Metabolite Depletion Affects Flux Profiling of Cell Lines.

Quantifying the rate of consumption and release of metabolites (i.e., flux profiling) has become integral to the study of cancer. The fluxes as well as the growth of the cells may be affected by metabolite depletion during cultivation.

An osteopontin-derived peptide inhibits human hair growth at least in part by decreasing fibroblast growth factor-7 production in outer root sheath keratinocytes.

BACKGROUND: Given that unwanted hair growth (hirsutism, hypertrichosis) can cause major psychological distress, new pharmacological treatment strategies with safe and effective hair growth inhibitors that do not destroy the hair follicle (HF) and its stem cells need to be developed. OBJECTIVES: To establish if osteopontin-derived fragments may modulate human hair growth given that human HFs express the multifunctional, immunomodulatory glycoprotein, osteopontin. METHODS: Our hypothesis was tested ex vivo and in vivo by using a newly generated, toxicologically well-characterized, modified osteopontin-derived peptide (FOL-005), which binds to the HF. RESULTS: In organ-cultured human HFs and scalp skin, and in human scalp skin xenotransplants onto SCID mice, FOL-005 treatment (60 nmol L-1 to 3 µmol L-1 ) significantly promoted premature catagen development without reducing the number of keratin 15-positive HF stem cells or showing signs of drug toxicity. Genome-wide DNA microarray, quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry revealed decreased expression of the hair growth promoter, fibroblast growth factor-7 (FGF7) by FOL-005, while cotreatment of HFs with recombinant FGF7 partially abrogated FOL-005-induced catagen promotion. CONCLUSIONS: With caveats in mind, our study identifies this osteopontin-derived peptide as an effective, novel inhibitory principle for human hair growth ex vivo and in vivo, which deserves systematic clinical testing in hirsutism and hypertrichosis. What's already known about this topic? The treatment of unwanted hair growth (hypertrichosis, hirsutism) lacks pharmacological intervention, with only few and often unsatisfactory treatments available. Osteopontin is prominently expressed in human HFs and has been reported to be elevated during catagen in the murine hair cycle. What does this study add? We tested the effects on hair growth of a novel, osteopontin-derived fragment (FOL-005) ex vivo and in vivo. In human hair follicles, high-dose FOL-005 significantly reduces hair growth both ex vivo and in vivo. What is the translational message? High-dose FOL-005 may provide a new therapeutic opportunity as a treatment for unwanted hair growth.

Predictive values of anti-cyclic citrullinated peptide antibodies and rheumatoid factor in relation to serological aspects of the ACR/EULAR 2010 classification criteria for rheumatoid arthritis.

Objective: In this retrospective population-based register study, we wanted to determine the positive predictive values (PPVs) of immunoglobulin M rheumatoid factor (IgM RF) and anti-citrullinated protein antibodies (ACPAs) at 3 × upper normal limit (UNL), since they are weighted equally in the American College of Rheumatology (ACR)/ European League Against Rheumatism (EULAR) 2010 criteria for rheumatoid arthritis (RA).Methods: Test results, ordering unit, test date, and patient social security number were collected from the Department of Clinical Immunology at Odense University Hospital from 2007 to 2016 and merged with patient diagnosis from the Danish National Patient Registry.Results: The PPV of IgM RF at 3 × UNL was 14%, compared to a PPV of 43% for ACPAs at 3 × UNL.Conclusion: The PPV of ACPAs is higher than the PPV of IgM RF at 3 × UNL. These findings are not reflected in the ACR/EULAR 2010 classification criteria for RA.

Ultrafast X-ray probing of water structure below the homogeneous ice nucleation temperature.

