RAMPVIS: Answering the challenges of building visualisation capabilities for large-scale emergency responses.

The effort for combating the COVID-19 pandemic around the world has resulted in a huge amount of data, e.g., from testing, contact tracing, modelling, treatment, vaccine trials, and more. In addition to numerous challenges in epidemiology, healthcare, biosciences, and social sciences, there has been an urgent need to develop and provide visualisation and visual analytics (VIS) capacities to support emergency responses under difficult operational conditions. In this paper, we report the experience of a group of VIS volunteers who have been working in a large research and development consortium and providing VIS support to various observational, analytical, model-developmental, and disseminative tasks. In particular, we describe our approaches to the challenges that we have encountered in requirements analysis, data acquisition, visual design, software design, system development, team organisation, and resource planning. By reflecting on our experience, we propose a set of recommendations as the first step towards a methodology for developing and providing rapid VIS capacities to support emergency responses.

The gut microbiota composition of Trichoplusia ni is altered by diet and may influence its polyphagous behavior.

Insects are known plant pests, and some of them such as Trichoplusia ni feed on a variety of crops. In this study, Trichoplusia ni was fed distinct diets of leaves of Arabidopsis thaliana or Solanum lycopersicum as well as an artificial diet. After four generations, the microbial composition of the insect gut was evaluated to determine if the diet influenced the structure and function of the microbial communities. The population fed with A. thaliana had higher proportions of Shinella, Terribacillus and Propionibacterium, and these genera are known to have tolerance to glucosinolate activity, which is produced by A. thaliana to deter insects. The population fed with S. lycopersicum expressed increased relative abundances of the Agrobacterium and Rhizobium genera. These microbial members can degrade alkaloids, which are produced by S. lycopersicum. All five of these genera were also present in the respective leaves of either A. thaliana or S. lycopersicum, suggesting that these microbes are acquired by the insects from the diet itself. This study describes a potential mechanism used by generalist insects to become habituated to their available diet based on acquisition of phytochemical degrading gut bacteria.

Bacillus subtilis DE111 intake may improve blood lipids and endothelial function in healthy adults.

Cardiovascular disease (CVD) is the leading cause of death in the US and worldwide. By 2030 it is anticipated that CVD will claim the lives of more than 24 million people. Throughout the last decade, researchers have investigated the role of the gut microbiota in the development of CVD. Evidence exists for a positive correlation between Bifidobacterium and vascular function, glucose tolerance, and reduced systemic inflammation. Another probiotic species, Bacillus subtilis, has also been found to reduce cholesterol levels in human and animal models. In light of these data, we examined various measures of cardiovascular health after consumption of Bifidobacterium animalis subsp. lactis strain BL04, with and without a cocktail of Escherichia coli-targeting bacteriophages (marketed as PreforPro), Bacillus subtilis strain DE111 or a maltodextrin-based placebo in a healthy human population. In a randomised, double-blind, placebo-controlled 4-week intervention conducted in individuals 18 to 65 years of age with a body mass index of 20 to 34.9, we saw no significant changes in measured CVD parameters among individuals consuming B. lactis with or without bacteriophages. However, B. subtilis supplementation resulted in a significant reduction in total cholesterol relative to baseline measures (-8 mg/dl; P=0.04, confidence interval (CI): -13.40, -0.19), as well as non-high-density lipoprotein-cholesterol (-11 mg/dl; P=0.01, CI: -12.43, -2.07). In addition we observed trending improvements in endothelial function (P=0.05, CI: -0.003, 0.370) and in low-density lipoprotein-cholesterol (P=0.06, CI:-12.29, 0.2864). Strikingly, these effects were seen in a largely healthy population. These data suggest that B. subtilis supplementation may be beneficial for improving risk factors associated with CVD. Further studies in populations of older adults or those with dyslipidaemia and endothelial dysfunction is warranted.

Clear aligners in orthodontic treatment.

Since the introduction of the Tooth Positioner (TP Orthodontics) in 1944, removable appliances analogous to clear aligners have been employed for mild to moderate orthodontic tooth movements. Clear aligner therapy has been a part of orthodontic practice for decades, but has, particularly since the introduction of Invisalign appliances (Align Technology) in 1998, become an increasingly common addition to the orthodontic armamentarium. An internet search reveals at least 27 different clear aligner products currently on offer for orthodontic treatment. The present paper will highlight the increasing popularity of clear aligner appliances, as well as the clinical scope and the limitations of aligner therapy in general. Further, the paper will outline the differences between the various types of clear aligner products currently available.

