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Abstract There are strong links between heritage and the environment yet, heritage is not fully included in existing ecosystem‐based frameworks. Different understandings of heritage values exist, and heritage values are not yet related to key value categories in environmental values research. To address this gap and facilitate a common values‐based approach, we develop a novel framework that links heritage and environmental values. First, we expand the understanding of heritage values by linking heritage to key environmental value categories. We then use the Life Framework of Values to show how heritage features in the different ways in which people relate to the world. The resulting heritage values framework is operationalised by applying it to six case examples drawn from participatory research on the governance of European coastal and maritime heritage. We found that the environment was not only considered to be a setting for heritage but was itself valued as heritage in different ways; that heritage is not extrinsic to the environment but is also a way in which people see meaning in the environment; and that multiple value frames and types were involved in shaping this perspective. The results highlight important discrepancies between stakeholders' perspectives and existing management approaches. Applying the framework shows the ways in which heritage and nature are entwined by providing a structure for elucidating what can be valued as heritage, what values can inform heritage values and how heritage values feature in human–nature relations. Read the free Plain Language Summary for this article on the Journal blog.

Fire has cultural and economic significance for Indigenous and rural peoples worldwide, being used to manage landscapes for activities such as hunting, gathering, cropping, and forestry, and for ceremonial and spiritual purposes. Policy interventions by state and non-state organizations, such as regulations, economic incentives, and communication campaigns, can target fire use directly, or affect it indirectly, for example, by restricting land access. Yet evidence of such impacts has not been synthesized at the global scale. We analyzed 512 examples in 68 countries to describe the range of policy interventions by state and non-state organizations that target and/or affect fire use, categorizing interventions based on the broad actor types involved, their mode of operation (e.g., regulation) and their intentionality and/or possible effects vis-a-vis fire use. Of these interventions, 74% involved only state agencies in policy design and implementations, 4% involved only non-state organizations, and 18% involved collaboration between state and/or non-state organizations and/or communities. Three hundred and nine interventions directly targeted fire use, of which 87% aimed to eliminate or constrain fire use. Two hundred and three affected fire use indirectly, of which 88% led to reductions in or constraints upon fire use. Though there is some recognition in the 21st century of a need, in certain contexts, to support local fire use, for reasons related to environmental justice, ecology, wildfire risk and climate change, the literature we reviewed points to several challenges for contemporary efforts toward this end. These include contradictions between policy interventions, mistrust between actors following histories of fire suppression, greater fuel loads increasing the risk of burning where fire has been suppressed, and the need to consider the indirect effects of other types of policy, such as those related to land tenure.

People depend on functioning ecosystems, which provide benefits that support human existence and wellbeing. The relationship between people and nature has been experienced and conceptualized in multiple ways. Recently, ecosystem services (ES) concepts have permeated science, government policies, multi-national environmental agreements, and science–policy interfaces. In 2017, the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) introduced a new and closely related concept – Nature’s Contributions to People (NCP). The introduction of NCP has sparked some lively discussion and confusion about the distinguishing characteristics between ES and NCP. In order to clarify their conceptual relation, we identify eleven specific claims about novel elements from the latest NCP literature and analyze how far ES research has already contributed to these corresponding conceptual claims in the existing ES literature. We find a mixed-picture, where on six specific conceptual claims (culture, social sciences and humanities, indigenous and local knowledge, negative contributions of nature, generalizing perspective, non-instrumental values and valuation) NCP does not differ greatly from past ES research, but we also find five conceptual claims (diverse worldviews, context-specific perspective, relational values, fuzzy and fluid reporting categories and groups, inclusive language and framing) where NCP provides novel conceptualizations of people and nature relations.

Identification of novel antibiotics remains a major challenge for drug discovery. The present study explores use of phenotypic readouts beyond classical antibacterial growth inhibition adopting a combined multiparametric high content screening and genomic approach. Deployment of the semi-automated bacterial phenotypic fingerprint (BPF) profiling platform in conjunction with a machine learning-powered dataset analysis, effectively allowed us to narrow down, compare and predict compound mode of action (MoA). The method identifies weak antibacterial hits allowing full exploitation of low potency hits frequently discovered by routine antibacterial screening. We demonstrate that BPF classification tool can be successfully used to guide chemical structure activity relationship optimization, enabling antibiotic development and that this approach can be fruitfully applied across species. The BPF classification tool could be potentially applied in primary screening, effectively enabling identification of novel antibacterial compound hits and differentiating their MoA, hence widening the known antibacterial chemical space of existing pharmaceutical compound libraries. More generally, beyond the specific objective of the present work, the proposed approach could be profitably applied to a broader range of diseases amenable to phenotypic drug discovery.

