Improvement of Left Ventricular Function under Cardiac Resynchronization Therapy Goes along with a Reduced Incidence of Ventricular Arrhythmia

Objectives

The beneficial effects of cardiac resynchronization therapy (CRT) are thought to result from favorable left ventricular (LV) reverse remodeling, however CRT is only successful in about 70% of patients. Whether response to CRT is associated with a decrease in ventricular arrhythmias (VA) is still discussed controversially. Therefore, we investigated the incidence of VA in CRT responders in comparison with non-responders.

Methods

In this nonrandomized, two-center, observational study patients with moderate-to-severe heart failure, LV ejection fraction (LVEF) ≤35%, and QRS duration >120 ms undergoing CRT were included. After 6 months patients were classified as CRT responders or non-responders. Incidence of VA was compared between both groups by Kaplan-Meier analysis and Cox regression analysis. ROC analysis was performed to determine the aptitude of LVEF cut-off values to predict VA.

Results

In total 126 consecutive patients (64±11years; 67%male) were included, 74 were classified as responders and 52 as non-responders. While the mean LVEF at baseline was comparable in both groups (25±7% vs. 24±8%; P = 0.4583) only the responder group showed an improvement of LVEF (36±6% vs. 24±7; p<0.0001) under CRT. In total in 56 patients VA were observed during a mean follow-up of 28±14 months, with CRT responders experiencing fewer VA than non-responders (35% vs. 58%, p<0.0061). Secondary preventive CRT implantation was associated with a higher likelihood of VA. As determined by ROC analysis an increase of LVEF by >7% was found to be a predictor of a significantly lower incidence of VA (AUC = 0.606).

Conclusions

Improvement of left ventricular function under cardiac resynchronization therapy goes along with a reduced incidence of ventricular arrhythmia.     

The germ cell determinant Blimp1 is not required for derivation of pluripotent stem cells

Blimp1 (Prdm1), the key determinant of primordial germ cells (PGCs), plays a combinatorial role with Prdm14 during PGC specification from postimplantation epiblast cells. They together initiate epigenetic reprogramming in early germ cells toward an underlying pluripotent state, which is equivalent to embryonic stem cells (ESCs). Whereas Prdm14 alone can?promote reprogramming and is important for the propagation of the pluripotent state, it is not known whether Blimp1 is similarly involved. By using a genetic approach, we demonstrate that Blimp1 is?dispensable for the derivation and maintenance of ESCs and postimplantation epiblast stem cells (epiSCs). Notably, Blimp1 is also dispensable for reprogramming epiSCs to ESCs. Thus, although Blimp1 is obligatory for PGC specification, it is not required for the reversion of epiSCs to ESCs and for their maintenance thereafter. This study suggests that reprogramming, including that of somatic cells to ESCs, may not entail an obligatory route through a Blimp1-positive PGC-like state.     

Simple additive effects are rare: a quantitative review of plant biomass and soil process responses to combined manipulations of CO2 and temperature

In recent years, increased awareness of the potential interactions between rising atmospheric CO₂ concentrations ([ CO₂ ]) and temperature has illustrated the importance of multifactorial ecosystem manipulation experiments for validating Earth System models. To address the urgent need for increased understanding of responses in multifactorial experiments, this article synthesizes how ecosystem productivity and soil processes respond to combined warming and [ CO₂ ] manipulation, and compares it with those obtained in single factor [ CO₂ ] and temperature manipulation experiments. Across all combined elevated [ CO₂ ] and warming experiments, biomass production and soil respiration were typically enhanced. Responses to the combined treatment were more similar to those in the [ CO₂ ]‐only treatment than to those in the warming‐only treatment. In contrast to warming‐only experiments, both the combined and the [ CO₂ ]‐only treatments elicited larger stimulation of fine root biomass than of aboveground biomass, consistently stimulated soil respiration, and decreased foliar nitrogen (N) concentration. Nonetheless, mineral N availability declined less in the combined treatment than in the [ CO₂ ]‐only treatment, possibly due to the warming‐induced acceleration of decomposition, implying that progressive nitrogen limitation (PNL) may not occur as commonly as anticipated from single factor [ CO₂ ] treatment studies. Responses of total plant biomass, especially of aboveground biomass, revealed antagonistic interactions between elevated [ CO₂ ] and warming, i.e. the response to the combined treatment was usually less‐than‐additive. This implies that productivity projections might be overestimated when models are parameterized based on single factor responses. Our results highlight the need for more (and especially more long‐term) multifactor manipulation experiments. Because single factor CO₂ responses often dominated over warming responses in the combined treatments, our results also suggest that projected responses to future global warming in Earth System models should not be parameterized using single factor warming experiments.     