Water has a number of anomalous physical properties, and some of these become drastically enhanced on supercooling below the freezing point. Particular interest has focused on thermodynamic response functions that can be described using a normal component and an anomalous component that seems to diverge at about 228 kelvin (refs 1-3). This has prompted debate about conflicting theories that aim to explain many of the anomalous thermodynamic properties of water. One popular theory attributes the divergence to a phase transition between two forms of liquid water occurring in the 'no man's land' that lies below the homogeneous ice nucleation temperature (TH) at approximately 232 kelvin and above about 160 kelvin, and where rapid ice crystallization has prevented any measurements of the bulk liquid phase. In fact, the reliable determination of the structure of liquid water typically requires temperatures above about 250 kelvin. Water crystallization has been inhibited by using nanoconfinement, nanodroplets and association with biomolecules to give liquid samples at temperatures below TH, but such measurements rely on nanoscopic volumes of water where the interaction with the confining surfaces makes the relevance to bulk water unclear. Here we demonstrate that femtosecond X-ray laser pulses can be used to probe the structure of liquid water in micrometre-sized droplets that have been evaporatively cooled below TH. We find experimental evidence for the existence of metastable bulk liquid water down to temperatures of 227(-1)(+2) kelvin in the previously largely unexplored no man's land. We observe a continuous and accelerating increase in structural ordering on supercooling to approximately 229 kelvin, where the number of droplets containing ice crystals increases rapidly. But a few droplets remain liquid for about a millisecond even at this temperature. The hope now is that these observations and our detailed structural data will help identify those theories that best describe and explain the behaviour of water.

Evaluation of environmental impacts for future influent scenarios using a model-based approach.

Changes in dilution of wastewater to a treatment plant due to infiltration or surface runoff can have a great impact on treatment process performance. This paper presents a model-based approach in which realistic influent scenarios are generated and used as inputs to a dynamic plant-wide process model of the wastewater treatment plant. The simulated operation is subsequently evaluated using life-cycle assessment (LCA) to quantify the environmental impacts of the future influent scenarios. The results show that increased infiltration led to higher environmental impact per kg nitrogen removed. The increase in surface runoff had a minor impact.

Cerebrospinal fluid biomarkers for predicting development of multiple sclerosis in acute optic neuritis: a population-based prospective cohort study.

BACKGROUND: Long-term outcome in multiple sclerosis (MS) depends on early treatment. In patients with acute optic neuritis (ON), an early inflammatory event, we investigated markers in cerebrospinal fluid (CSF), which may predict a diagnosis of MS. METHODS: Forty patients with acute ON were recruited in a prospective population-based cohort with median 29 months (range 19-41) of follow-up. Paired CSF and serum samples were taken within 14 days (range 2-38), prior to treatment. Prospectively, 16/40 patients were by a uniform algorithm diagnosed with MS (MS-ON) and 24 patients continued to manifest isolated ON (ION) during follow-up. Levels of cytokines and neurofilament light chain (NF-L) were measured at the onset of acute ON and compared to healthy controls (HC). Significance levels were corrected for multiple comparisons ("q"). The predictive value of biomarkers was determined with multivariable prediction models using nomograms. RESULTS: CSF TNF-α, IL-10, and CXCL13 levels were increased in MS-ON compared to those in ION patients (q = 0.021, 0.004, and 0.0006, respectively). MS-ON patients had increased CSF pleocytosis, IgG indices, and oligoclonal bands (OCBs) compared to ION (q = 0.0007, q = 0.0058, and q = 0.0021, respectively). CSF levels of IL-10, TNF-a, IL-17A, and CXCL13 in MS-ON patients correlated with leukocyte counts (r > 0.69 and p < 0.002) and IgG index (r > 0.55, p < 0.037). CSF NF-L levels were increased in ON patients compared to those in HC (q = 0.0077). In MS-ON, a progressive increase in NF-L levels was observed at 7 to 14 days after disease onset (r = 0.73, p < 0.0065). Receiver-operating characteristic (ROC) curves for two multivariable prediction models were generated, with IL-10, CXCL13, and NF-L in one ("candidate") and IgG index, OCB, and leukocytes in another ("routine"). Area under the curve was 0.89 [95% CI 0.77-1] and 0.86 [0.74-0.98], respectively. Predictions of the risk of MS diagnosis were illustrated by two nomograms. CONCLUSIONS: CSF TNF-α, IL-10, CXCL13, and NF-L levels were associated with the development of MS, suggesting that the inflammatory and neurodegenerative processes occurred early. Based on subsequent diagnosis, we observed a high predictive value of routine and candidate biomarkers in CSF for the development of MS in acute ON. The nomogram predictions may be useful in the diagnostic work-up of MS.

Extensive undertreatment of osteoporosis in older Swedish women.