The role of visceral and subcutaneous adipose tissue fatty acid composition in liver pathophysiology associated with NAFLD.

Visceral adiposity is associated with type-2-diabetes, inflammation, dyslipidemia and non-alcoholic fatty liver disease (NAFLD), whereas subcutaneous adiposity is not. We hypothesized that the link between visceral adiposity and liver pathophysiology involves inherent or diet-derived differences between visceral and subcutaneous adipose tissue to store and mobilize saturated fatty acids. The goal of the present study was to characterize the fatty acid composition of adipose tissue triglyceride and portal vein fatty acids in relation to indices of liver dysregulation. For 8 weeks rats had free access to control (CON; 12.9% corn/safflower oil; 3.6 Kcal/g), high saturated fat (SAT; 45.2% cocoa butter; 4.5 Kcal/g) or high polyunsaturated fat (PUFA; 45.2% safflower oil; 4.5 Kcal/g) diets. Outcome measures included glucose tolerance, visceral and subcutaneous adipose tissue triglyceride, liver phospholipids and plasma (portal and systemic) free fatty acid composition, indices of inflammation and endoplasmic reticulum stress in the liver and adipose tissue depots and circulating adipo/cytokines. Hepatic triglycerides were significantly increased in both high fat diet groups compared to control and were significantly higher in PUFA compared to SAT. Although glucose tolerance was not different among diet groups, SAT increased markers of inflammation and ER stress in the liver and both adipose tissue depots. Fatty acid composition did not differ among adipose depots or portal blood in any dietary group. Overall, these data suggest that diets enriched in saturated fatty acids are associated with liver inflammation, ER stress and injury, but that any link between visceral adipose tissue and these liver indices does not involve selective changes to fatty acid composition in this depot or the portal vein.

Driven dynamics and rotary echo of a qubit tunably coupled to a harmonic oscillator.

We have investigated the driven dynamics of a superconducting flux qubit that is tunably coupled to a microwave resonator. We find that the qubit experiences an oscillating field mediated by off-resonant driving of the resonator, leading to strong modifications of the qubit Rabi frequency. This opens an additional noise channel, and we find that low-frequency noise in the coupling parameter causes a reduction of the coherence time during driven evolution. The noise can be mitigated with the rotary-echo pulse sequence, which, for driven systems, is analogous to the Hahn-echo sequence.

Down regulation of virulence factors of Pseudomonas aeruginosa by salicylic acid attenuates its virulence on Arabidopsis thaliana and Caenorhabditis elegans.

Salicylic acid (SA) is a phenolic metabolite produced by plants and is known to play an important role in several physiological processes, such as the induction of plant defense responses against pathogen attack. Here, using the Arabidopsis thaliana-Pseudomonas aeruginosa pathosystem, we provide evidence that SA acts directly on the pathogen, down regulating fitness and virulence factor production of the bacteria. Pseudomonas aeruginosa PA14 showed reduced attachment and biofilm formation on the roots of the Arabidopsis mutants lox2 and cpr5-2, which produce elevated amounts of SA, as well as on wild-type Arabidopsis plants primed with exogenous SA, a treatment known to enhance endogenous SA concentration. Salicylic acid at a concentration that did not inhibit PA14 growth was sufficient to significantly affect the ability of the bacteria to attach and form biofilm communities on abiotic surfaces. Furthermore, SA down regulated three known virulence factors of PA14: pyocyanin, protease, and elastase. Interestingly, P. aeruginosa produced more pyocyanin when infiltrated into leaves of the Arabidopsis transgenic line NahG, which accumulates less SA than wild-type plants. This finding suggests that endogenous SA plays a role in down regulating the synthesis and secretion of pyocyanin in vivo. To further test if SA directly affects the virulence of P. aeruginosa, we used the Caenorhabditis elegans-P. aeruginosa infection model. The addition of SA to P. aeruginosa lawns significantly diminished the bacterium's ability to kill the worms, without affecting the accumulation of bacteria inside the nematodes' guts, suggesting that SA negatively affects factors that influence the virulence of P. aeruginosa. We employed microarray technology to identify SA target genes. These analyses showed that SA treatment affected expression of 331 genes. It selectively repressed transcription of exoproteins and other virulence factors, while it had no effect on expression of housekeeping genes. Our results indicate that in addition to its role as a signal molecule in plant defense responses, SA works as an anti-infective compound by affecting the physiology of P. aeruginosa and ultimately attenuating its virulence.

Plant models for animal pathogenesis.