Proposed Local Ecological Impact Categories and Indicators for Life Cycle Assessment of Aquaculture

In this study we discuss impact categories and indicators to incorporate local ecological impacts into life cycle assessment (LCA) for aquaculture. We focus on the production stages of salmon farming—freshwater hatcheries used to produce smolts and marine grow‐out sites using open netpens. Specifically, we propose two impact categories: impacts of nutrient release and impacts on biodiversity. Proposed indicators for impacts of nutrient release are (1) the area altered by farm waste, (2) changes in nutrient concentration in the water column, (3) the percent of carrying capacity reached, (4) the percent of total anthropogenic nutrient release, and (5) release of wastes into freshwater. Proposed indicators for impacts on biodiversity are (1) the number of escaped salmon, (2) the number of reported disease outbreaks, (3) parasite abundance on farms, and (4) the percent reduction in wild salmon survival. For each proposed indicator, an example of how the indicator could be estimated is given and the strengths and weaknesses of that indicator are discussed. We propose that including local environmental impacts as well as global‐scale ones in LCA allows us to better identify potential trade‐offs, where actions that are beneficial at one scale are harmful at another, and synchronicities, where actions have desirable or undesirable effects at both spatial scales. We also discuss the potential applicability of meta‐analytic statistical techniques to LCA.     

Genotyping Yersinia pestis in Historical Plague: Evidence for Long-Term Persistence of Y. pestis in Europe from the 14th to the 17th Century

Ancient DNA (aDNA) recovered from plague victims of the second plague pandemic (14^th to 17^th century), excavated from two different burial sites in Germany, and spanning a time period of more than 300 years, was characterized using single nucleotide polymorphism (SNP) analysis. Of 30 tested skeletons 8 were positive for Yersinia pestis-specific nucleic acid, as determined by qPCR targeting the pla gene. In one individual (MP-19-II), the pla copy number in DNA extracted from tooth pulp was as high as 700 gene copies/μl, indicating severe generalized infection. All positive individuals were identical in all 16 SNP positions, separating phylogenetic branches within nodes N07_N10 (14 SNPs), N07_N08 (SNP s19) and N06_N07 (s545), and were highly similar to previously investigated plague victims from other European countries. Thus, beside the assumed continuous reintroduction of Y. pestis from central Asia in multiple waves during the second pandemic, long-term persistence of Y. pestis in Europe in a yet unknown reservoir host has also to be considered.     

Sex-Related Differences in the Trade-Off between Foraging and Vigilance in a Granivorous Forager

The relationship between intake rate and food density can provide the foundation for models that predict the spatiotemporal distribution of organisms across a range of resource densities. The functional response, describing the relationship between resource density and intake rate is often interpreted mechanistically as the relationships between times spend searching and handling. While several functional response models incorporate anti-predator vigilance (defined here as an interruption of feeding or some other activity to visually scan the environment, directed mainly towards detecting potential predators), the impacts of environmental factors influencing directly anti-predator vigilance remains unclear. We examined the combined effects of different scenarios of predation risk and food density on time allocation between foraging and anti-predator vigilance in a granivorous species. We experimentally exposed Skylarks to various cover heights and seed densities, and measured individual time budget and pecking and intake rates. Our results indicated that time devoted to different activities varied as a function of both seed density and cover height. Foraging time increased with seed density for all cover heights. Conversely, an increased cover height resulted in a decreased foraging time. Contrary to males, the decreased proportion of time spent foraging did not translate into a foraging disadvantage for females. When vegetation height was higher, females maintained similar pecking and intake rates compared to intermediate levels, while males consistently decreased their energy gain. This difference in anti-predator responses suggests a sexually mediated strategy in the food-safety trade-off: when resource density is high a females would adopt a camouflage strategy while an escape strategy would be adopted by males. In other words, males would leave risky-areas, whereas females would stay when resource density is high. Our results suggest that increased predation risk might generate sexually mediated behavioural responses that functional response models should perhaps better consider in the future.     