Prior limited research indicates that children with pulmonary hypertension (PH) have higher rates of adverse perioperative outcomes when undergoing non-cardiac procedures and cardiac catheterizations. We examined a single-center retrospective cohort of children with active or pharmacologically controlled PH who underwent cardiac catheterization or non-cardiac surgery during 2006-2014. Preoperative characteristics and perioperative courses were examined to determine relationships between the severity or etiology of PH, type of procedure, and occurrence of major and minor events. We identified 77 patients who underwent 148 procedures at a median age of six months. The most common PH etiologies were bronchopulmonary dysplasia (46.7%), congenital heart disease (29.9%), and congenital diaphragmatic hernia (14.3%). Cardiac catheterizations (39.2%), and abdominal (29.1%) and central venous access (8.9%) were the most common procedures. Major events included failed planned extubation (5.6%), postoperative cardiac arrest (4.7%), induction or intraoperative cardiac arrest (2%), and postoperative death (1.4%). Major events were more frequent in patients with severe baseline PH ( P = 0.006) and the incidence was associated with procedure type ( P = 0.05). Preoperative inhaled nitric oxide and prostacyclin analog therapies were associated with decreased incidence of minor events (odds ratio [OR] = 0.32, P = 0.046 and OR = 0.24, P = 0.008, respectively), but no change in the incidence of major events. PH etiology was not associated with events ( P = 0.24). Children with PH have increased risk of perioperative complications; cardiac arrest and death occur more frequently in patients with severe PH and those undergoing thoracic procedures. Risk may be modified by using preoperative pulmonary vasodilator therapy and lends itself to further prospective studies.

Quality control of ribosomes is critical for cellular function since protein mistranslation leads to severe physiological consequences. We report evidence of a previously unrecognized ribosome quality control system in bacteria that operates at the level of 70S to remove defective ribosomes. YbeY, a previously unidentified endoribonuclease, and the exonuclease RNase R act together by a process mediated specifically by the 30S ribosomal subunit, to degrade defective 70S ribosomes but not properly matured 70S ribosomes or individual subunits. Furthermore, there is essentially no fully matured 16S rRNA in a ΔybeY mutant at 45°C, making YbeY the only endoribonuclease to be implicated in the critically important processing of the 16S rRNA 3' terminus. These key roles in ribosome quality control and maturation indicate why YbeY is a member of the minimal bacterial gene set and suggest that it could be a potential target for antibacterial drugs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The UPF0054 protein family is highly conserved with homologues present in nearly every sequenced bacterium. In some bacteria, the respective gene is essential, while in others its loss results in a highly pleiotropic phenotype. Despite detailed structural studies, a cellular role for this protein family has remained unknown. We report here that deletion of the Escherichia coli homologue, YbeY, causes striking defects that affect ribosome activity, translational fidelity and ribosome assembly. Mapping of 16S, 23S and 5S rRNA termini reveals that YbeY influences the maturation of all three rRNAs, with a particularly strong effect on maturation at both the 5'- and 3'-ends of 16S rRNA as well as maturation of the 5'-termini of 23S and 5S rRNAs. Furthermore, we demonstrate strong genetic interactions between ybeY and rnc (encoding RNase III), ybeY and rnr (encoding RNase R), and ybeY and pnp (encoding PNPase), further suggesting a role for YbeY in rRNA maturation. Mutation of highly conserved amino acids in YbeY, allowed the identification of two residues (H114, R59) that were found to have a significant effect in vivo. We discuss the implications of these findings for rRNA maturation and ribosome assembly in bacteria., (© 2010 Blackwell Publishing Ltd.)

Protein kinase C delta (PKCdelta) is induced by insulin to rapidly associate with insulin receptor (IR) and upregulates insulin signaling. We utilized specific JM and CT receptor domains and chimeras of PKCalpha and PKCdelta regulatory and catalytic domains to elucidate which components of PKCdelta are responsible for positive regulatory effects of PKCdelta on IR signaling. Studies were performed on L6 and L8 skeletal muscle myoblasts and myotubes. PKCdelta was preferentially bound to the JM domain of IR, and insulin stimulation increased this binding. Both PKCdelta/alpha and PKCalpha/delta chimeras (regulatory/catalytic) were bound preferentially to the JM but not to the CT domain of IR. Although IR-PKCdelta binding was higher in cells expressing either the PKCdelta/alpha or PKCalpha/delta chimera than in control cells, upregulation of IR signaling was observed only in PKCdelta/alpha cells. Thus, in response to insulin increases in tyrosine phosphorylation of IR and insulin receptor substrate-1, downstream signaling to protein kinase B and glycogen synthase kinase 3 (GSK3) and glucose uptake were greater in cells overexpressing PKCdelta/alpha and the PKCdelta/delta domains than in cells expressing the PKCalpha/delta domains. Basal binding of Src to PKCdelta was higher in both PKCdelta/alpha- and PKCalpha/delta-expressing cells compared to control. Binding of Src to IR was decreased in PKCalpha/delta cells but remained elevated in the PKCdelta/alpha cells in response to insulin. Finally, insulin increased Src activity in PKCdelta/alpha-expressing cells but decreased it in PKCalpha/delta-expressing cells. Thus, the regulatory domain of PKCdelta via interaction with Src appears to determine the role of PKCdelta as a positive regulator of IR signaling in skeletal muscle.