In a population-based study of older Swedish women, we investigated the proportion of women treated with osteoporosis medication in relation to the proportion of women eligible for treatment according to national guidelines. We found that only a minority (22%) of those eligible for treatment were prescribed osteoporosis medication. INTRODUCTION: Fracture rates increase markedly in old age and the incidence of hip fracture in Swedish women is among the highest in the world. Although effective pharmacological treatment is available, treatment rates remain low. Limited data are available regarding treatment rates in relation to fracture risk in a population-based setting in older women. Therefore, we aimed to investigate the proportion of older women eligible for treatment according to Swedish Osteoporosis Society (SvOS) guidelines. METHODS: A population-based study was performed in Gothenburg in 3028 older women (77.8 ± 1.6 years [mean ± SD]). Bone mineral density of the spine and hip was measured with dual-energy X-ray absorptiometry. Clinical risk factors for fracture and data regarding osteoporosis medication was collected with self-administered questionnaires. Logistic regression was used to evaluate whether the 10-year probability of sustaining a major osteoporotic fracture (FRAX-score) or its components predicted treatment with osteoporosis medication. RESULTS: For the 2983 women with complete data, 1107 (37%) women were eligible for treatment using SvOS criteria. The proportion of these women receiving treatment was 21.8%. For women eligible for treatment according to SvOS guidelines, strong predictors for receiving osteoporosis medication were glucocorticoid treatment (odds ratio (95% CI) 2.88 (1.80-4.59)) and prior fracture (2.58 (1.84-3.61)). CONCLUSION: This study demonstrates that a substantial proportion of older Swedish women should be considered for osteoporosis medication given their high fracture risk, but that only a minority receives treatment.

Increased B-cell activating factor, interleukin-6, and interleukin-8 in induced sputum from primary Sjögren's syndrome patients.

OBJECTIVE: Small airway disease and chronic obstructive pulmonary disease are common in primary Sjögren's syndrome (pSS). However, the underlying inflammatory mechanisms behind pSS-associated airway disease have not been studied in detail. We therefore wanted to study cytokine and leucocyte levels in induced sputum in never-smoking patients with pSS. METHOD: Induced sputum cytokines and leucocytes were assessed in 20 never-smoking patients with pSS and 19 age- and gender-matched population-based controls. In addition, pulmonary function, disease activity, respiratory symptoms, and inflammatory and serological features of pSS were assessed. RESULTS: B-cell activating factor (BAFF), interleukin-6 (IL-6) and IL-8 were significantly increased in induced sputum in pSS patients compared to population-based controls, while IL-1ß, interferon-α, and tumour necrosis factor-α levels and leucocytes were not. The proportion of lymphocytes and BAFF levels in induced sputum correlated significantly in pSS patients. However, cytokine levels in induced sputum were not associated with pulmonary function tests, disease activity, respiratory symptoms, or serological features of pSS. CONCLUSION: The increase in BAFF, IL-6, and IL-8 in induced sputum suggests a specific ongoing inflammatory disease process in the airways in pSS patients. Its association with pSS-associated airway disease needs to be further examined in future larger studies.

Mast cell-dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma.

Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell-deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh + MC-WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in BALF. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR.

Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial.

BACKGROUND: The importance of the gut microbiome for bone metabolism in mice has recently been demonstrated, but no studies are available in humans. Lactobacillus reuteri ATCCPTA 6475 (L. reuteri 6475) has been reported to increase bone mineral density (BMD) in mice but its effect on the human skeleton is unknown. The objective of this trial was to investigate if L. reuteri 6475 affects bone loss in older women with low BMD. METHODS: In this double-blind, placebo-controlled study, women from the population who were 75 to 80 years old and had low BMD were randomized to orally receive 1010 colony-forming units of L. reuteri 6475 daily or placebo. The predefined primary end-point was relative change after 12 months in tibia total volumetric BMD (vBMD). RESULTS: Ninety women were included and 70 completed the study. L. reuteri 6475 reduced loss of total vBMD compared to placebo both in the intention-to-treat (ITT) analysis [-0.83% (95% confidence interval [CI], -1.47 to -0.19%) vs. -1.85% (95% CI, -2.64 to -1.07%); mean difference 1.02% (95% CI, 0.02-2.03)] and per protocol analysis [-0.93% (95% CI, -1.45 to -0.40) vs. -1.86% (95% CI, -2.35 to -1.36); mean difference 0.93% (95% CI, 0.21-1.65)]. In general, similar but smaller effects were observed in the secondary bone variable outcomes, but these differences did not reach statistical significance in the ITT population. Adverse events did not differ between groups. CONCLUSIONS: Supplementation with L. reuteri 6475 should be further explored as a novel approach to prevent age-associated bone loss and osteoporosis.

