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Sideroxydans sp. CL21 is a microaerobic, acid-tolerant Fe(II)-oxidizer, isolated from the Schlöppnerbrunnen fen. Since the genome size of Sideroxydans sp. CL21 is 21% larger than that of the neutrophilic Sideroxydans lithotrophicus ES-1, we hypothesized that strain CL21 contains additional metabolic traits to thrive in the fen. The common genomic content of both strains contains homologs of the putative Fe(II) oxidation genes, mtoAB and cyc2. A large part of the accessory genome in strain CL21 contains genes linked to utilization of alternative electron donors, including NiFe uptake hydrogenases, and genes encoding lactate uptake and utilization proteins, motility and biofilm formation, transposable elements, and pH homeostasis mechanisms. Next, we incubated the strain in different combinations of electron donors and characterized the fen microbial communities. Sideroxydans spp. comprised 3.33% and 3.94% of the total relative abundance in the peatland soil and peatland water, respectively. Incubation results indicate Sideroxydans sp. CL21 uses H2 and thiosulfate, while lactate only enhances growth when combined with Fe, H2, or thiosulfate. Rates of H2 utilization were highest in combination with other substrates. Thus, Sideroxydans sp. CL21 is a mixotroph, growing best by simultaneously using substrate combinations, which helps to thrive in dynamic and complex habitats.

Plant physiology can offer invaluable insights to accelerate genetic gain. However, translating physiological understanding into breeding decisions has been an ongoing and complex endeavor. Here we demonstrate an approach to leverage physiology and genomics to hasten crop improvement. A half-diallel maize (Zea mays) experiment resulting from crossing 9 elite inbreds was conducted at 17 locations in the USA corn belt and 6 locations at managed stress environments between 2017 and 2019 covering a range of water environments from 377 to 760 mm of evapotranspiration and family mean yields from 542 to 1,874 g m−2. Results from analyses of 35 families and 2,367 hybrids using crop growth models linked to whole-genome prediction (CGM–WGP) demonstrated that CGM–WGP offered a predictive accuracy advantage compared to BayesA for untested genotypes evaluated in untested environments (r = 0.43 versus r = 0.27). In contrast to WGP, CGMs can deal effectively with time-dependent interactions between a physiological process and the environment. To facilitate the selection/identification of traits for modeling yield, an algorithmic approach was introduced. The method was able to identify 4 out of 12 candidate traits known to explain yield variation in maize. The estimation of allelic and physiological values for each genotype using the CGM created in silico phenotypes (e.g. root elongation) and physiological hypotheses that could be tested within the breeding program in an iterative manner. Overall, the approach and results suggest a promising future to fully harness digital technologies, gap analysis, and physiological knowledge to hasten genetic gain by improving predictive skill and definition of breeding goals.

Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) might underpin the 3-fold increase in maize (Zea mays L.) grain yield over the last century. Here we show that both RSA and yield have changed with decades of maize breeding, but not the crop water uptake. Results from X-ray phenotyping in controlled environments showed that single cross (SX) hybrids have smaller root systems than double cross (DX) hybrids for root diameters between 2465 µm and 181µm (P, Emerging opportunity to continue long-term genetic gain in maize yield in the US corn belt by improving the balance between canopy, root, and reproductive growth and development.

Background Nephrotic-range proteinuria (NRP) is associated with rapid kidney function loss and increased cardiovascular (CV) disease risk. We assessed the effects of linagliptin (LINA) on CV and kidney outcomes in people with Type 2 diabetes (T2D) with or without NRP. Methods Cardiovascular and renal microvascular outcome study with LINA randomized participants with T2D and CV disease and/or kidney disease to LINA 5 mg or placebo (PBO). The primary endpoint [time to first occurrence of 3-point major adverse cardiac events (3P-MACE)], and kidney outcomes, were evaluated by NRP status [urinary albumin:creatinine ratio (UACR) ≥2200 mg/g] at baseline (BL) in participants treated with one or more dose of study medication. Results NRP was present in 646/6979 [9.3% (LINA/PBO n = 317/n = 329); median UACR 3486 (Q1: 2746/Q3: 4941) mg/g] participants, who compared with no-NRP were younger (62.3/66.1 years) and had lower estimated glomerular filtration rate (eGFR) (39.9/56.1 mL/min/1.73 m2). Over a median of 2.2 years, 3P-MACE occurred with a 2.0-fold higher rate in NRP versus no-NRP (PBO group), with a neutral LINA effect, regardless of NRP. The composite of time to renal death, end-stage kidney disease (ESKD) or decrease of ≥40 or ≥50% in eGFR, occurred with 12.3- and 13.6-fold higher rate with NRP (PBO group); evidence of heterogeneity of effects with LINA was observed for the former [NRP yes/no: hazard ratio 0.80 (0.63–1.01)/1.25 (1.02–1.54); P-interaction 0.005], but not the latter [0.83 (0.64–1.09)/1.17 (0.91–1.51), P-interaction 0.07]. No heterogeneity was observed for renal death or ESKD [0.88 (0.64–1.21)/0.94 (0.67–1.31), P-interaction 0.79]. Glycated haemoglobin A1c (HbA1c) was significantly reduced regardless of NRP, without increasing hypoglycaemia risk. Regression to normoalbuminuria [1.20 (1.07–1.34)] and reduction of UACR ≥50% [1.15 (1.07–1.25)] from BL, occurred more frequently with LINA, regardless of NRP status (P-interactions >0.05). Conclusions Individuals with T2D and NRP have a high disease burden. LINA reduces their albuminuria burden and HbA1c, without affecting CV or kidney risk., Graphical Abstract

Vascularized composite allotransplantation (VCA) is the most advanced reconstructive technique available to patients who suffer devastating burns to the limbs or face. However, VCA requires donor–recipient matching. Burn patients have been reported to experience sensitization, or the development of anti-human leukocyte antigen antibodies, during resuscitation and wound coverage, potentially precluding them from future VCA. This study sought to investigate the contributions of both blood and allograft to sensitization in burn patients. Four groups were compared: burn patients who received blood products and allograft (group 1), burn patients who received blood products only (group 2), trauma patients who received blood products only (group 3), and healthy volunteer controls (group 4). The average calculated panel-reactive antibody (indicating sensitization) was higher in group 1 compared to group 4 (P = .035). Additionally, the incidence of severe sensitization was higher in group 1 relative to the other groups (P = .049). When comparing groups of patients who had no sensitization, mild sensitization, moderate sensitization, and severe sensitization, there were no significant differences in age, sex, blood products received, total body surface area burned, or allograft used between groups, though severely sensitized patients tended to have greater total body surface area involvement and received more units of packed red blood cells and allograft (P = .079, P = .196, and P = .072, respectively). We therefore conclude that while burn patients who received allograft and blood demonstrated a higher incidence of anti-human leukocyte antigen sensitization relative to healthy controls, this difference cannot solely be attributed to either allograft use or transfusion.

Conradie et al. (2020) recently modelled the vulnerability of Australian arid birds to a changing climate. While the approach used by Conradie et al. (2020) is valuable, we argue that key assumptions in their study are poorly supported and the risks of a changing climate to arid zone avifauna are consequently overstated.

Atherosclerosis, as manifested clinically by myocardial infarction, stroke and peripheral vascular disease, is a major contributor to cardiovascular disease, the leading cause of death in patients with diabetes. The lipid-laden plaque development within the arterial vessel wall is a progressive process initiated with endothelial cell activation and monocyte adhesion. These cellular events occur primarily at the regions of blood vessels exposed to turbulent blood flow (TBF) and low shear stress such as vascular bends and bifurcations. Exposure of the vascular cells to chronic hyperglycaemia and TBF induces a proatherogenic transcriptional profile. Studies have shown that shear stress regulates vascular pathophysiology via differential regulation of transcription factors (TFs) such as KLF4, EGR1 and AP-1, hence named as mechanosensitive TFs. AP-1 is a heterodimer composed of FOS, Jun and ATF family of TFs. Studies have shown that it is activated by low shear stress in cultured endothelial cells. Increasing evidence supports the vital role of AP-1 family members in inflammation and diabetes-induced myocardial dysfunction. However, gene targets and the mechanisms underlying hyperglycemia-induced activation of AP-1 transcription factor cFOS in vascular regions exposed to TBF are not known.Although a novel approach not previously studied in diabetes associated atherosclerosis, we used a single cell RNA sequencing (scRNA-seq) approach to identify endothelial cells from TBF regions of aorta. Diabetes was induced with streptozotocin (STZ) in Apoe−/− mice and followed for 10 weeks. Cells from digested aortae of control and diabetic mice were subjected to scRNA-seq using 10X Genomics system and Illumina Nova-seq 6000. Unsupervised graph based clustering grouped cells into fourteen cell clusters with similar gene expression profile. We applied a list of mechanosensitive gene markers including EGR1, cFOS, Junb and ICAM1 in scRNA-seq analysis to identify endothelial cells from TBF regions of aorta. This approach identified atheroprone endothelial cells exposed to persistent TBF that showed a distinct transcriptional profile with more than six hundred genes differentially expressed. Importantly, cFOS was the most significantly upregulated gene in endothelial cells exposed to TBF. We next generated adiabetes associated transcriptional signature unique to endothelial cells exposed to TBF as compared to all other cell types in the aorta. We identified several genes in endothelial cells exposed to TBF and hyperglycaemia uniquely dysregulated in diabetic Apoe−/− mice as compared to control mice (cut off = FDR Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): National Heart Foundation of Australia

