Heart rate-associated mechanical stress impairs carotid but not cerebral artery compliance in dyslipidemic atherosclerotic mice

The cardiac cycle imposes a mechanical stress that dilates elastic carotid arteries, while shear stress largely contributes to the endothelium-dependent dilation of downstream cerebral arteries. In the presence of dyslipidemia, carotid arteries stiffen while the endothelial function declines. We reasoned that stiffening of carotid arteries would be prevented by reducing resting heart rate (HR), while improving the endothelial function would regulate cerebral artery compliance and function. Thus we treated or not 3-mo-old male atherosclerotic mice (ATX; LDLr(-/-):hApoB(+/+)) for 3 mo with the sinoatrial pacemaker current inhibitor ivabradine (IVA), the β-blocker metoprolol (METO), or subjected mice to voluntary physical training (PT). Arterial (carotid and cerebral artery) compliance and endothelium-dependent flow-mediated cerebral dilation were measured in isolated pressurized arteries. IVA and METO similarly reduced (P < 0.05) 24-h HR by ≈15%, while PT had no impact. As expected, carotid artery stiffness increased (P < 0.05) in ATX mice compared with wild-type mice, while cerebral artery stiffness decreased (P < 0.05); this paradoxical increase in cerebrovascular compliance was associated with endothelial dysfunction and an augmented metalloproteinase-9 (MMP-9) activity (P < 0.05), without changing the lipid composition of the wall. Reducing HR (IVA and METO) limited carotid artery stiffening, but plaque progression was prevented by IVA only. In contrast, IVA maintained and PT improved cerebral endothelial nitric oxide synthase-dependent flow-mediated dilation and wall compliance, and both interventions reduced MMP-9 activity (P < 0.05); METO worsened endothelial dysfunction and compliance and did not reduce MMP-9 activity. In conclusion, HR-dependent mechanical stress contributes to carotid artery wall stiffening in severely dyslipidemic mice while cerebrovascular compliance is mostly regulated by the endothelium.     

A sticky situation: solifugids (Arachnida, Solifugae) use adhesive organs on their pedipalps for prey capture

Solifugids (Arachnida, Solifugae) have unique evertable adhesive organs on the tips of their pedipalps, named ‘suctorial’ or ‘palpal’ organs. Previous studies have shown that these organs enable solifugids to climb smooth glass-like surfaces and have hypothesized that these structures facilitate prey capture. Here, we use high-speed videography to demonstrate that the suctorial organs of Eremochelis bilobatus are its primary means of capturing insect prey. We also present calculations of the adhesive pressure exerted by these suctorial organs during real prey capture events.     

A critical perspective of the use of (13)C-isotopomer analysis by GCMS and NMR as applied to cardiac metabolism

The aim of this article is to provide a guide for metabolic physiologists and bioengineers to the combined use of gas chromatography-mass spectrometry (GCMS) and nuclear magnetic resonance (NMR) in stable isotope investigations in any biological systems. Building on our past experience with these two techniques, as applied separately to the investigation of citric acid metabolism in the ex vivo perfused rat heart we initiated a collaborative study for their critical evaluation. This article, which expands on our previous work (Mol. Cel. Biol., 2003), directly compares GCMS- and NMR-determined 13C-isotopomer and flux data obtained from ex vivo rat heart perfusion studies with 13C-substrates. Overall we have found excellent agreement between the 13C-enrichments of GCMS- and NMR-determined citric acid cycle metabolites (citrate, 2-ketoglutarate, succinate and malate) and glutamate; however the unlabeled component (M) was consistently underestimated by NMR. Despite this discrepancy there was reasonably good agreement in the relative fluxes of 13C-substrates through the citric acid cycle determined by the two techniques. Nevertheless, further investigations appear necessary before maximal advantage can be taken of the complementary 13C-isotopomer and flux data of GCMS and NMR for probing the dynamics of cellular metabolism.     