In vitro activity of a combination of bacteriophages and antimicrobial plant extracts.

The continuing threat of antimicrobial resistance presents a considerable challenge to researchers to develop novel strategies ensuring that bacterial infections remain treatable. Many plant extracts have been shown to have antibacterial properties and could potentially be combined with other antibacterial agents to create more effective formulations. In this study, the antibacterial activity of three plant extracts and virulent bacteriophages have been assessed as individual components and in combination. When assessed with a modified suspension test, these plant extracts also exhibit antiviral activity at bacterial inhibitory concentrations. Hence, to investigate any potential additive effects between the extracts and virulent phages, the extracts were tested at subantiviral concentrations. Phages alone and in combination with plant extracts significantly reduced (P < 0·05) the bacterial concentration compared to untreated and extract treated controls up to 6 h (2-3log10 ), but this reduction did not extend to 24 h. In most cases, the phage and extract combinations did not significantly reduce bacterial content compared to phages alone. Additionally, there was little impact on the ability of the phages to reproduce within their bacterial hosts. To our knowledge, this study represents the first of its kind, in which antimicrobial plant extracts have been combined with virulent phages and has highlighted the necessity for plant extracts to be functionally characterized prior to the design of combinatorial therapies. Significance and Impact of Study This preliminary study provides insights into the potential combination of bacteriophages and antimicrobial plant bulk extracts to target bacterial pathogens. It is to our knowledge the first time in which virulent bacteriophages have been combined with antimicrobial plant extracts.

Prediction of some vibro-acoustic properties of sandwich plates with honeycomb and foam cores.

A sixth-order differential equation governing the flexural vibration of sandwich plates is derived. The sandwich plates considered consist of laminates bonded to honeycomb or foam cores. The structures are assumed to be symmetric. Shear and rotation in core are included in the model. The effect on the bending stiffness of rotation and shear in the core is discussed. Shear effects are of great importance, whereas rotation of the core has only a marginal effect on the bending stiffness of lightweight sandwich plates. The bending stiffness of a sandwich plate is found to strongly depend on frequency. The bending stiffness of a structure determines its acoustical coupling to any surrounding fluid and thus its sound transmission loss and sound radiation ratio. Loss factors of sandwich plates are discussed. Boundary conditions are formulated for rectangular plates having simply supported, clamped, or free edges. There are five boundary conditions to be satisfied at each edge of the plate. The bending stiffness of simply supported and infinite plates is presented as a function of frequency. Expressions for the point mobility for infinite or simply supported finite panels are given.

Increased cortical porosity in women with hip fracture.

BACKGROUND: Hip fractures cause increased mortality and disability and consume enormous healthcare resources. Only 46% of hip fracture patients have osteoporosis at the total hip according to dual-energy X-ray absorptiometry (DXA) measurement. Cortical porosity increases with ageing and is believed to be important for bone strength. OBJECTIVE: To investigate whether older women with hip fracture have higher cortical porosity than controls, and if so whether this difference is independent of clinical risk factors and areal bone mineral density (aBMD). METHODS: From an ongoing population-based study, we identified 46 women with a prevalent X-ray-verified hip fracture and 361 control subjects without any fractures. aBMD was measured with DXA. High-resolution peripheral quantitative computed tomography was used to measure bone microstructure at the standard (ultradistal) site and at 14% (distal) of the tibial length. RESULTS: Women with a previous hip fracture had lower aBMD at the femoral neck (-11.8%) and total hip (-14.6%) as well as higher cortical porosity at the ultradistal (32.1%) and distal (29.3%) tibia compared with controls. In multivariable logistic regression analysis, with adjustment for covariates (age, height, weight, smoking, calcium intake, physical activity, walk time, oral glucocorticoids, parental hip fracture, rheumatoid arthritis, previous fall, current bisphosphonate treatment and femoral neck aBMD), cortical porosity at the ultradistal [odds ratio per standard deviation increase (95% confidence interval) 2.61 (1.77-3.85)] and distal [1.57 (1.12-2.20)] sites was associated with prevalent hip fracture. CONCLUSION: Cortical porosity was associated with prevalent hip fracture in older women independently of femoral neck aBMD and clinical risk factors.