Evaluation of Four Commercial Multiplex Molecular Tests for the Diagnosis of Acute Respiratory Infections

Acute Respiratory Infections (ARIs) are responsible for considerable morbidity and mortality worldwide. Documentation of respiratory specimens can help for an appropriate clinical management with a significant effect on the disease progress in patient, the antimicrobial therapy used and the risk of secondary spread of infection. Here, we compared the performances of four commercial multiplex kits used in French University Hospital diagnostic microbiology laboratories for the detection of ARI pathogens (i.e., the xTAG Respiratory Viral Panel Fast, RespiFinder SMART 22, CLART PneumoVir and Fast Track Diagnostics Respiratory Pathogen 33 kits). We used a standardised nucleic acids extraction protocol and a comprehensive comparative approach that mixed reference to well established real-time PCR detection techniques and analysis of convergent positive results. We tested 166 respiratory clinical samples and identified a global high degree of correlation for at least three of the techniques (xTAG, RespiFinder and FTD33). For these techniques, the highest Youden’s index (YI), positive predictive (PPV) and specificity (Sp) values were observed for Core tests (e.g., influenza A [YI:0.86–1.00; PPV:78.95–100.00; Sp:97.32–100.00] & B [YI:0.44–1.00; PPV:100.00; Sp:100.00], hRSV [YI:0.50–0.99; PPV:85.71–100.00; Sp:99.38–100.00], hMPV [YI:0.71–1.00; PPV:83.33–100.00; Sp:99.37–100.00], EV/hRV [YI:0.62–0.82; PPV:93.33–100.00; Sp:94.48–100.00], AdV [YI:1.00; PPV:100.00; Sp:100.00] and hBoV [YI:0.20–0.80; PPV:57.14–100.00; Sp:98.14–100.00]). The present study completed an overview of the multiplex techniques available for the diagnosis of acute respiratory infections.     

Biochemistry and Crystal Structure of Ectoine Synthase: A Metal-Containing Member of the Cupin Superfamily

Ectoine is a compatible solute and chemical chaperone widely used by members of the Bacteria and a few Archaea to fend-off the detrimental effects of high external osmolarity on cellular physiology and growth. Ectoine synthase (EctC) catalyzes the last step in ectoine production and mediates the ring closure of the substrate N-gamma-acetyl-L-2,4-diaminobutyric acid through a water elimination reaction. However, the crystal structure of ectoine synthase is not known and a clear understanding of how its fold contributes to enzyme activity is thus lacking. Using the ectoine synthase from the cold-adapted marine bacterium Sphingopyxis alaskensis (Sa), we report here both a detailed biochemical characterization of the EctC enzyme and the high-resolution crystal structure of its apo-form. Structural analysis classified the (Sa)EctC protein as a member of the cupin superfamily. EctC forms a dimer with a head-to-tail arrangement, both in solution and in the crystal structure. The interface of the dimer assembly is shaped through backbone-contacts and weak hydrophobic interactions mediated by two beta-sheets within each monomer. We show for the first time that ectoine synthase harbors a catalytically important metal co-factor; metal depletion and reconstitution experiments suggest that EctC is probably an iron-dependent enzyme. We found that EctC not only effectively converts its natural substrate N-gamma-acetyl-L-2,4-diaminobutyric acid into ectoine through a cyclocondensation reaction, but that it can also use the isomer N-alpha-acetyl-L-2,4-diaminobutyric acid as its substrate, albeit with substantially reduced catalytic efficiency. Structure-guided site-directed mutagenesis experiments targeting amino acid residues that are evolutionarily highly conserved among the extended EctC protein family, including those forming the presumptive iron-binding site, were conducted to functionally analyze the properties of the resulting EctC variants. An assessment of enzyme activity and iron content of these mutants give important clues for understanding the architecture of the active site positioned within the core of the EctC cupin barrel.     

The Type III Secretion System-Related CPn0809 from Chlamydia pneumoniae

Chlamydia pneumoniae is an intracellular Gram-negative bacterium that possesses a type III secretion system (T3SS), which enables the pathogen to deliver, in a single step, effector proteins for modulation of host-cell functions into the human host cell cytosol to establish a unique intracellular niche for replication. The translocon proteins located at the top of the T3SS needle filament are essential for its function, as they form pores in the host-cell membrane. Interestingly, unlike other Gram-negative bacteria, C. pneumoniae has two putative translocon operons, named LcrH_1 and LcrH_2. However, little is known about chlamydial translocon proteins. In this study, we analyzed CPn0809, one of the putative hydrophobic translocators encoded by the LcrH_1 operon, and identified an ‘SseC-like family’ domain characteristic of T3S translocators. Using bright-field and confocal microscopy, we found that CPn0809 is associated with EBs during early and very late phases of a C. pneumoniae infection. Furthermore, CPn0809 forms oligomers, and interacts with the T3SS chaperone LcrH_1, via its N-terminal segment. Moreover, expression of full-length CPn0809 in the heterologous host Escherichia coli causes a grave cytotoxic effect that leads to cell death. Taken together, our data indicate that CPn0809 likely represents one of the translocon proteins of the C. pneumoniae T3SS, and possibly plays a role in the translocation of effector proteins in the early stages of infection.