The short-chain dehydrogenase/reductase (SDR) family is one of the largest and most ubiquitous protein families in bacterial genomes. Despite there being a few well-characterized examples, the substrate specificities or functions of most members of the family are unknown. In this study, we carried out a large-scale mutagenesis of the SDR gene family in the alfalfa root nodule symbiont Sinorhizobium meliloti. Subsequent phenotypic analysis revealed phenotypes for mutants of 21 of the SDR-encoding genes. This brings the total number of S. meliloti SDR-encoding genes with known function or associated phenotype to 25. Several of the mutants were deficient in the utilization of specific carbon sources, while others exhibited symbiotic deficiencies on alfalfa (Medicago sativa), ranging from partial ineffectiveness to complete inability to form root nodules. Five of the mutants had both symbiotic and carbon utilization phenotypes. These results clearly demonstrate the importance of the SDR family in both symbiosis and saprotrophy, and reinforce the complex nature of the interaction of S. meliloti with its plant hosts. Further analysis of the genes identified in this study will contribute to the overall understanding of the biology and metabolism of S. meliloti in relation to its interaction with alfalfa.

Whereas positive regulatory events triggered by insulin binding to insulin receptor (IR) have been well documented, the mechanism by which the activated IR is returned to the basal status is not completely understood. Recently studies focused on the involvement of protein tyrosine phosphatases (PTPs) and how they might influence IR signaling. In this study, we examined the possibility that cytosolic PTPepsilon (cytPTPepsilon) is involved in IR signaling. Studies were performed on L6 skeletal muscle cells. cytPTPepsilon was overexpressed by using pBABE retroviral expression vectors. In addition, we inhibited cytPTPepsilon by RNA silencing. We found that insulin induced rapid association of cytPTPepsilon with IR. Interestingly, this association appeared to occur in the plasma membrane and on stimulation with insulin the two proteins internalized together. Moreover, it appeared that almost all internalized IR was associated with cytPTPepsilon. We found that knockdown of cytPTPepsilon by RNA silencing increased insulin-induced tyrosine phosphorylation of IR and IR substrate (IRS)-1 as well as phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin-induced stimulation of glucose uptake. Moreover, overexpression of wild-type cytPTPepsilon reduced insulin-induced tyrosine phosphorylation of IR, IRS-1, and phosphorylation of protein kinase B and glycogen synthase kinase-3 and insulin-induced stimulation of glucose uptake. Finally, insulin-induced tyrosine phosphorylation of IR and IRS-1 was greater in skeletal muscle from mice lacking the cytPTPepsilon gene than that from wild-type control animals. We conclude that cytPTPepsilon serves as another major candidate negative regulator of IR signaling in skeletal muscle.

Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536+/-70 muleq/ml (mean+/-SE) (nl < 100 muleq/ml) before treatment to 291+/-25 muleq/ml at 12 wk (P < 0.001) and 157+/-32 muleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7+/-0.9 mg/dl to 3.4+/-0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4+/-4.3 pg/ml to 51.8+/-2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (-347+/-84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141+/-409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion. These observations indicate that cimetidine suppressed circulating concentration of biologically active parathyroid hormone. A probable net decrease in the loss of phosphorus from bone to blood ensued, resulting in a fall in serum phosphorus. This may have stimulated synthesis of 1,25-dihydroxycholecalciferol and led to a positive calcium balance, thereby maintaining the serum ionized calcium concentration. The maintenance of phosphate balance, despite suppression of iPTH by cimetidine, indicates that factors other than hyperparathyroidism relate to phosphate homeostasis in chronically uremic dogs.

In order to determine whether endotoxin is normally found in the portal system, intraoperative samples of portal and peripheral blood were drawn from 34 consecutive elective abdominal surgery patients. The limulus lysate test was used to detect endotoxin. Ninety-seven per cent of patients had a positive limulus test in portal blood. Twelve of these patients were tested for portal bacteremia and only one showed growth. Four patients also had systemic endotoxemia. Three of these had liver disease and one had a gram-negative sepsis. This study demonstrates that endotoxin is a normal constituent of portal venous blood in man and does not represent a pathological process. It is suggested that the Kupffer cells of the liver normally protect the systemic circulation from endotoxin, and that endotoxin is present in systemic blood only when liver function is impaired or gram-negative bacteremia is present.