Background Increased allostatic load is linked with racial discrimination exposure, providing a mechanism for the biological embedding of racism as a psychosocial stressor. We undertook an examination of how racial discrimination interacts with socioecological, environmental and health conditions to affect multisystem dysregulation in a First Nations population. Methods We conducted latent class analysis (LCA) using indicators of life stress, socioeconomic background and physical and mental health from a nationally representative sample of Australian Aboriginal adults (N = 2 056). We used LCA with distal outcomes to estimate the effect of the latent class variable on our derived allostatic load index and conducted a stratified analysis to test whether allostatic load varied based on exposure to racial discrimination across latent classes. Results Our socioecological, environmental and health measures informed a four-class structure; ‘Low risk’ (30.8%), ‘Challenged but healthy’ (27.8%), ‘Mental health risk’ (24.0%) and ‘Multiple challenges’ (17.4%). Mean allostatic load was highest in ‘Multiple challenges’ compared to all other classes, both in those exposed (4.5; 95% CI: 3.9, 5.0) and not exposed (3.9; 95% CI: 3.7, 4.2) to racial discrimination. Allostatic load was significantly higher for those with exposure to racial discrimination in the ‘Multiple challenges’ class (t = 1.74, p=.04) and significantly lower in the ‘Mental health risk’ class (t=-1.67, p=.05). Conclusions Racial discrimination may not always modify physiological vulnerability to disease. Social and economic contexts must be considered when addressing the impact of racism, with a focus on individuals and sub-populations experiencing co-occurring life challenges. Key messages Racial discrimination can increase physiological dysregulation in Aboriginal and Torres Strait Islander adults with a profile of psychosocial stress and adverse health.

Introduction Infection and prolonged inflammation in deep partial-thickness burns can lead to inadequate healing. In addition to their role in hemostasis, activated platelets also contain granules with anti-inflammatory properties which may impact wound healing. However, portability and storage of platelets remain a challenge. Synthetic platelet-mimetics (SPM) avoid these difficulties, but like natural platelets, SPM have vesicles that can transport bioactive agents, such as antibiotics. We sought to evaluate wound healing outcomes in deep partial-thickness burns treated topically with SPM. Methods A total of 30 circular, deep partial-thickness burns were created on the dorsum of 2 porcine models. Each wound measured 5cm in diameter and was standardized using a thermocoupled burn device. Sets of six wounds were randomized into five groups: SPM, gentamicin alone, SPM with gentamicin, a vehicle control (saline), or dry gauze (the standard of care, SOC). Additionally, two separate 5cm diameter circular areas were demarcated to serve as normal skin controls. Wounds were assessed at post-burn days 3, 7, 14, 21, 28, 60 and 90 with a variety of non-invasive imaging and punch biopsies. Treatments were re-applied at each assessment. The primary outcome was the amount of wound re-epithelialization, measured histologically, at post-burn day 28. Secondary outcomes consisted of the percentage of wound contraction, amount of superficial blood flow, and mean bacterial load. Results The amount of wound re-epithelialization in wounds treated with SPM was 96% whereas those treated with the SOC measured only slightly less at 92% (p = 0.56). The percentage of wound contraction was 39% in the SPM with gentamicin group, while in the SOC group contraction was higher at 45% (p = 0.20). Moreover, superficial blood flow in the SPM group was measured to be 168% of normal skin controls, while wounds in the SPM with gentamicin group were slightly lower at 160%, and in wounds treated with the SOC blood flow was 110% of normal skin controls (p = 0.27). The mean bacterial load in each group was measured at post-burn day 3 and notably consisted of bacterial load being the lowest in wounds treated with gentamicin alone at 17/100, meanwhile in wounds treated with the SOC or those in the SPM with gentamicin group, mean bacterial loads were significantly higher at 43/100 and 47/100, respectively (p = 0.02). Conclusions SPM applied to deep partial-thickness burns did not significantly improve measured outcomes over the SOC. Although numerical improvements were shown in all measured outcomes, no significant differences were noted. The theoretical and observed potential for SPM to improve wound healing deserves additional evaluation in larger preclinical studies.

Introduction Burns are common injuries in the battlefield. Given austere environments, prolonged field care (PFC) is often necessary. Delays in surgical debridement create a risk of infection and deranged healing for burn patients. As such, this study attempts to identify the best commercially available off-the-shelf (OTS) dressings with field-deployable potential. Methods Deep-partial thickness burns (1" diameter) were created on the dorsum of 3 anesthetized pigs utilizing a thermocoupled burn device at 100°C for 15s. Non-surgical debridement was done 1-h post-burn creation and either an OTS dressing or standard-of-care (SOC) treatment (Silver Sulfadiazine) was applied to the wound in order to simulate a PFC environment. OTS dressings were randomized and included irradiated sterile human skin allograft (ISHSA), alloplastic absorbable skin substitute (AASS), and synthetic polyurethane dermal matrix (SPDM). Wounds were serially assessed on post-burn days 3, 7, 14, 21, and 28. Assessments were conducted using a combination of photographs, histology, and quantitative bacteriology. Endpoints included burn wound progression, re-epithelialization, wound contraction, scar elevation index (SEI), and colony forming units (CFU). Results No statistically significant differences in burn wound progression were seen on days 3 and 7 for the ISHSA or SPDM and the SOC. The differences between the AASS and the SOC were statistically significant on both days (p≤0.05). Day 21 re-epithelialization results for the ISHSA, AASS, SPDM and SOC treated wounds were 30%, 85%, 95%, and 78% re-epithelialized, respectively. The difference between the AASS and the SOC was statistically significant (p≤0.05). Results showed that by day 28, wound contraction for the ISHSA, AASS, SPDM and SOC treated wounds were 65%, 80%, 82%, and 78%, respectively. No statistically significant differences in wound contraction were seen for any of the OTS dressings and the SOC. SEI showed no statistically significant difference in scar hypertrophy between the OTS dressings and the SOC on day 28. CFU results showed no statistically significant differences between the OTS dressings and the SOC on days 3 and 7. Conclusions Three OTS dressings were compared to the SOC for use in the PFC setting. Generally, all the dressings performed well when compared to the SOC in terms of burn wound progression, re-epithelialization, wound contraction, SEI, and CFU. Although significant differences in burn progression and re-epithelialization for burns treated with AASS were seen. In the future, we hope to continue to discover and test various OTS dressings to determine their appropriateness for use in the PFC setting.

Background Unlike the other 2 criteria for diagnosing premature ejaculation (PE), namely lack of ejaculatory control and short ejaculation latency (EL), the role of bother/distress has received only minimal consideration and investigation. Aim The specific aim was to determine both why distress is included in the PE diagnosis and whether such inclusion is advantageous to achieving better diagnostic outcomes. To this end, the review explored the historical and theoretical underpinnings of the inclusion of “bother/ distress” in the diagnosis of PE, with reference to the larger role that distress has played in the diagnosis of mental disorders, in an attempt to understand the utility (or lack thereof) of this construct in making a PE diagnosis. Methods We reviewed the role of bother/distress across current professional definitions for PE and then expanded this discussion to include the role of distress in other sexual dysfunctions. We then included a brief historical perspective regarding the role that distress has played in the diagnosis of PE. This discussion is followed by a deeper look at 2 nosological systems, namely DSM and ICD, to allow perspective on the inclusion of the bother/distress construct in the diagnosis of mental and behavioral disorders, including the assumptions/arguments put forward to include or exclude bother/distress as an important criterion underlying various professional assumptions. Outcome Determination of the value and/or need of including bother/distress as a necessary criterion for the diagnosis of PE. Results Based on the research literature, bother/distress does not appear to be as critical for a PE diagnosis as either the lack of ejaculatory control or short EL. It is the weakest of the differences among men with and without PE, and recent evidence suggests that its inclusion is generally redundant with the severity of the 2 other criteria for PE, ejaculatory control and EL. Clinical Translation Bother/distress appears to serve little purpose in the diagnosis of PE yet its assessment may be important for the treatment strategy and for assessing treatment effectiveness. Strengths and Limitations This review did not provide a critical analysis of the literature regarding the role of bother/distress in PE, but rather focused on its potential value in understanding and diagnosing PE. Conclusion Although bother/distress appears to add little to the improvement of accuracy for a PE diagnosis, understanding and assessing the man's or couple's experience of distress has important implications for the treatment strategy and focus, as well as for assessing treatment success.