Isolation and phenotypic characterization of Pseudomonas aeruginosa pseudorevertants containing suppressors of the catabolite repression control-defective crc-10 allele

The amiE gene encodes an aliphatic amidase capable of converting fluoroacetamide to the toxic compound fluoroacetate and is one of many genes whose expression is subject to catabolite repression control in Pseudomonas aeruginosa. The protein product of the crc gene, Crc, is required for repression of amiE and most other genes subject to catabolite repression control in this bacterium. When grown in a carbon source such as succinate, wild-type P. aeruginosa is insensitive to fluoroacetamide (due to repression of amiE expression). In contrast, mutants harboring the crc-10 null allele cannot grow in the presence of fluoroacetamide (due to lack of repression of amiE). Selection for succinate-dependent, fluoroacetamide-resistant derivatives of the crc-10 mutant yielded three independent pseudorevertants containing suppressors that restored a degree of catabolite repression control. Synthesis of Crc protein was not reestablished in these pseudorevertants. All three suppressors of crc-10 were extragenic, and all three also suppressed a Delta crc::tetA allele. In each of the three pseudorevertants, catabolite repression control of amidase expression was restored. Catabolite repression control of mannitol dehydrogenase production was also restored in two of the three isolates. None of the suppressors restored repression of glucose-6-phosphate dehydrogenase or pyocyanin production.     

Improving the science-policy dialogue to meet the challenges of biodiversity conservation: having conversations rather than talking at one-another

A better, more effective dialogue is needed between biodiversity science and policy to underpin the sustainable use and conservation of biodiversity. Many initiatives exist to improve communication, but these largely conform to a ‘linear’ or technocratic model of communication in which scientific “facts” are transmitted directly to policy advisers to “solve problems”. While this model can help start a dialogue, it is, on its own, insufficient, as decision taking is complex, iterative and often selective in the information used. Here, we draw on the literature, interviews and a workshop with individuals working at the interface between biodiversity science and government policy development to present practical recommendations aimed at individuals, teams, organisations and funders. Building on these recommendations, we stress the need to: (a) frame research and policy jointly; (b) promote inter- and trans-disciplinary research and “multi-domain” working groups that include both scientists and policy makers from various fields and sectors; (c) put in place structures and incentive schemes that support interactive dialogue in the long-term. These are changes that are needed in light of continuing loss of biodiversity and its consequences for societal dependence on and benefits from nature.     

Long-Term Citizen-Collected Data Reveal Geographical Patterns and Temporal Trends in Lake Water Clarity

We compiled a lake-water clarity database using publically available, citizen volunteer observations made between 1938 and 2012 across eight states in the Upper Midwest, USA. Our objectives were to determine (1) whether temporal trends in lake-water clarity existed across this large geographic area and (2) whether trends were related to the lake-specific characteristics of latitude, lake size, or time period the lake was monitored. Our database consisted of >140,000 individual Secchi observations from 3,251 lakes that we summarized per lake-year, resulting in 21,020 summer averages. Using Bayesian hierarchical modeling, we found approximately a 1% per year increase in water clarity (quantified as Secchi depth) for the entire population of lakes. On an individual lake basis, 7% of lakes showed increased water clarity and 4% showed decreased clarity. Trend direction and strength were related to latitude and median sample date. Lakes in the southern part of our study-region had lower average annual summer water clarity, more negative long-term trends, and greater inter-annual variability in water clarity compared to northern lakes. Increasing trends were strongest for lakes with median sample dates earlier in the period of record (1938–2012). Our ability to identify specific mechanisms for these trends is currently hampered by the lack of a large, multi-thematic database of variables that drive water clarity (e.g., climate, land use/cover). Our results demonstrate, however, that citizen science can provide the critical monitoring data needed to address environmental questions at large spatial and long temporal scales. Collaborations among citizens, research scientists, and government agencies may be important for developing the data sources and analytical tools necessary to move toward an understanding of the factors influencing macro-scale patterns such as those shown here for lake water clarity.     

