influenced alignment repeatability. We show that previous critiques of auto3dgm were based on poorly parameterized alignments and suggest that sample‐specific sensitivity analyses should be added to any research protocol including auto3dgm. Auto3dgm is a useful tool for studying samples when pseudolandmark placement error is small relative to the true differences between specimens. This method therefore represents a promising avenue forward in morphometric studies at a wide range of scales, from samples that differ by a single genetic locus to samples that represent multiple phylogenetically diverse clades.     

The biomechanical and perceptual influence of chain resistance on the performance of the olympic clean

Proponents of chain training suggest that using chains hung from the ends of barbells rather than using conventional barbells alone enhances strength, power, and neuromuscular adaptations. The purpose of this study was to determine whether a conventional barbell with chains compared to a conventional barbell without chains would affect the performance of an Olympic Clean. The subjects were also asked regarding their perception of how chains affected their lifting. Four male and 3 female competitive weightlifters who used chains as part of their training participated in the study. The testing protocol compared the subjects' lifting 80% and 85% of their 1 repetition maximum (1RM) using conventional barbells and their lifting 80% and 85% of their 1RM using chains (75% conventional barbells + 5% chains and 80% conventional barbells + 5% chains, respectively). Video analysis evaluated the bar's vertical displacement and velocity and the rate of force production. Vertical ground reaction forces for the first-pull, unweighting, and second-pull phases of the lift were evaluated by using a force plate. After testing, the subjects completed a 2-item questionnaire asking individual perception of the effects of the chains. The results showed no significant difference for condition for any of the variables examined. In contrast, all subjects perceived that the chains required a greater effort. In conclusion, the results indicated that the addition of chains provided no greater value over lifting conventional barbells alone in the performance of the Olympic Clean, although the subjects perceived the chains to have a positive effect.     

Synthesis and SAR of novel 1,1-dialkyl-2(1H)-naphthalenones as potent HCV polymerase inhibitors

A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated according to their structure-activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at low nanomolar concentrations in both enzymatic and cell-based HCV genotype 1a assays.     

The Method of ABA Application Affects Salt Stress Responses in Resistant and Sensitive Potato Lines

The phytohormone abscisic acid (ABA) has been proposed to act as a mediator in plant responses to a range of stresses, including salt stress. Most studies of ABA response apply ABA as a single dose. This may not resemble the prolonged increasing endogenous ABA levels that can occur in association with slowly increasing salinity stresses in nature or field situations. Salt stress response based on method of ABA application was examined in four potato genotypes of varying salt stress resistance: the sensitive ABA-deficient mutant and its normal sibling, a resistant genotype line 9506, and commercial cultivar ‘Norland’ of moderate resistance. ABA was applied by root drench at 0, 50, 75, or 100 μM concentrations through a single dose, or by slowly increasing multiple ABA doses in a sand-based growing system under greenhouse conditions. Salt tolerance was then evaluated after 2 weeks of exposure to 150–180 mM NaCl stress. The method of ABA application had a marked effect on the responses to salt stress. Plant responses to the method of ABA application were differentiated according to (1) growth rate, (2) root water content, and (3) apparent shoot growth response. Under a single dose, growth rate increased in all genotypes under salt stress, whereas slowly increasing multiple ABA applications generally maintained stable growth rates except in the ABA-deficient mutant where there was an upward growth trend. Percent root water content was elevated only under slowly increasing multiple ABA doses in two genotypes, whereas none of the single-dose treatments induced any change. The single ABA dose enhanced vertical growth, whereas the slowly increasing multiple ABA dose applications enhanced lateral shoot growth. Because exogenous application is still an artificial system, endogenous ABA was supplied through grafting of ABA-deficient mutant scions onto rootstocks with known elevated ABA levels. Multiple exogenous ABA applications as low as 50 μM elicited similar shoot water content responses as grafting treatments without ABA application in the mutant genotype but had no effect on the ABA normal sibling. Shoot dry weight was significantly increased through grafting over all exogenous ABA treatments. Our study further indicates that the method of ABA application regime in itself can alter plant responses under salt stress and that certain application regimes may reflect responses to elevated endogenous levels of ABA.     