Plant-breeding programs are designed and operated over multiple cycles to systematically change the genetic makeup of plants to achieve improved trait performance for a Target Population of Environments (TPE). Within each cycle, selection applied to the standing genetic variation within a structured reference population of genotypes (RPG) is the primary mechanism by which breeding programs make the desired genetic changes. Selection operates to change the frequencies of the alleles of the genes controlling trait variation within the RPG. The structure of the RPG and the TPE has important implications for the design of optimal breeding strategies. The breeder’s equation, together with the quantitative genetic theory behind the equation, informs many of the principles for design of breeding programs. The breeder’s equation can take many forms depending on the details of the breeding strategy. Through the genetic changes achieved by selection, the cultivated varieties of crops (cultivars) are improved for use in agriculture. From a breeding perspective, selection for specific trait combinations requires a quantitative link between the effects of the alleles of the genes impacted by selection and the trait phenotypes of plants and their breeding value. This gene-to-phenotype link function provides the G2P map for one to many traits. For complex traits controlled by many genes, the infinitesimal model for trait genetic variation is the dominant G2P model of quantitative genetics. Here we consider motivations and potential benefits of using the hierarchical structure of crop models as CGM-G2P trait link functions in combination with the infinitesimal model for the design and optimization of selection in breeding programs.

Background Transcriptomic analyses have provided invaluable information for linking genotypes to phenotypes. However, despite the near identical genotype, each cell types in our body has a unique gene expression signature. Deep sequencing at single cell resolution has provided a unique opportunity to unbiasedly discover cellular heterogeneity, disease associated cell populations and to characterise the cell specific transcriptomic landscape. Cardiovascular (CV) disease, a leading cause of death worldwide, is caused mainly by atherosclerosis, a pathological build-up of plaque within arterial vessel walls. Fluid mechanical forces generated by disturbed blood flow are long known to cause structural and transcriptional changes in the vascular endothelium. Atherosclerosis develops near branches and bends of arteries exposed to disturbed blood flow. Diabetes accelerates atherosclerosis development and indeed, represents an independent risk factor. However, the transcriptional signature of atheroprone endothelium in the diabetic aorta has not been investigated previously for this CV complication. Purpose This study was designed to apply a single cell RNA sequencing (scRNA-seq) approach to identify the transcriptional signature of atherosusceptible endothelium in diabetes associated atherosclerosis. Methods Diabetes was induced with streptozotocin in ApoEs−/− mice and followed for 10 weeks. Cells from digested aortae of control and diabetic mice were FACS-sorted for viable and metabolically active cells. These cells were loaded onto the Chromium Single Cell Controller (10X Genomics) to generate a single cell and gel bead emulsion. ScRNA-seq libraries were prepared with Single Cell 3' Solution V2 kit (10X Genomics) and sequenced with Illumina Nova-seq 6000. We have applied scRNA-seq to identify atheroprone endothelial cells in the aorta. Results and conclusion The atheroprone endothelial cells show distinct transcriptional profile with more than six hundred genes differentially expressed. ScRNA-seq allowed us not only to distinguish the two transcriptionally distinct endothelial subpopulations but also to identify a diabetes associated gene expression signature unique to atheroprone endothelial cells as compared to all other cell types in the aorta. We identified seventeen genes uniquely dysregulated in the diabetic atheroprone endothelial cell (Cut off = FDR s Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Heart Foundation of Australia; NHMRC National Health and Medical Research Council of Australia

BACKGROUND: Polymyxin B and E (colistin) have been pivotal in the treatment of XDR Gram-negative bacterial infections; however, resistance has emerged. A structurally related lipopeptide, octapeptin C4, has shown significant potency against XDR bacteria, including polymyxin-resistant strains, but its mode of action remains undefined. OBJECTIVES: We sought to compare and contrast the acquisition of resistance in an XDR Klebsiella pneumoniae (ST258) clinical isolate in vitro with all three lipopeptides to potentially unveil variations in their mode of action. METHODS: The isolate was exposed to increasing concentrations of polymyxins and octapeptin C4 over 20 days. Day 20 strains underwent WGS, complementation assays, antimicrobial susceptibility testing and lipid A analysis. RESULTS: Twenty days of exposure to the polymyxins resulted in a 1000-fold increase in the MIC, whereas for octapeptin C4 a 4-fold increase was observed. There was no cross-resistance observed between the polymyxin- and octapeptin-resistant strains. Sequencing of polymyxin-resistant isolates revealed mutations in previously known resistance-associated genes, including crrB, mgrB, pmrB, phoPQ and yciM, along with novel mutations in qseC. Octapeptin C4-resistant isolates had mutations in mlaDF and pqiB, genes related to phospholipid transport. These genetic variations were reflected in distinct phenotypic changes to lipid A. Polymyxin-resistant isolates increased 4-amino-4-deoxyarabinose fortification of lipid A phosphate groups, whereas the lipid A of octapeptin C4-resistant strains harboured a higher abundance of hydroxymyristate and palmitoylate. CONCLUSIONS: Octapeptin C4 has a distinct mode of action compared with the polymyxins, highlighting its potential as a future therapeutic agent to combat the increasing threat of XDR bacteria.

Aims Renal inflammation, leading to fibrosis and impaired function is a major contributor to the development of hypertension. The NLRP3 inflammasome mediates inflammation in several chronic diseases by processing the cytokines pro-interleukin (IL)-1β and pro-IL-18. In this study, we investigated whether MCC950, a recently-identified inhibitor of NLRP3 activity, reduces blood pressure (BP), renal inflammation, fibrosis and dysfunction in mice with established hypertension. Methods and results C57BL6/J mice were made hypertensive by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/day, s.c.) and 0.9% NaCl in the drinking water (1K/DOCA/salt). Normotensive controls were uninephrectomized and received normal drinking water. Ten days later, mice were treated with MCC950 (10 mg/kg/day, s.c.) or vehicle (saline, s.c.) for up to 25 days. BP was monitored by tail-cuff or radiotelemetry; renal function by biochemical analysis of 24-h urine collections; and kidney inflammation/pathology was assessed by real-time PCR for inflammatory gene expression, flow cytometry for leucocyte influx, and Picrosirius red histology for collagen. Over the 10 days post-surgery, 1K/DOCA/salt-treated mice became hypertensive, developed impaired renal function, and displayed elevated renal levels of inflammatory markers, collagen and immune cells. MCC950 treatment from day 10 attenuated 1K/DOCA/salt-induced increases in renal expression of inflammasome subunits (NLRP3, ASC, pro-caspase-1) and inflammatory/injury markers (pro-IL-18, pro-IL-1β, IL-17A, TNF-α, osteopontin, ICAM-1, VCAM-1, CCL2, vimentin), each by 25–40%. MCC950 reduced interstitial collagen and accumulation of certain leucocyte subsets in kidneys of 1K/DOCA/salt-treated mice, including CD206+ (M2-like) macrophages and interferon-gamma-producing T cells. Finally, MCC950 partially reversed 1K/DOCA/salt-induced elevations in BP, urine output, osmolality, [Na+], and albuminuria (each by 20–25%). None of the above parameters were altered by MCC950 in normotensive mice. Conclusion MCC950 was effective at reducing BP and limiting renal inflammation, fibrosis and dysfunction in mice with established hypertension. This study provides proof-of-concept that pharmacological inhibition of the NLRP3 inflammasome is a viable anti-hypertensive strategy.

