Modeling impacts of dynamic ventilation strategies on indoor air quality of offices in six US cities

a b s t r a c t A potential source of energy savings in buildings is demand controlled ventilation (DCV), or dynamic modulation of the ventilation rate based on current occupancy. The impact of DCV on indoor air quality (IAQ) has not been investigated over a large range of indoor air processes or under the revised ventilation rate procedure (VRP) introduced in ASHRAE Standard 62.1-2004, which reduced per-occupant rates and added a constant per-area rate. A transient, multi-contaminant model of an area-normalized US office was created, and best estimates for distributions of model inputs across the US office sector were developed and used in a six city Monte Carlo simulation of dynamic ventilation strategies, including DCV and morning flushes. DCV implementation had a very minor effect on concentrations of ozone, particles, and carbon dioxide. The greatest effect was on daytime mean and peak concentration of total volatile organic compounds (TVOC). TVOC daytime means increased by 7e10% and peaks increased by 10e14%, depending on city. Adding a medium intensity morning flush to DCV almost completely mitigated the increase in mean concentration and reduced the peak concentration below the fixed ventilation baseline in most cases. Differences among offices due to input variations were far greater than changes observed from implementing DCV, and a sensitivity analysis indicated that the TVOC emission rate was more influential than the ventilation strategy. The distribution-based, sector-wide Monte Carlo method developed here should also be useful for assessing other ventilation strategies and input parameter impacts and informing the development of IAQ guidelines

Seasonal total methane depletion in limestone caves

Methane concentration in caves is commonly much lower than the external atmosphere, yet the cave CH4 depletion causal mechanism is contested and dynamic links to external diurnal and seasonal temperature cycles unknown. Here, we report a continuous 3-year record of cave methane and other trace gases in Jenolan Caves, Australia which shows a seasonal cycle of extreme CH4 depletion, from ambient ∼1,775 ppb to near zero during summer and to ∼800 ppb in winter. Methanotrophic bacteria, some newly-discovered, rapidly consume methane on cave surfaces and in external karst soils with lifetimes in the cave of a few hours. Extreme bacterial selection due to the absence of alternate carbon sources for growth in the cave environment has resulted in an extremely high proportion 2-12% of methanotrophs in the total bacteria present. Unexpected seasonal bias in our cave CH4 depletion record is explained by a three-step process involving methanotrophy in aerobic karst soil above the cave, summer transport of soil-gas into the cave through epikarst, followed by further cave CH4 depletion. Disentangling cause and effect of cave gas variations by tracing sources and sinks has identified seasonal speleothem growth bias, with implied palaeo-climate record bias

Site-Specific Mutation of the Sensor Kinase GraS in Staphylococcus aureus Alters the Adaptive Response to Distinct Cationic Antimicrobial Peptides

The Staphylococcus aureus two-component regulatory system, GraRS, is involved in resistance to killing by distinct host defense cationic antimicrobial peptides (HD-CAPs). It is believed to regulate downstream target genes such as mprF and dltABCD to modify the S. aureus surface charge. However, the detailed mechanism(s) by which the histidine kinase, GraS, senses specific HD-CAPs is not well defined. Here, we studied a well-characterized clinical methicillin-resistant S. aureus (MRSA) strain (MW2), its isogenic graS deletion mutant (ΔgraS strain), a nonameric extracellular loop mutant (ΔEL strain), and four residue-specific ΔEL mutants (D37A, P39A, P39S, and D35G D37G D41G strains). The ΔgraS and ΔEL strains were unable to induce mprF and dltA expression and, in turn, demonstrated significantly increased susceptibilities to daptomycin, polymyxin B, and two prototypical HD-CAPs (hNP-1 and RP-1). Further, P39A, P39S, and D35G-D37G-D41G ΔEL mutations correlated with moderate increases in HD-CAP susceptibility. Reductions of mprF and dltA induction by PMB were also found in the ΔEL mutants, suggesting these residues are pivotal to appropriate activation of the GraS sensor kinase. Importantly, a synthetic exogenous soluble EL mimic of GraS protected the parental MW2 strain against hNP-1- and RP-1-mediated killing, suggesting a direct interaction of the EL with HD-CAPs in GraS activation. In vivo, the ΔgraS and ΔEL strains displayed dramatic reductions in achieved target tissue MRSA counts in an endocarditis model. Taken together, our results provide new insights into potential roles of GraS in S. aureus sensing of HD-CAPs to induce adaptive survival responses to these molecules