It is well established that the calcemic response to parathyroid hormone (PTH) is blunted in chronic uremia and is corrected partially by 1,25(OH)2D treatment. Recent evidence suggests that PTH(1-34) and not PTH(1-84) may be the actual calcemic fragment. Equivalent doses of both peptides were infused into five normal dogs (GFR = 51 ml/min) and eight dogs with a remnant kidney and chronic renal insufficiency (GFR = 15 ml/min). Both the calcemic and phosphaturic responses were studied. Remnant dogs had a blunted calcemic response to bPTH(1-84). The increase in fractional phosphate excretion was similar. In contrast, the calcemic response to bPTH(1-34) was equivalent in remnant and normal dogs. Treatment of uremic dogs with 400 ng 1,25(OH)2D daily for 3 days restored the effect of bPTH(1-84) on serum calcium and increased the control value for tubular phosphate reabsorption from 28 +/- 3 micrograms/ml GFR to 37 +/- 4 micrograms/ml GFR (P less than 0.01). These results suggest that there is an impaired conversion of PTH(1-84) to PTH(1-34) in chronic renal insufficiency and that 1,25 (OH)2D may be involved in metabolism of PTH(1-84). In addition, the effect of PTH on fractional phosphate excretion is not magnified in nonparathyroidectomized uremic dogs.

Complement activation during exposure of plasma to cuprophan has been postulated to cause leukopenia and hypoxia in hemodialysis patients. To determine if hypoxia is related to leukopenia and if complement activation leads to a depletion of functional complement components, we dialyzed four patients three times sequentially against each of four types of membranes: cuprophan, regenerated cellulose, cellulose acetate, and polyacrilonitrile. Within 20 min there was a marked leukopenia with cuprophan from 5541 +/- 376 to 1216 +/- 94 (P less than 0.001) and with regenerated cellulose from 5541 +/- 411 to 1533 +/- 203 (P less than 0.001). With cellulose acetate, the change from 5558 +/- 400 to 3783 +/- 341 (P less than 0.001) was less dramatic, and with polyacrilonitrile the fall from 5591 +/- 381 to 464 +/- 401 (P less than 0.02) was minimal. After 2 and 4 hours of dialysis, a rebound leukocytosis was seen with cuprophan, regenerated cellulose, and cellulose acetate, but not with polyacrilonitrile. Transient thrombocytopenia occurred with cuprophan and regenerated cellulose. In spite of the variable degree of leukopenia, all membranes induced a similar and significant hypoxia, which was progressive throughout dialysis, even during the rebound leukocytosis. After 4 hours, the mean PO2 ranged from 91 to 93 mm Hg with all membranes. Functional hemolytic titers of whole complement, C3, C5, and C4 were normal prior to hemodialysis and failed to decrease after 4 hours with any membrane. It is concluded that hemodialysis leukopenia is membrane-dependent and is not the cause of hypoxia. In addition, hemodialysis complement activation does not lead to functional complement depletion and is of no clinical significance.

The initial step in cholecalciferol (vitamin D3) metabolism is the photo-conversion of 7-dehydrocholesterol to previtamin D3. This reaction occurs in the epidermis and requires ultraviolet light. We measured the circulating concentration of vitamin D (ergocalciferol and cholecalciferol), 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in 14 normal white, 9 normal black subjects, and in 9 white and 17 black hemodialysis patients. The mean plasma vitamin D in normal white subjects was greater than in normal black subjects, 4.01 +/- 1.02 ng/ml versus 0.96 +/- 0.30 ng/ml, respectively (P less than 0.05). Plasma 25-hydroxyvitamin D in normal blacks was also less than in normal whites, 17.7 +/- 1.5 ng/ml versus 31.3 +/- 3.0 ng/ml, respectively (P less than 0.01). In uremic white subjects, plasma vitamin D, 6.7 +/- 2.6 ng/ml, was similar to normal white subjects. However, vitamin D was not detectable in 12 of 17 uremic black subjects and was depressed in the remainder of the group. Following exposure to a single minimal erythema dose of ultraviolet-B irradiation, the maximal increase in plasma vitamin D was depressed in white dialysis patients as compared to healthy white subjects, 6.3 +/- 1.9 ng/ml versus 21.3 +/- 2.8 ng/ml, respectively (P less than 0.02). 7-Dehydrocholesterol content was similar in epidermis from site-matched skin of fresh cadavers and white hemodialysis patients, 131 +/- 23 ng/mg versus 124 +/- 14 ng/mg skin, respectively. It is concluded that chronic hemodialysis patients exhibit defective photoproduction of cholecalciferol, despite normal epidermal content of substrate, 7-dehydrocholesterol.