Introduction Split-thickness skin grafts (STSGs) are the mainstay of skin replacement therapy but fail to adequately reproduce basic skin functions and subject patients to new, open wounds that can cause significant pain and scarring. Full-thickness skin grafts (FTSGs) have improved cosmetic outcomes and better recapitulate skin functions, but few sites can serve as donors and requirement for “take” is greater. Prior research has shown that full-thickness skin column (FTSC) harvest results in improved healing of the injured site and decreased morbidity of the donor site at 10% harvest density. This study aims to determine the maximal harvest density of FTSC donor sites. Methods Ten donor sites were created on the dorsum of anesthetized swine (Sus scrofa domestica). STSG donor sites were harvested with a dermatome (12/1000 inch) and compared to FTSC donor sites with the highest possible harvest ratio of sixteen 1.5mm-diameter skin columns/1cm2 (28% harvest density). Donor site morbidity was assessed via re-epithelialization, contraction, pigmentation, number of hair follicles, and scar thickness on post-burn day (PBD) 7, 14, 21, 28, 60, and 90. Results There were no significant differences in re-epithelialization or contraction between FTSC and STSG donor sites. STSG donor site pigmentation was significantly decreased as compared to control on all assessment days (p=0.0161, 0.0003, 0.0031, 0.0095, 0.0244, respectively), and remained significantly hypopigmented as compared to FTSC starting at PBD 14 (p< 0.0001). Pigmentation was decreased for FTSC donor sites at PBD 14 (p=0.0204) but significance was lost by PBD 21. Both FTSC and STSG donor sites showed significantly fewer hair follicles as compared to control at PBD 7 (p=0.0011, 0.0003, respectively). On PBD 21, STSG had significantly less hair follicles as compared to FTSC donor sites (p=0.0010). This resolved by PBD 28. FTSC scars were significantly thicker than both control and STSG at PBD 28 (p=0.0348, 0.0038, respectively) and PBD 60 (p=0.0174, 0.0329, respectively). This significance was lost by PBD 90. Conclusions No statistically significant differences were seen in re-epithelialization and contraction between FTSC and STSG donor sites. STSG were hypopigmented as compared to FTSC donor sites and had significantly less hair follicles at day 21. FTSC donor site scars were significantly thicker than STSG. Although decreased donor site morbidity has been observed at lower harvest densities (10%), these results were not seen at 28%, which likely exceeds the optimal harvest density.

Introduction Despite advances in burn care, hypertrophic burn scars (HTBS) remain a significant source of morbidity. Treatment often involves use of CO2 lasers to reduce thickness and pulse-dye lasers (PDL) to reduce erythema. Despite frequent utilization, little quantitative data exists. This study seeks to objectively determine the effects of these laser treatments on burn scars. Methods Patients found to have HTBS undergoing laser treatments were approached for enrollment. Following enrollment, an area of HTBS outside of the treatment area was divided into 4 equal 3x3cm squares which were randomized to receive either CO2, PDL, CO2+PDL, or no treatment. Patients underwent a total of 3 treatments, 4–6 weeks apart, and were seen for follow-up over 3–6 months. Scar assessments occurred at each visit prior to treatment and consisted of digital photographs, ultrasound assessment for scar thickness, colorimetry, and the Patient and Observer Scar Assessment Score (POSAS). Results Twenty-five patients were enrolled at our institution. To date, 12 (48%) have completed all 3 treatments and the remainder are still in their follow-up period. Median initial scar thickness (ST) was 0.3cm. Mean time since injury was 9 months. Overall, there was a significant decrease in ST over time (p=0.0246) but not between treatment groups. There were no significant changes seen in melanin, erythema, or POSAS scores (p=0.9030, 0.6470, and 0.1495, respectively). When separated by ST before initiation of treatment, thin scars (< 3cm) appeared to be overall less erythematous in groups treated with PDL and CO2+PDL and untreated groups (p=0.0358, 0.0027. 0.0118, respectively) as compared to thick scars (≥3cm). Thin scars treated with PDL and CO2+PDL were also less pigmented than thick scars (p=0.0127, 0.0213, respectively). Erythema significantly decreased between the last treatment and the final visit for PDL and CO2+PDL groups (p< 0.0001). Older scars (≥9 months prior to treatment) tended to have a greater reduction in thickness as compared to newer scars but the difference was not significant to date. Conclusions Laser therapy is often employed in the treatment of HTBS. However, few studies have determined their objective benefits. Based on a preliminary analysis of our data, we have shown an overall decrease in scar thickness, less pigmentation, and less erythema in thin scars treated with PDL or CO2+PDL. Further analysis will be performed after additional follow-up information is collected.

Cell wall peptidoglycan stimulates interleukin 10 (IL-10) production in Staphylococcus aureus bacteremia (SaB) animal models, but clinical data are not available. This study evaluates the impact of intravascular bacterial cell numbers (ie, the level of bacteremia), in patients at the time of clinical presentation on IL-10 production and its association with S. aureus bacteremia (SaB) mortality. Blood and isolates were collected in 133 consecutive SaB patients. Serum IL-10 was quantified by an electrochemoluminescence assay. Bacterial inoculum was measured in patient sera with elevated (n = 8) or low (n = 8) IL-10 using a magnetic bacterial capture assay. Staphylococcus aureus from these 2 groups were introduced into whole blood ex vivo to determine IL-10 production with variable inocula. IL-10 serum concentration was higher in SaB patient mortality (n = 27) vs survival (n = 106) (median, 36.0 pg/mL vs 10.4 pg/mL, respectively, P Elevated IL-10 serum concentrations at clinical presentation of SaB were highly associated with mortality. High intravascular peptidoglycan concentration, driven by a higher level of bacteremia, is a key mediator of IL-10 anti-inflammatory response that portends poor clinical outcome. Using IL-10 as an initial biomarker, clinicians may consider more aggressive antimicrobials for rapid bacterial load reduction in high-risk SaB patients.

Introduction Skin graft survival relies on imbibition, inosculation, and revascularization from the wound bed. When a wound bed is poorly vascularized, as in the case of exposed fascia, tendon or bone, skin grafting may be delayed until the wound bed improves. We propose that topical nutrient supplementation may be able to increase take of skin grafts applied over an avascular wound bed. Methods Twenty full-thickness 5cm-diameter wounds were created on the dorsum of anesthetized swine and a dermal substitute (0.4mm, 0.8mm, 1.2mm, or 1.6mm thick) was placed on each wound. Negative pressure therapy with and without intermittent (3x per day) saline instillation was applied. Wounds were analyzed using a non-contact 3D camera at day 7 and day 14. Results Dermal substitutes of 0.8mm, 1.2mm, and 1.6mm thicknesses inhibited graft take significantly (p< 0.01, p=0.02, p< 0.01, respectively) for all wounds treated with wound vac alone. Addition of the normal saline instill showed a significant improvement in graft take (p=0.03) over wound vac alone for the wounds treated with the 0.8mm dermal substitute. Wounds covered with 1.2mm and 1.6mm dermal substitute continued to show significantly decreased graft take (p=0.03 and p=0.02, respectively). Wounds with 0.4mm dermal substitute showed similar graft take to control for both the wound vac and wound vac + instill treatments. Conclusions Dermal substitutes ≥0.8mm create a successful model of an avascular wound bed. Vac + instill treatment overcame the impedance of an avascular wound bed only for the 0.8mm dermal substitute thickness. This thickness of dermal substitute creates an ideal avascular wound bed model from which to conduct further studies incorporating topical nutrients instilled directly onto skin grafts placed onto avascular wound beds. Applicability of Research to Practice Single-stage skin grafting procedures onto avascular wound beds may become feasible with topical nutrient supplementation providing the environment to maintain graft survival until the wound bed is able to support the skin graft.