HSV-2 Co-Infection as a Driver of HIV Transmission among Heterosexual Non-Injecting Drug Users in New York City

Objective

To examine herpes simplex virus 2 (HSV-2)/HIV co-infection as a contributing factor in the increase in HIV infection among non-injecting heroin and cocaine users in New York City.

Methods

Subjects were recruited from the Beth Israel Medical Center drug detoxification and methadone maintenance programs in New York City in 1995–1999 and 2005–2011. All reported current heroin and/or cocaine use and no injection drug use. A structured questionnaire was administered and serum samples collected for HIV and HSV-2 testing. Population-attributable risk percentages (PAR%s) were estimated for associations between HSV-2 and increased susceptibility to and increased transmissibility of HIV among female NIDUs.

Results

785 subjects were recruited from 1995–1999, and 1764 subjects from 2005–2011. HIV prevalence increased from 7% to 13%, with nearly uniform increases among all demographic subgroups. HSV-2/HIV co-infection was common in both time periods, with an average (over the two time periods) of 80% of HIV negative females infected with HSV-2, an average of 43% of HIV negative males infected with HSV-2; an average of 97% of HIV positive females also infected with HSV-2 and an average of 67% of HIV positive males also infected with HSV-2. The increase in HIV prevalence was predominantly an increase in HSV-2/HIV co-infection, with relatively little HIV mono-infection in either time period. The estimated PAR%s indicate that approximately half of HIV acquisition among females was caused by HSV-2 infection and approximately 60% of HIV transmission from females was due to HSV-2 co-infection.

Conclusions

The increase in HIV infection among these non-injecting drug users is better considered as an increase in HSV-2/HIV co-infection rather than simply an increase in HIV prevalence. Additional interventions (such as treatment as prevention and suppressing the effects of HSV-2 on HIV transmission) are needed to reduce further HIV transmission from HSV-2/HIV co-infected non-injecting drug users.     

The Anticancer Agent Di-2-pyridylketone 4,4-Dimethyl-3-thiosemicarbazone (Dp44mT) Overcomes Prosurvival Autophagy by Two Mechanisms: PERSISTENT INDUCTION OF AUTOPHAGOSOME SYNTHESIS AND IMPAIRMENT OF LYSOSOMAL INTEGRITY

Autophagy functions as a survival mechanism during cellular stress and contributes to resistance against anticancer agents. The selective antitumor and antimetastatic chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) causes lysosomal membrane permeabilization and cell death. Considering the integral role of lysosomes in autophagy and cell death, it was important to assess the effect of Dp44mT on autophagy to further understand its mechanism of action. Notably, Dp44mT affected autophagy by two mechanisms. First, concurrent with its antiproliferative activity, Dp44mT increased the expression of the classical autophagic marker LC3-II as a result of induced autophagosome synthesis. Second, this effect was supplemented by a reduction in autophagosome degradation as shown by the accumulation of the autophagic substrate and receptor p62. Conversely, the classical iron chelator desferrioxamine induced autophagosome accumulation only by inhibiting autophagosome degradation. The formation of redox-active iron or copper Dp44mT complexes was critical for its dual effect on autophagy. The cytoprotective antioxidant N-acetylcysteine inhibited Dp44mT-induced autophagosome synthesis and p62 accumulation. Importantly, Dp44mT inhibited autophagosome degradation via lysosomal disruption. This effect prevented the fusion of lysosomes with autophagosomes to form autolysosomes, which is crucial for the completion of the autophagic process. The antiproliferative activity of Dp44mT was suppressed by Beclin1 and ATG5 silencing, indicating the role of persistent autophagosome synthesis in Dp44mT-induced cell death. These studies demonstrate that Dp44mT can overcome the prosurvival activity of autophagy in cancer cells by utilizing this process to potentiate cell death.