A population-based prospective study of optic neuritis.

BACKGROUND: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. OBJECTIVE: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. METHOD: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. RESULTS: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16-66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44-4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. CONCLUSION: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

Antibiotic use during infectious episodes in the first 6 months of anticancer treatment-A Swedish cohort study of children aged 7-16 years.

BACKGROUND: Children undergoing cancer therapy are at risk for infectious complications that require hospitalization and antimicrobial therapy. Host factors such as age and underlying disease may predict the risk of severe infections in these children. To describe the increased morbidity due to infections in children with cancer, we characterized the antibiotic use during the infectious complications in a national cohort of children 7-16 years of age with cancer. PROCEDURE: Data on infectious complications were prospectively collected from the medical records of all newly diagnosed children with cancer, aged 7-16 years, in Sweden between 2004 and 2006. An episode of infection was defined as a period of time when oral or intravenous antimicrobial treatment was prescribed because of symptoms of infection. RESULTS: A total of 230 infectious episodes occurred in 80 of the 101 patients. Pathogens were isolated in 15% of the blood cultures that showed a predominance of Gram-positive bacteria. Intravenous broad-spectrum antibiotics with cephalosporins and carbapenems were mostly used as single drugs but also in combination with aminoglycosides and glycopeptide. The median treatment length varied between 6 and 11 days depending on cancer diagnosis. CONCLUSION: Our data demonstrate that infectious complications contribute significantly to morbidity in children with cancer aged 7-16 years. At the time of this survey, antibiotic prescription patterns varied and cephalosporins and carbapenems were mostly used. With increasing antibiotic resistance, a more stringent antibiotic stewardship with less use of cephalosporins and carbapenems should be encouraged for children with cancer. Data on prescription patterns should be incorporated as a quality measurement in pediatric cancer care.

Low serum vitamin D is associated with higher cortical porosity in elderly men.

BACKGROUND: Bone loss at peripheral sites in the elderly is mainly cortical and involves increased cortical porosity. However, an association between bone loss at these sites and 25-hydroxyvitamin D has not been reported. OBJECTIVE: To investigate the association between serum levels of 25-hydroxyvitamin D, bone microstructure and areal bone mineral density (BMD) in elderly men. METHODS: A population-based cohort of 444 elderly men (mean ± SD age 80.2 ± 3.5 years) was investigated. Bone microstructure was measured by high-resolution peripheral quantitative computed tomography, areal BMD by dual-energy X-ray absorptiometry and serum 25-hydroxyvitamin D and parathyroid hormone levels by immunoassay. RESULTS: Mean cortical porosity at the distal tibia was 14.7% higher (12.5 ± 4.3% vs. 10.9 ± 4.1%, P < 0.05) whilst cortical volumetric BMD, area, trabecular bone volume fraction and femoral neck areal BMD were lower in men in the lowest quartile of vitamin D levels compared to the highest. In men with vitamin D deficiency (<25 nmol L-1 ) or insufficiency [25-49 nmol L-1 , in combination with an elevated serum level of parathyroid hormone (>6.8 pmol L-1 )], cortical porosity was 17.2% higher than in vitamin D-sufficient men (P < 0.01). A linear regression model including age, weight, height, daily calcium intake, physical activity, smoking vitamin D supplementation and parathyroid hormone showed that 25-hydroxyvitamin D independently predicted cortical porosity (standardized ß = -0.110, R2 = 1.1%, P = 0.024), area (ß = 0.123, R2 = 1.4%, P = 0.007) and cortical volumetric BMD (ß = 0.125, R2 = 1.4%, P = 0.007) of the tibia as well as areal BMD of the femoral neck (ß = 0.102, R2 = 0.9%, P = 0.04). CONCLUSION: Serum vitamin D is associated with cortical porosity, area and density, indicating that bone fragility as a result of low vitamin D could be due to changes in cortical bone microstructure and geometry.

Daily life consequences, cognitive impairment, and fatigue after transient ischemic attack.