Introduction The ability of laser speckle contrast imaging (LSCI) to provide real-time images of blood flow makes this modality appealing in the assessment of burn wounds, particularly for clinicians making treatment decisions based on burn wound depth and presumed progression. Here we present 2 preclinical studies that used LSCI to assess wound progress, both immediately and months after injury. Methods LSCI images were taken 10-40cm away from the wound and captured with a 1388x1038-pixel CCD camera. In the first study, LSCI images were captured prior to and immediately following creation of superficial partial-thickness (SPTB, 10s), deep partial-thickness (DPTB, 15s), and full-thickness burns (FTB, 20s), and on post-burn day (PBD) 1, 2, and 3. In the second study, LSCI images were obtained before and after DPTB creation and on PBD 7, 14, 21, 28, 60, 90, and 120. Results 92 wounds from 9 swine were included. Speckle data was normalized to control sites and converted to percentages ([speckle wound/speckle control] x 100), producing speckle percentage of control (SPOC) which quantifies the relative decrease or increase in speckle output (vascularity). SPOC was significantly decreased for all burn times on PBD 0, 1, and 2. By PBD 3, only DPTB and FTB remained diminished (p=0.028 and p=0.005, respectively), and FTB SPOC was significantly less than the SPTB (p=0.015). In the second study, SPOC showed an increase post-debridement on PBD 7, noted as post-debridement day (PDD) 0. SPOC continued to increase significantly to a peak at PDD 7 (p< 0.0001) and remained elevated until PDD 28. By PDD 60, SPOC was no longer significantly increased. Conclusions LSCI is a reliable method for analyzing burn depth and wound progression in the preclinical setting. LSCI data shows an immediate decrease in vascularity at all burn depths immediately following burn creation, followed by a peak in vascularity on PDD 7, with a trend back to normal by PDD 60. Applicability of Research to Practice The correlation of wound bed vascularity based on LSCI to known data on burn depth and progression suggests that LSCI could be a useful measurement tool in the clinical setting for the provider determining wound viability.

Background/Introduction CARMELINA was a randomized placebo-controlled clinical trial designed to demonstrate the cardiovascular (CV) safety of linagliptin in patients with type 2 diabetes (T2D) and concomitant cardiorenal disease. Despite a particularly elevated CV risk, only limited long-term evidence from randomized controlled trials for safety and efficacy of glucose lowering medications is available for this population. Purpose To characterize the effects of linagliptin on net CV disease and hospitalization burden in this population. Methods People with T2D and either i) urine albumin creatinine ratio (UACR) >30 mg/g with concomitant CV disease, or ii) estimated glomerular filtration rate (eGFR) 200 mg/g, were randomized to linagliptin 5 mg or placebo q.d. in a double-blind fashion in addition to standard of care. We assessed the effects of linagliptin versus placebo on all first plus recurrent CV events and all-cause hospitalizations using a using a negative binomial model to account for within-subject correlation. Results A total of 6979 participants were enrolled (mean age 66 years, 63% male, eGFR 54.6 ml/min/1.73m2, median UACR 162 mg/g, 59% with history of ischemic heart disease, 27% with history of heart failure (HF)) and followed for a median of 2.2 years. Adding recurrent events increased the number of events for analysis from 5.3–57.5% across CV/HF outcomes and 112.4% for hospitalizations. In analyses of first plus recurrent events, the event rate ratio (95% CI) with linagliptin versus placebo was 0.98 (0.82, 1.16; p=0.78) for 3-point MACE, 1.03 (0.79, 1.35; p=0.83) for myocardial infarction 1.03 (0.83, 1.29; p=0.77) for myocardial infarction plus revascularization, 0.89 (0.65, 1.22; p=0.48) for stroke, 0.94 (0.70, 1.27; p=0.69) for stroke plus TIA, 0.94 (0.75, 1.20; p=0.63) for hospitalized HF, 0.92 (0.77, 1.11; p=0.40) for the composite of CV death or hospitalized HF, and 0.96 (0.87, 1.06; p=0.40) for all-cause hospitalization (Figure). Conclusion Linagliptin showed similar risk of either first or recurrent CV or hospitalization events compared with placebo in patients with T2D and cardiorenal disease. These data support the CV safety of linagliptin and, considering the high volume of recurrent events, underscores the significant CV disease burden experienced by patients with T2D and cardiorenal disease Acknowledgement/Funding Boehringer Ingelheim and Eli Lilly

Reproductive failure under drought in maize (Zea mays) is a major cause of instability in global food systems. While there has been extensive research on maize reproductive physiology, it has not been formalized in mathematical form to enable the study and prediction of emergent phenotypes, physiological epistasis and pleiotropy. We developed a quantitative synthesis organized as a dynamical model for cohorting of reproductive structures along the ear while accounting for carbon and water supply and demand balances. The model can simulate the dynamics of silk initiation, elongation, fertilization and kernel growth, and can generate well-known emergent phenotypes such as the relationship between plant growth, anthesis-silking interval, kernel number and yield, as well as ear phenotypes under drought (e.g. tip kernel abortion). Simulation of field experiments with controlled drought conditions showed that predictions tracked well the observed response of yield and yield components to timing of water deficit. This framework represents a significant improvement from previous approaches to simulate reproductive physiology in maize. We envisage opportunities for this predictive capacity to advance our understanding of maize reproductive biology by informing experimentation, supporting breeding and increasing productivity in maize.

Introduction Skin grafting of poorly vascularized wound beds, (e.g. exposed fascia, tendon, or bone) is often a multi-stage procedure, resulting in persistent open wounds and long-term complications such as scarring and contracture. Single-stage skin replacement could mitigate these downsides. Here we present the addition of topical nutrients and negative-pressure wound therapy (NPWT) + saline instill to improve graft take, and a case report of treatment of a non-healing wound in a single-stage procedure. Methods Ex vivo, STSGs (12/1000ths in) were harvested from swine (Sus scrofa domestica) post-euthanasia and transferred into wells with distilled water, PBS, Tyrode’s Buffer, high (4.5g/L) and low (2g/L) glucose DMEM, EpiLife, or William’s E (WE) media for 7 days, followed by performance of biochemical analyses and immunohistochemistry. In vivo, 20 full-thickness 5cm-diameter excisional wounds on the dorsum of two anesthetized swine were treated with dermal substitutes (DS, 0.4mm, 0.8mm, 1.2mm, or 1.6mm thickness), STSG, and NPWT with or without intermittent saline instill (3x daily, 300mL, 15-minute soak). Re-epithelialization was assessed at day 7 and 14. Lastly, a chronic 800cm2 left knee wound was treated with NPWT + instill (every 3.5 hours, 80mL, 10-minute soak, 3-day duration) over a 12/1000ths inch STSG. Results DMEM with high glucose (DMEM-HG) and WE produced the most lactic acid and enzymatic carbonate. Lactate dehydrogenase activity was lowest with WE. DMEM-HG had the highest glucose consumption but the most unconsumed glucose, with WE resulting in the next highest amount. Immunohistochemistry showed DMEM-HG or WE had the most dividing and least dying cells. In the porcine model, DS of 0.8mm, 1.2mm, and 1.6mm thicknesses inhibited graft take significantly (p< 0.01, p=0.02, p< 0.01, respectively) for all NPWT alone wounds. Addition of saline instill showed significant improvement in graft take (p=0.03) for 0.8mm DS wounds. 1.2mm and 1.6mm DS wounds continued to show significantly decreased graft take (p=0.03 and p=0.02, respectively). All 0.4mm DS wounds performed similar to control. Clinically, following NPWT removal on post-op day 3, almost complete STSG take was observed without exudate, pus, or malodor within the wound bed. Conclusions While additional studies are ongoing to determine the optimal nutrient supplementation, WE performed the best overall thus far. In vivo, 0.8mm DS created a successful model of a poorly vascularized wound bed, as NPWT + instill overcame this thickness. The novel use of NPWT + instill treatment over STSG clinically shows promise to improve graft take in the future.

When an immobile prey has detected an immobile predator nearby, predation risk is greater when the predator is closer. Consequently, prey flee with shorter latency as standing distance (predator-prey distance when both are still) decreases. Since it was first reported in 2009, this relationship has been confirmed in the few species studied. However, little is known about the functional relationship between standing distance and latency to flee (LF). We hypothesized that LF increases as standing distance increases at short distances, but reaches a plateau at longer distances where prey can escape reliably if attacked. We simulated immobile predators by moving slowly into positions near striped plateau lizards Sceloporus virgatus, stopping and then remaining immobile, and recording LF from the stopping time. LF increased from shorter to longer standing distances in a decelerating manner. The relationship was concave downward, and LF was indistinguishable among the longer standing distance groups. Latency to flee appears to reach a plateau or approach an asymptotic value as standing distance increases. The effect size of standing distance was large, indicating that S. virgatus sensitively adjusts LF to the level of risk associated with standing distance. Relationships between risk assessment and theoretical zones associated with risk, its assessment by prey, and escape decisions are discussed. Effect sizes of standing distance were substantial to large in all studies to date, indicating that standing distance is an important predation risk factor when both predator and prey are immobile.