Gait Speed and Mood, Cognition, and Quality of Life in Older Adults With Atrial Fibrillation

Background: Low gait speed has been linked with impaired mood, cognition, and quality of life (QOL) in older adults. We examined whether low gait speed was associated with impaired mood, cognition, and QOL among older adults with atrial fibrillation (AF). Methods and Results: Participants (n=1185) had a diagnosis of AF, aged \u3e /=65 years, CHA2DS2VASc \u3e /=2 and had no contraindications to anticoagulation. Participants completed a 15-foot walk test, and low gait speed was categorized using cutoffs from the Fried Frailty Index. Participants self-reported measures of depressive symptoms (Patient Health Questionnaire 9 \u3e /=10), anxiety symptoms (Generalized Anxiety Disorder 7 \u3e /=10), cognitive impairment (Montreal Cognitive Assessment \u3c /=23), and potentially impaired Atrial Fibrillation Effect Quality-of-Life Questionnaire \u3c 80. Participants were on average aged 75.3 (SD: 7.0) years, 48.0% were women, and 85.5% were non-Hispanic white; 85.6% were taking an oral anticoagulant, 26.1% had low gait speed, 8.4% had elevated depressive symptoms, 5.7% had elevated anxiety symptoms, 41.1% were cognitively impaired, and 41.6% had potentially impaired AF-related QOL. Participants with low gait speed were significantly more likely to have elevated depressive symptoms (adjusted odds ratio: 2.1, 95% CI: 1.3-3.4), elevated anxiety symptoms (adjusted odds ratio: 2.2, 95% CI: 1.2-3.9), and cognitive impairment (adjusted odds ratio: 1.5, 95% CI: 1.1-2.1). Impaired AF-related QOL did not differ by gait speed after adjustment for clinical characteristics (adjusted odds ratio: 1.1, 95% CI: 0.8-1.5). Conclusions: Twenty-six percent of older adults with AF had low gait speed, and low gait speed was associated with impaired mood and cognition. Further research is needed to determine whether declines in gait speed lead to impaired mood and cognition or whether these conditions develop concurrently

The GraS Sensor in Staphylococcus Aureus Mediates Resistance to Host Defense Peptides Differing in Mechanisms of Action

Staphylococcus aureus uses the two-component regulatory system GraRS to sense and respond to host defense peptides (HDPs). However, the mechanistic impact of GraS or its extracellular sensing loop (EL) on HDP resistance is essentially unexplored. Strains with null mutations in the GraS holoprotein (ΔgraS) or its EL (ΔEL) were compared for mechanisms of resistance to HDPs of relevant immune sources: neutrophil α-defensin (human neutrophil peptide 1 [hNP-1]), cutaneous β-defensin (human β-defensin 2 [hBD-2]), or the platelet kinocidin congener RP-1. Actions studied by flow cytometry included energetics (ENR); membrane permeabilization (PRM); annexin V binding (ANX), and cell death protease activation (CDP). Assay conditions simulated bloodstream (pH 7.5) or phagolysosomal (pH 5.5) pH contexts. S. aureus strains were more susceptible to HDPs at pH 7.5 than at pH 5.5, and each HDP exerted a distinct effect signature. The impacts of ΔgraS and ΔΕL on HDP resistance were peptide and pH dependent. Both mutants exhibited defects in ANX response to hNP-1 or hBD-2 at pH 7.5, but only hNP-1 did so at pH 5.5. Both mutants exhibited hyper-PRM, -ANX, and -CDP responses to RP-1 at both pHs and hypo-ENR at pH 5.5. The actions correlated with ΔgraS or ΔΕL hypersusceptibility to hNP-1 or RP-1 (but not hBD-2) at pH 7.5 and to all study HDPs at pH 5.5. An exogenous EL mimic protected mutant strains from hNP-1 and hBD-2 but not RP-1, indicating that GraS and its EL play nonredundant roles in S. aureus survival responses to specific HDPs. These findings suggest that GraS mediates specific resistance countermeasures to HDPs in immune contexts that are highly relevant to S. aureus pathogenesis in humans

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.