Scion and Rootstock Effects on ABA-mediated Plant Growth Regulation and Salt Tolerance of Acclimated and Unacclimated Potato Genotypes

Tolerance of salt stress in potato (Solanum tuberosum L.) increased when the plants were pre-exposed to low concentrations of salt (salt acclimation). This acclimation was accompanied by increased levels of abscisic acid (ABA) in the shoot. To further study the role of roots and shoots in this acclimation process, reciprocal grafts were made between a salt-tolerant (9506) and salt-sensitive ABA(−) mutant and its ABA(+) normal sibling potato genotype. The grafted plants were acclimated with 75 or 100 mM NaCl for 3 weeks and then exposed to 150–180 mM NaCl, depending on the salt tolerance of the rootstock. After 2 weeks of exposure to the salt stress, the acclimated and unacclimated plants were compared for physiologic and morphologic parameters. The response to the salt stress was strongly influenced by the rootstock. The salt-tolerant 9506 rootstock increased the salt tolerance of scions of both the ABA-deficient mutant and its ABA(+) sibling. This salt tolerance induced by the rootstock was primarily modulated by salt acclimation and manifested in the scion via increased plant water content, stem diameter, dry matter accumulation, stomatal conductivity, and osmotic potential, and is associated with a reduction in leaf necrosis. There was also a pronounced scion effect on the rootstock. Using 9506 as a scion significantly increased root fresh and dry weights, stem diameter, and root water content of ABA(−) mutant rootstocks. Specific evidence was found of the role of exogenous ABA in the enhancement of water status in grafted plants under salt stress beyond that of grafting alone. This was verified by more positive stomatal conductivity and upward water flow in ABA-treated grafted and nongrafted plants and the absence of upward water flow in nontreated grafted plants through NMR imaging. Grafting using either salt-tolerant scions or rootstocks with inherently high ABA levels may positively modify subsequent responses of the plant under salt stress.     

Clinical Characteristics and Outcomes in Patients with Pulmonary Blastomycosis

Background  Blastomycosis is an uncommon granulomatous infection caused by the thermally dimorphic fungus Blastomyces dermatitidis. The most frequent clinical infections involve the lung, skin, and bone. Pulmonary manifestations range from asymptomatic self-limited infection to severe diffuse pneumonia causing respiratory failure. Objectives  To establish the clinical characteristics and outcomes of patients with pulmonary blastomycosis diagnosed at hospitals in Manitoba and northwestern Ontario, Canada. Methods  A retrospective review of medical records was done for 318 patients with blastomycosis in these regions. Results  The majority of patients were Caucasian (198 (62.5%) patients), male (193 (61%) patients), and residents of Ontario (209 (65.7%) patients). Most patients were treated in an inpatient hospital ward (266 (84%) patients) and survived (294 (92%) patients). Pulmonary involvement, either alone or associated with other sites, was present in 296 (93%) of the 318 patients; 22 (7%) patients had no evidence of pulmonary blastomycosis. The majority of patients had localized lung disease (1–3 quadrants on chest radiograph involved; 225 (82%) patients). Of 294 (92%) patients requiring hospitalization, 266 (90%) patients received all inpatient care on a general medical ward; 28 (10%) patients received some care in the intensive care unit (ICU). Factors associated with ICU admission included diffuse pulmonary disease (four quadrants involved on chest radiograph), diabetes, and prior use of antimicrobial therapy. Twenty-four (8%) patients died, and multivariate analysis showed that older age and Aboriginal ethnicity were the significant risk factors for death from blastomycosis. Conclusion  Blastomycosis is a cause of serious, potentially life-threatening pulmonary infection in this geographic region. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Mitochondrial DNA mutations and ageing

The mechanism by which we age has sparked a huge number of theories, and is an area of intense debate. As the elderly population rises, the importance of elucidating these mechanisms is becoming more apparent as age is the single biggest risk factor for a number of diseases such as cancer, diabetes and neurodegenerative disease. Mitochondrial DNA (MtDNA) mutations have been shown to accumulate in cells and tissues during the ageing process; however the question as to whether these mutations have a causal role in the ageing process remains an area of uncertainty. Here we review the current literature, and discuss the evidence for and against a causal role of mtDNA mutations in ageing and in the pathogenesis of age-related disease.     

Discovery of GlyT1 inhibitors with improved pharmacokinetic properties

Glycine transporter 1 (GlyT1) represents a novel target for the treatment of schizophrenia via the potentiation of glutamatergic NMDA receptors. The discovery of 4,4-disubstituted piperidine inhibitors of GlyT1 which exhibit improved pharmacokinetic properties, including oral bioavailability, is discussed.