Germplasm, genetics, phenotyping, and selection, combined with a clear definition of product targets, are the foundation of successful hybrid maize breeding. Breeding maize hybrids with superior yield for the drought-prone regions of the US corn-belt involves integration of multiple drought-specific technologies together with all of the other technology components that comprise a successful maize hybrid breeding programme. Managed-environment technologies are used to enable scaling of precision phenotyping in appropriate drought environmental conditions to breeding programme level. Genomics and other molecular technologies are used to study trait genetic architecture. Genetic prediction methodology was used to breed for improved yield performance for drought-prone environments. This was enabled by combining precision phenotyping for drought performance with genetic understanding of the traits contributing to successful hybrids in the target drought-prone environments and the availability of molecular markers distributed across the maize genome. Advances in crop growth modelling methodology are being used to evaluate the integrated effects of multiple traits for their combined effects and evaluate drought hybrid product concepts and guide their development and evaluation. Results to date, lessons learned, and future opportunities for further improving the drought tolerance of maize for the US corn-belt are discussed.

INTRODUCTION Longitudinal imaging evaluation of brain tumor patients with MRI is a challenging endeavor, as there is considerable overlap between imaging findings of tumor progression and treatment related changes. There is felt to be a high degree of variation between individual interpreters, particularly in complex cases. Structured reporting systems, such as the recently described brain tumor reporting and data system (BT-RADS), attempt to maximize consistency between reading radiologists, although how successful they are at achieving this is unknown. METHODS Patients with a diagnosis of a primary brain tumor with imaging presented at adult brain tumor board between October 2017 and March 2019 were reviewed. The most recent follow-up MRI was scored on an 8-point scale as described by BT-RADS, ranging from 0 to 4 with increasing suspicion for worsening disease, as described in the original radiologist report. Secondary review of MRI was performed by one of three neuroradiologists routinely participating in brain tumor conference. Interrater agreement between primary and secondary review were calculated using rates of exact agreement and linear weighted kappa. RESULTS Of studies reviewed, 270 out of 275 had imaging and reports suitable for repeat structured scoring. Grade 4 astrocytoma (glioblastoma) was the most common diagnosis, followed by grade 2 oligodendroglioma and grade 2 astrocytoma. The overall agreement rate between initial and secondary review was 83.0% with kappa of 0.89 +/- .05. There was perfect agreement on studies with improvement (1a or 1b) with lower levels of agreement (63.6–82.4%) for studies with worsening imaging findings (3a-4). CONCLUSIONS Using a structured reporting system to categorize MRIs in brain tumor patients allows for precise characterization of variation between report conclusions on primary and secondary review. Overall agreement is good, but variation rates increase with worsening findings which may be harder to correctly interpret.

Economic escape theory predicts flight initiation distance (FID, predator–prey distance when fleeing from an approaching predator begins), but currently cannot account for an observed increase in FID as alert distance (AD, predator–prey distance when a prey becomes alert to a predator), or its surrogate, starting distance (SD, predator–prey distance when approach begins) increases. The flush early and avoid the rush hypothesis suggests that FID increases as AD increases due to costs of monitoring the predator. However, the AD–FID relationship and the cost of monitoring have been questioned. Nevertheless, recent evidence shows that FID remains correlated with AD even when spontaneous movements are removed. We discuss possible effects of monitoring that might explain the AD–FID relationship and ways to improve understanding of the influence of spontaneous movements. We disentangle possible effects of 3 distinct phenomena associated with monitoring predators and incorporate them into escape theory. Cost of fleeing might increase as an attentional monitoring cost increases as duration of approach increases. Cost of not fleeing might increase as AD increases due to a physiological cost of monitoring and because assessed risk might increase as duration of approach increases. The attentional cost and effect on assessed risk occur in addition to the effect of decreasing distance in prey that do not account for duration of approach, while assessing costs of fleeing and not fleeing. Some of these effects may operate simultaneously. We describe research needed to better understand the flush early hypothesis and proposed costs associated with monitoring approaching predators.

The recently introduced Oxford Nanopore MinION platform generates DNA sequence data in real-time. This has great potential to shorten the sample-to-results time and is likely to have benefits such as rapid diagnosis of bacterial infection and identification of drug resistance. However, there are few tools available for streaming analysis of real-time sequencing data. Here, we present a framework for streaming analysis of MinION real-time sequence data, together with probabilistic streaming algorithms for species typing, strain typing and antibiotic resistance profile identification. Using four culture isolate samples, as well as a mixed-species sample, we demonstrate that bacterial species and strain information can be obtained within 30 min of sequencing and using about 500 reads, initial drug-resistance profiles within two hours, and complete resistance profiles within 10 h. While strain identification with multi-locus sequence typing required more than 15x coverage to generate confident assignments, our novel gene-presence typing could detect the presence of a known strain with 0.5x coverage. We also show that our pipeline can process over 100 times more data than the current throughput of the MinION on a desktop computer. Electronic supplementary material The online version of this article (doi:10.1186/s13742-016-0137-2) contains supplementary material, which is available to authorized users.

The round-tailed horned lizard Phrynosoma modestum is cryptically colored and resembles a small stone when it draws legs close to its body and elevates its back. We investigated effectiveness of camouflage in P. modestum and its dependence on stones by placing a lizard in one of two microhabitats (uniform sand or sand with surface rocks approximately the same size as lizards). An observer who knew which microhabitat contained the lizard was asked to locate the lizard visually. Latency to detection was longer and probability of no detection within 60 s was higher for lizards on rock background than on bare sand. In arenas where lizards could choose to occupy rock or bare sand, much higher proportions selected rocky backgrounds throughout the day; at night all lizards slept among stones. A unique posture gives P. modestum a rounded appearance similar to many natural stones. Lizards occasionally adopted the posture, but none did so in response to a nearby experimenter. Stimuli that elicit the posture are unknown. That P. modestum is better camouflaged among rocks than on bare sand and prefers to occupy rocky areas suggests that special resemblance to rocks (masquerade) enhances camouflage attributable to coloration and immobility.

Island tameness (reduced escape behaviour on islands where prey have experienced prolonged relaxation of predation pressure) is known in several taxa, although the relationships between recent predation pressure and escape on islands are poorly known. We investigated escape by numerous populations exposed to differing predation pressure of two sister species of Podarcis lizards in the Balearic Islands. Our main findings are that flight initiation distance was greater in Podarcis pityusensis than Podarcis lilfordi and increased as predation pressure increased in P. pityusensis. Island tameness led to extinction of P. lilfordi on Menorca and Mallorca following anthropogenic introduction of predators; this species is extant only on nearby islets. The lack of relationship between recent predation pressure and flight initiation distance in P. lilfordi indicates that the historically acquired deficit in the ability to adjust escape behaviour to predation pressure still exists. Podarcis pityusensis, which was exposed to greater natural predation pressure before human introduction of predators, survives on Ibiza and Formentera, as well as on islets. Retention of the ability to respond to predation pressure is consistent with our finding that flight initiation distance increases as predation pressure increases among current populations. © 2012 The Linnean Society of London, Biological Journal of the Linnean Society, 2012, ••, ••–••.

When a predator is immobile near an immobile prey, the probability that the predator will detect and attack increases over time. The prey’s cost of moving, thereby abandoning crypsis due to immobility, therefore decreases. Cost of not moving increases over time if movement is required for prey to conduct fitness-enhancing activities. We tested a cost-benefit model that predicts effects of factors that affect predation risk and cost of not moving on a prey’s latency to flee. Acting as simulated predators, we conducted experiments on the lizards Iberolacerta cyreni and Podarcis lilfordi. All predictions for 5 risk factors and a cost of moving factor were verified. Lizards fled sooner when the predator stood closer, approached rapidly rather than slowly before stopping, approached directly rather than indirectly, and gazed at the lizard rather than away from it, and after the second of 2 successive approaches. Latency to move was shorter in the presence than absence of a mealworm, suggesting the importance of opportunity cost of immobility. The effect of standing distance has 2 components, greater rate of detection by the predator and greater risk of being captured if detected at shorter distances. Escape theory has been highly successful in predicting how close a prey allows a predator to approach before fleeing. Our model extends an economic approach to study of escape decisions in response to an immobile predator that may be an ambush forager or an active forager that has stopped moving nearby. Key words: ambush, escape, latency to flee, opportunity cost, predation risk, standing distance. [Behav Ecol]

Flight initiation distance is the distance separating predator and prey when escape begins. The optimal flight initiation distance occurs where expected postencounter fitness is maximized, which depends on the prey's initial fitness, benefits obtainable by not fleeing, energetic escape costs, and expected fitness loss due to predation risk. In current optimal escape theory, prey die when contacted by a predator. We explore effects of variable lethality, L, the probability of being killed on contact. Optimal flight initiation distance increases as lethality increases, matching expectations that prey should not flee when contact entails no fitness loss but should be increasingly wary as expected fitness loss on contact increases. Addition of lethality improves the ability of optimal escape theory to predict effects of factors affecting escape ability. Autotomy, the voluntary shedding of tails or other expendable parts as a last-ditch defense to permit escape, provides an example. After autotomy, running speed decreases in many prey, lethality increases because autotomy cannot be used again until the lost part has regenerated, and ability to obtain benefits may decrease due to reduced social status and foraging ability. These changes favor longer flight initiation distance but lowered initial fitness after autotomy has the opposite effect. Optimal escape theory including a lethality term clarifies how autotomy may lead to increase or decrease in flight initiation distance depending on the balance of its multiple effects. Effects of additional factors that may alter multiple parameters of the model, including age, sex, reproductive condition, injury, disease, and parasitism are discussed. Copyright 2009, Oxford University Press.