With a resurgence in interest in covalent drugs, there is a need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a cysteine reactive warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification while avoiding some of the limitations generally associated with established moieties

Use of Unstructured Event-Based Reports for Global Infectious Disease Surveillance

Free or low-cost unstructured reports offer an alternative to traditional indicator-based outbreak reporting

Origin and History of Mitochondrial DNA Lineages in Domestic Horses

Domestic horses represent a genetic paradox: although they have the greatest number of maternal lineages (mtDNA) of all domestic species, their paternal lineages are extremely homogeneous on the Y-chromosome. In order to address their huge mtDNA variation and the origin and history of maternal lineages in domestic horses, we analyzed 1961 partial d-loop sequences from 207 ancient remains and 1754 modern horses. The sample set ranged from Alaska and North East Siberia to the Iberian Peninsula and from the Late Pleistocene to modern times. We found a panmictic Late Pleistocene horse population ranging from Alaska to the Pyrenees. Later, during the Early Holocene and the Copper Age, more or less separated sub-populations are indicated for the Eurasian steppe region and Iberia. Our data suggest multiple domestications and introgressions of females especially during the Iron Age. Although all Eurasian regions contributed to the genetic pedigree of modern breeds, most haplotypes had their roots in Eastern Europe and Siberia. We found 87 ancient haplotypes (Pleistocene to Mediaeval Times); 56 of these haplotypes were also observed in domestic horses, although thus far only 39 haplotypes have been confirmed to survive in modern breeds. Thus, at least seventeen haplotypes of early domestic horses have become extinct during the last 5,500 years. It is concluded that the large diversity of mtDNA lineages is not a product of animal breeding but, in fact, represents ancestral variability

Is Aboriginal Food Less Allergenic? Comparing IgE-Reactivity of Eggs from Modern and Ancient Chicken Breeds in a Cohort of Allergic Children

BACKGROUND: Hen's egg allergy ranks among the most frequent primary food allergies in children. We aimed to investigate sensitization profiles of egg allergic patients and compare in vitro IgE reactivities of eggs from ancient chicken breeds (Araucana and Maran) with those from conventional laying hen hybrids. METHODOLOGY: Egg allergic children (n = 25) were subjected to skin prick test, double blind placebo controlled food challenge, and sensitization profiles to Gal d 1-5 were determined by allergen microarray. IgE binding and biological activity of eggs from different chicken breeds were investigated by immunoblot, ELISA, and mediator release assays. PRINCIPAL FINDINGS: We found that Gal d 1 and Gal d 2 are generally major egg allergens, whereas Gal d 3-5 displayed high sensitization prevalence only in patients reacting to both, egg white and yolk. It seems that the onset of egg allergy is mediated by egg white allergens expanding to yolk sensitization in later stages of disease. Of note, egg white/yolk weight ratios were reduced in eggs from Auraucana and Maran chicken. As determined in IgE immunoblots and mass analysis, eggs from ancient chicken breeds did not differ in their protein composition. Similar IgE-binding was observed for all egg white preparations, while an elevated allergenicity was detected in egg yolk from Araucana chicken. CONCLUSION/SIGNIFICANCE: Our results on allergenicity and biological activity do not confirm the common assumption that aboriginal food might be less allergenic. Comprehensive diagnosis of egg allergy should distinguish between reactivity to hen's egg white and yolk fractions to avoid unnecessary dietary restrictions to improve life quality of the allergic child and its family

Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hepatitis-associated aplastic anemia is a common syndrome in patients with bone marrow failure. However, hepatitis-associated aplastic anemia is an immune-mediated disease that does not appear to be caused by any of the known hepatitis viruses including hepatitis C virus. In addition, to the best of our knowledge there are no reported cases of patients with chronic hepatitis C virus infection developing aplastic anemia associated with pegylated interferon alpha 2a treatment.</p> <p>Case presentation</p> <p>We report the case of a 46-year-old Greek man who developed severe aplastic anemia during treatment with pegylated interferon alpha 2a for chronic hepatitis C virus infection. He presented with generalized purpura and bruising, as well as pallor of the skin and mucous membranes. His blood tests showed pancytopenia. He underwent allogeneic bone marrow transplantation after completing two courses of immunosuppressive therapy with antithymocyte globulin and cyclosporin A.</p> <p>Conclusions</p> <p>The combination of a specific environmental precipitant represented by the hepatitis C virus infection, an altered metabolic detoxification pathway due to treatment with pegylated interferon alpha 2a and a facilitating genetic background such as polymorphism in metabolic detoxification pathways and specific human leukocyte antigen genes possibly conspired synergistically in the development of aplastic anemia in this patient. Our case clearly shows that the causative role of pegylated interferon alpha 2a in the development of aplastic anemia must not be ignored.</p