OBJECTIVES: Studies suggest that fatigue and cognitive impairment may be present after transient ischemic attack (TIA), but little is known about consequences in daily life. The main aim was to longitudinally explore the presence of fatigue, cognitive impairment, and consequences in daily life including communication after clinically diagnosed TIA at 1 and 9 months after the event. MATERIAL AND METHODS: A consecutive sample of 46 patients (23 women, 69 ± 12.3 years) was assessed at discharge from hospital and at 1 and 9 months after TIA regarding cognition, mental fatigue, tiredness, and activities of daily life. This served as basis for an interview concerning experienced changes related to the TIA. RESULTS: Problems in daily life with probable association with the TIA were experienced by 37% (n = 45) of participants 9 months after the TIA event. Cognitive impairment was present in 40% (n = 44) after 1 month and 30% (n = 23) after 9 months. Mental fatigue was experienced by 26% (n = 42) after 1 month and 17% (n = 39) after 9 months. Communication problems were reported and increased from 7 to 14 participants between the two time points. CONCLUSIONS: A third of the TIA patients experienced problems in performance of complex activities in daily life and often communication problems within the first 9 months. Cognitive impairment and mental fatigue could be factors influencing performance in daily life and at work, but this needs to be verified in a larger sample. The risk of activity limitations indicates need for multiprofessional support and systematic routines for TIA follow-up.

The structural validity of various thermodynamical models of supercooled water.

The thermodynamic response functions of water exhibit an anomalous increase upon cooling that becomes strongly amplified in the deeply supercooled regime due to structural fluctuations between disordered and tetrahedral local structures. Here, we compare structural data from recent x-ray laser scattering measurements of water at 1 bar and temperatures down to 227 K with structural properties computed for several different water models using molecular dynamics simulations. Based on this comparison, we critically evaluate four different thermodynamic scenarios that have been invoked to explain the unusual behavior of water. The critical point-free model predicts small variations in the tetrahedrality with decreasing temperature, followed by a stepwise change at the liquid-liquid transition around 228 K at ambient pressure. This scenario is not consistent with the experimental data that instead show a smooth and accelerated variation in structure from 320 to 227 K. Both the singularity-free model and ice coarsening hypothesis give trends that indirectly indicate an increase in tetrahedral structure with temperature that is too weak to be consistent with experiment. A model that includes an apparent divergent point (ADP) at high positive pressure, however, predicts structural development consistent with our experimental measurements. The terminology ADP, instead of the commonly used liquid-liquid critical point, is more general in that it focuses on the growing fluctuations, whether or not they result in true criticality. Extrapolating this model beyond the experimental data, we estimate that an ADP in real water may lie around 1500 ± 250 bars and 190 ± 6 K.

The small leucine-rich repeat proteoglycans in tissue repair and atherosclerosis.

Proteoglycans consist of a protein core with one or more covalently attached glycosaminoglycan (GAG) side chains and have multiple roles in the initiation and progression of atherosclerosis. Here we discuss the potential and known functions of a group of small leucine-rich repeat proteoglycans (SLRPs) in atherosclerosis. We focus on five SLRPs, decorin, biglycan, lumican, fibromodulin and PRELP, because these have been detected in atherosclerotic plaques or demonstrated to have a role in animal models of atherosclerosis. Decorin and biglycan are modified post-translationally by substitution with chondroitin/dermatan sulphate GAGs, whereas lumican, fibromodulin and PRELP have keratan sulphate side chains, and the core proteins have leucine-rich repeat (LRR) motifs that are characteristic of the LRR superfamily. The chondroitin/dermatan sulphate GAG side chains have been implicated in lipid retention in atherosclerosis. The core proteins are discussed here in the context of (i) interactions with collagens and their implications in tissue integrity, fibrosis and wound repair and (ii) interactions with growth factors, cytokines, pathogen-associated molecular patterns and cell surface receptors that impact normal physiology and disease processes such as inflammation, innate immune responses and wound healing (i.e. processes that are all important in plaque development and progression). Thus, studies of these SLRPs in the context of wound healing are providing clues about their functions in early stages of atherosclerosis to plaque vulnerability and cardiovascular disease at later stages. Understanding of signal transduction pathways regulated by the core protein interactions is leading to novel roles and therapeutic potential for these proteins in wound repair and atherosclerosis.