Background: Osteoprotegerin (OPG) has been associated with cardiovascular events but currently the mechanisms underlying this association are unknown. OPG is thought to play a role in controlling artery calcification and small studies have suggested that it may influence artery structure. We examined the association between single nucleotide polymorphisms (SNPs) in the gene encoding OPG (tumor necrosis factor receptor superfamily, member 11b, TNFRSF11B), with blood pressure in a large cohort of elderly men. Methods: 21 tagging SNPs in the region encoded by TNFRSF11B were examined in 1,071 men recruited in a population-based study of elderly men. Genotyping was carried out using the Illumina Golden Gate assay. SNPs were investigated for their association with resting systolic and diastolic blood pressure after adjusting for other variables using linear regression. The association of SNPs in the region encoded by TNFRSF11B with plasma OPG was assessed in a random subset of 467 men. Results: One SNP, rs11573901, was significantly associated with diastolic blood pressure, after adjusting for other risk factors and multiple testing (coefficient -4.36, P = 0.001). Men with the TC genotype had lower diastolic blood pressure than those with the common CC variation. This SNP was not associated with plasma OPG in the 467 men in which this was examined. Conclusions: This study suggests that a SNP within the region encoded by TNFRSF11B, which is believed to code for OPG, is associated with blood pressure. The mechanism underlying this observed association is currently unclear.

Prey evaluate risk implied by a predator during its approach, intrinsic prey features, and environmental factors to weigh risk against costs. Most studies of escape and hiding time in refuge focus on a single factor, but prey that ignore other factors may soon be dead. Two hypotheses make different predictions about additivity versus interaction of risk–cost factors. The risksensitivity hypothesis predicts that multiple factors have additive effects, but optimality theory suggests that interaction is more common. In the only previous study, flight initiation distance (FID ¼ predator–prey distance when escape begins) was affected interactively by 2 risk factors (predator approach speed and directness) but additively by a risk and an escape cost (approach speed and food presence). I predicted that effects of approach speed and other risk factors interact because differences in risk are likely to increase more rapidly with increase in approach speed than other factors. FID by lizards that I approached increased interactively with approach speed and directness in the Sceloporus virgatus and speed and predator persistence in Sceloporus jarrovii. During indirect approaches, fewer S. virgatus fled, and they ran shorter distances. A review of effects of multiple risks and costs on FID and hiding time revealed far more frequent interactive than additive effects between 2 risk factors, as predicted by optimality theory. Additive and interactive effects were equally common between a risk and a cost factor. Findings for some factors differ between FID and hiding time and in other ways. I propose hypotheses to explain some differences. Key words: escape behavior, flight initiation distance, hiding time, refuge use, squamata. [Behav Ecol] P rey must cope with predation risk posed by predators that vary in many ways relevant to escape decisions, as well as assess environmental factors and intrinsic prey characteristics affecting risk. Prey that can evaluate multiple risks simultaneously should have higher long-term survival than prey that react to only a single factor. Experiments on escape behavior usually examine effects of single risk factors and control others, but it may be anticipated that many prey can take into account multiple risk factors operating during short-term encounters with predators. Prey able to respond to multiple risks might treat them additively or interactively (Smith and Belk 2001). Studies bearing on this issue for pairs of risk factors or factors affecting risk and cost of escaping or hiding (lost opportunities) are limited to lizards and turtles. Although information is beginning to accumulate about effects of simultaneous risk on escape behavior (Table 1), conditions leading to additivity or interaction between the factors are poorly understood. Escape theory predicts flight initiation distance (FID ¼ distance between predator and prey when escape begins) and sometimes distance fled based on risks and costs (Ydenberg and Dill 1986; Cooper and Frederick 2007a). Predictions are made from expected fitness determined jointly by multiple factors that affect predation risk and escape cost. Without knowledge of the form of functions relating fitness to distance between predator and prey, escape theory does not predict whether effects are additive or interactive.

Contains fulltext : 81639.pdf (Publisher’s version ) (Closed access) AIMS: The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation (AF) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF, among individuals with type 2 diabetes. METHODS AND RESULTS: About 11 140 patients with type 2 diabetes (7.6% of whom had AF at baseline) were randomized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. We compared total mortality and cardiovascular disease outcomes and effects of randomized treatment for 4.3 years on such outcomes between patients with and without AF at baseline. After multiple adjustments, AF was associated with a 61% (95% confidence interval 31-96, P < 0.0001) greater risk of all-cause mortality and comparable higher risks of cardiovascular death, stroke, and heart failure (all P < 0.001). Routine treatment with a fixed combination of perindopril and indapamide produced similar relative, but greater absolute, risk reductions for all-cause and cardiovascular mortalities in patients with AF, compared with those without AF. The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline. CONCLUSION: Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes. This arrhythmia identifies individuals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment. Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors.

Escape theory predicts flight initiation distance (FID, predator-to-prey distance when escape begins) based on fixed functions relating costs and benefits of fleeing to distance between a prey and an approaching predator. Theory accurately predicts effects of costs for fixed functions and changes in functions due to changes in predator behavior approach. Less obvious is how the effect of starting distance (predator-to-prey distance when approach begins) on FID can be explained when predator behavior does not change during approach. We simulated predators to study effects of starting distance on FID in Balearic lizards (Podarcis lilfordi). Starting distance and approach speed affected FID interactively. It increased as starting distance increased during faster, but not slower, approaches. Because risk functions are considered fixed for a given approach speed, we must explain why FID varies with starting distance, why only for rapid approach, and how risk is assessed. Because prey approached slowly assess risk as small until the predator is very close, approach from greater distance has little effect on risk curves. Because continued rapid approach suggests that the predator has detected the prey and is attacking, not merely approaching, risk varies with starting distance. Theoretical difficulty in explaining the effect of starting distance on FID disappears if risk curves vary among starting distances at faster approach speeds, but each curve is fixed. This might occur if prey use a temporal rule of thumb assigning increasing risk as duration of rapid approach increases. Key words: antipredatory behavior, approach distance, escape, flight initiation distance, flush distance, starting distance. [Behav Ecol]

This paper sympathetically examines the neglected ‘virtue-centric’ idea that the primary location of beauty is in bodily expressions of human virtues, so that things like buildings are beautiful only because of an appropriate relationship they have to beautiful people. After a brief ‘history’ of the idea as articulated by, for example, Kant, it is then distinguished from accounts of beauty with which it might be confused, such as the view that something is beautiful only if it helps to instil virtue. In the central part of the paper, the attractions of virtue-centrism are articulated. These primarily consist in its explanatory power. It is argued, too, that virtue-centrism steers attractively between a rigidly conservative attitude towards beauty and an ‘anything goes’ one. The final sections respond to some likely objections, the last of which provides an opportunity for correcting an impression that my formulation of the virtue-centrist idea might have given.

Factors affecting emergence by prey that enter refuges when approached by predators have been studied intensively, but only two theoretical models predict how long prey should remain in a refuge before emerging. We argue that prey can make better decisions than allowed by one model; the other model describes cases in which predators wait for prey to emerge. We present optimality models that permit prey to select a time to emerge that maximizes fitness. When in a refuge, a prey cannot obtain benefits outside; emerging too soon can be catastrophic, but delaying emergence entails loss of fitness. If predators resume foraging quickly rather than engaging in strategic waiting games, current theory suggests that prey emerge when the costs of remaining in a refuge and of emerging are equal. However, prey often can do better by emerging at the time maximizing fitness rather than when benefits equal costs (i.e. when prey break even). Optimal emergence time depends on initial fitness, benefits lost by remaining in refuge, and the decay rate of predation risk. Benefits lost if a prey is killed are modelled separately from benefits that contribute to lifetime fitness, even if the prey is killed (individual reproduction, altruism). Fitness of prey emerging at the optimal emergence time may be greater than, equal to or less than initial fitness. Break-even and optimality models base predictions on the opposing effects of risk and loss of benefits. Thus, many empirically verified predictions are identical at the ordinal level although differing quantitatively. Optimality models provide novel testable predictions for the effects of initial fitness, benefits, and, for ectotherms, the rate of cooling in refuge. They predict earlier emergence for equal retainable benefits than for those lost upon death. © 2007 The Linnean Society of London, Biological Journal of the Linnean Society, 2007, 91, 375–382.

In hospital cardiac arrest is associated with high mortality rates.[1][1] Many patients who suffer cardiac arrest or pulmonary arrest have preexisting respiratory or metabolic abnormalities and clinical deterioration.[2][2] Risk factors for avoidable inhospital cardiac arrests include abnormal

Backgound. Peroxisome proliferator-activated receptor (PPAR)-a and PPAR-g agonists are widely used in diabetes. In addition to their effects on lipid and glucose homeostasis, these agents have been postulated to have independent renoprotective actions. In the current study, we assess the efficacy of the PPAR-a agonist, gemfibrozil, the PPAR-g agonist rosiglitazone and the non-thiazolidinedione PPAR-a/g coagonist, compound 3q, on kidney structure and function in streptozotocin-treated apolipoprotein E knockout mice. Methods. Control and streptozotocin-diabetic mice were randomized to receive rosiglitazone (20 mg/kg/ day), gemfibrozil (100 mg/kg/day), or compound 3q (3 mg/kg/day) by gavage, or no treatment for a period of 20 weeks. Renal fibrosis was assessed by standard histology and collagen IV immunohistochemistry. Kidney function was assessed by urinary albumin excretion and creatinine clearance. Results. Diabetes in this model was associated with an increase in glomerulosclerosis, tubulointerstitial fibrosis and increased collagen IV deposition in the glomeruli and tubules. All three agents significantly attenuated glomerulosclerosis, tubulointerstitial expansion and collagen IV deposition. The increase in albuminuria and the decline in kidney function associated with diabetes in this model were also attenuated by each of these agents, with no superiority observed among various treatment groups. These renoprotective effects were observed in the absence of changes in glucose, insulin or lipid levels or a reduction in blood pressure. Conclusions. Combined with their independent antiatherosclerotic actions, and their important effects on dyslipidaemia and insulin resistance, PPAR agonists may be useful for the prevention of diabetic complications, including kidney disease, even in type 1 diabetes.

Background: Acoustic sensors that exploit resonating quartz crystals directly detect the binding of an analyte to a receptor. Applications include detection of bacteria, viruses, and oligonucleotides and measurement of myoglobin, interleukin 1 (IL-1), and enzyme cofactors. Methods: Resonant Acoustic Profiling TM was combined with a microfluidic lateral flow device incorporating an internal reference control, stable linker chemistry, and immobilized receptors on a disposable sensor “chip”. Analyte concentrations were determined by analyzing the rate of binding of the analyte to an appropriate receptor. Results: The specificity and affinity of antibody–antigen and enzyme–cofactor interactions were determined without labeling of the receptor or the analyte. We measured protein concentrations (recombinant human IL-1 and recombinant human myoglobin) and quantified binding of cofactors (NADP and NAD )t o the enzyme glucose dehydrogenase. Lower limits of detection were 1 nmol/L (17 ng/mL) for both IL-1 and human myoglobin. The equilibrium binding constant for NADP binding to glucose dehydrogenase was 2.8 mmol/L. Conclusions: Resonant Acoustic Profiling detects analytes in a relatively simple receptor-binding assay in

Although the features of diabetic cardiomyopathy, atherosclerosis, and nephropathy have been clinically characterized, the pathogenesis and the mechanisms underlying the abnormalities in the diabetic heart and kidney are not fully understood. During the past several years, in an attempt to discover interventions for diabetes-related complications, researchers have refocused their attention from the hemodynamic aspects of the disease to the biochemical interactions of glucose and proteins. Diabetes is a disorder of chronic hyperglycemia, and glucose participates in diabetic complications such as atherosclerosis, cardiac dysfunction, and nephropathy. Chronic hyperglycemia accelerates the reaction between glucose and proteins and leads to the formation of advanced glycation end products (AGE), which form irreversible cross-links with many macromolecules such as collagen. In diabetes, these AGE accumulate in tissues at an accelerated rate. The development of the novel compound dimethyl-3-phenacylthiazolium chloride (alagebrium chloride), which chemically breaks AGE cross-links, led to several preclinical animal studies that showed an attenuation or reversal of disease processes of the heart and kidney. In diabetes, AGE not only structurally stiffen structural collagen backbones but also act as agonists to AGE receptors (RAGE) on various cell types, which stimulate the release of profibrotic growth factors, promote collagen deposition, increase inflammation, and ultimately lead to tissue fibrosis. In the heart, large vessels, and kidney, these reactions produce diastolic dysfunction, atherosclerosis, and renal fibrosis. Administration of the cross-link breaker alagebrium chloride in these diabetic animals attenuates these pathologic phenomena, restoring functionality to the heart, vasculature, and kidney.

Recently, a dimeticone formulation has been shown to be effective at preventing Schistosoma cercariae infecting skin, while DEET (N,N-diethyl-m-toluamide), a highly effective insecticide, has been shown to have activity against cercariae. Seven formulations, 3 containing DEET, were prepared and applied to excised human skin in Franz cells for 1 h. Schistosoma cercariae were applied for 30 min at 1 and 24 h, and the number that penetrated the skin calculated (n = 9). DEET could not be incorporated into the dimeticone formulation, yet it remained the most effective at preventing cercarial penetration, both 1 and 24 h after application. The ointments that contained DEET did prevent penetration but their mode of action was due to the toxicity of DEET against the cercariae. The persistence of the protection afforded by the dimeticone formulation after washing suggests that the formulation may be interacting with the stratum corneum to prevent cercarial recognition of skin.

Classical quantitative genetics has applied linear modeling to the problem of mapping genotypic to phenotypic variation. Much of this theory was developed prior to the availability of molecular biology. The current understanding of the mechanisms of gene expression indicates the importance of nonlinear effects resulting from gene interactions. We provide a bridge between genetics and gene network theories by relating key concepts from quantitative genetics to the parameters, variables, and performance functions of genetic networks. We illustrate this methodology by simulating the genetic switch controlling galactose metabolism in yeast and its response to selection for a population of individuals. Results indicate that genes have heterogeneous contributions to phenotypes and that additive and nonadditive effects are context dependent. Early cycles of selection suggest strong additive effects attributed to some genes. Later cycles suggest the presence of strong context-dependent nonadditive effects that are conditional on the outcomes of earlier selection cycles. A single favorable allele cannot be consistently identified for most loci. These results highlight the complications that can arise with the presence of nonlinear effects associated with genes acting in networks when selection is conducted on a population of individuals segregating for the genes contributing to the network.

BACKGROUND Minimal change disease (MCD) is one of the major causes of nephrotic syndrome both in children and adults. The pathogenesis of this condition is not clear and it has been suggested that a plasma permeability factor may play a role. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has been thought to be one the factors involved. The aim of this study was thus to investigate the role of VEGF in the pathogenesis of MCD. METHODS The expression of the gene for VEGF and VEGF receptor-2 (VEGFR-2) was estimated using in situ hybridization in renal biopsy specimens taken from patients with nephrotic syndrome and diagnosed histologically as MCD. The results were compared with those obtained in normal renal tissue. Biopsy specimens from eight patients diagnosed as having MCD were randomly selected for the study. The patients were aged 4-60 years at the time of the biopsy. There were four females and four males. All patients had presented with a nephrotic syndrome, five with recent onset of the disease, two with repeated attacks of the syndrome and one had reduced renal function. RESULTS The gene expression for VEGF, measured as the proportional glomerular area occupied by autoradiographic grains, was significantly less in the patients with MCD than in controls (1.9 +/- 0.4 vs 4.8 +/- 0.6%, P < 0.0025), whereas the gene expression for VEGFR-2 was no different to controls (1.9 +/- 0.4 vs 2.0 +/- 0.2%). CONCLUSIONS MCD is associated with a reduction in the expression of the gene for VEGF. As VEGF may play an important role in renal repair and survival, it is postulated that the deficiency, which we have shown, may lead to the dysregulation of the repair process in MCD.