Several bacteria that are pathogenic to animals also infect plants. Mechanistic studies have proven that some human/animal pathogenic bacteria employ a similar subset of virulence determinants to elicit disease in animals, invertebrates and plants. Therefore, the results of plant infection studies are relevant to animal pathogenesis. This discovery has resulted in the development of convenient, cost-effective, and reliable plant infection models to study the molecular basis of infection by animal pathogens. Plant infection models provide a number of advantages in the study of animal pathogenesis. Using a plant model, mutations in animal pathogenic bacteria can easily be screened for putative virulence factors, a process which if done using existing animal infection models would be time-consuming and tedious. High-throughput screening of plants also provides the potential for unravelling the mechanisms by which plants resist animal pathogenic bacteria, and provides a means to discover novel therapeutic agents such as antibiotics and anti-infective compounds. In this review, we describe the developing technique of using plants as a model system to study Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus aureus pathogenesis, and discuss ways to use this new technology against disease warfare and other types of bioterrorism.

Renal stone analysis: why and how?

Upper urinary tract stone disease is widespread in the developed world. On both clinical and economic grounds it is now accepted that evidence-based medical intervention is the only approach likely to make a significant impact on the incidence, and more importantly, the recurrence rates of this disease. Targeted medical prophylaxis requires reliable information on stone type which, when combined with relevant blood and urine analyses, allows identification of treatable risk factors. Data from an external quality assurance scheme indicate that stone analysis is poorly performed in many laboratories, and it is probable that this results in ill-informed patterns of investigation, inappropriate therapy, missed diagnoses of rarer causative disorders and wasteful further investigation of 'non-renal' stone artefacts. Renal stone analysis is a specialist investigation requiring appropriate analytical and interpretative expertise if the information is to be used to enhance patient care. For those laboratories not able to offer this, for whatever reason, referral is the only defensible approach to service provision. The methods currently employed in many departments have no place in modern clinical biochemistry practice.

Polymorphisms in the beta2 adrenergic receptor and bronchodilator response, bronchial hyperresponsiveness, and rate of decline in lung function in smokers.

BACKGROUND: Non-specific bronchial hyperresponsiveness (NSBH) is a known predictor of accelerated rate of decline in lung function in smokers. Polymorphisms of the beta(2) adrenergic receptor (ADRB2) have previously been associated with NSBH and bronchodilator response (BDR) in asthmatics. Based on these associations, we hypothesised that ADRB2 polymorphisms would be associated with NSBH and BDR as well as an accelerated rate of decline in lung function among smokers. METHODS: The prevalence of two ADRB2 polymorphisms, Arg16-->Gly and Gln27-->Glu, was examined in 587 smokers chosen from the NHLBI Lung Health Study for having the fastest (n=282) and slowest (n=305) 5 year rate of decline in forced expiratory volume in 1 second (FEV(1); mean DeltaFEV(1) -4.14 and +1.08% predicted/year, respectively). RESULTS: Contrary to our hypothesis, no ADRB2 allele or haplotype was associated with NSBH, BDR, or rate of decline in lung function. However, there was a significant negative association between heterozygosity at position 27 and a fast decline in lung function (adjusted odds ratio 0.56, 95% CI 0.40 to 0.78, p=0.0007). CONCLUSIONS: Heterozygosity at position 27 may be protective against an accelerated rate of decline in lung function. The polymorphism at position 16 does not contribute to the rate of decline in lung function, measures of NSBH, or BDR in smokers.

Association of IL-1beta and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers.

BACKGROUND: There is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent that binds to the IL-1 receptor but does not possess agonist activity. Each of the genes of the IL-1 locus on chromosome 2q14 is polymorphic. The IL1RN gene contains an 86 bp tandem repeat and allele 2 of this polymorphism has been associated with various inflammatory diseases. The IL-1beta (IL1B) gene contains a promoter polymorphism (C-511T) that has been associated with inflammatory diseases and is in linkage disequilibrium with the IL1RN polymorphism. METHODS: We investigated whether polymorphisms in the IL1B and IL1RN genes were associated with rate of decline of lung function. Genotypes were determined in 284 smokers with a rapid decline in lung function and 306 smokers with no decline in lung function. RESULTS: None of the genotypes was associated with the rate of decline of lung function. However, the distribution of IL1B/IL1RN haplotypes was different between smokers with a rapid decline in lung function and those with no decline in lung function (p=0.0005). CONCLUSION: These results suggest that IL1B/IL1RN haplotypes play a role in the rate of decline in lung function in smokers.

Susceptibility genes for rapid decline of lung function in the lung health study.

The genes that contribute to the genetic susceptibility to chronic obstructive pulmonary disease (COPD) remain largely unknown. We hypothesized that widely divergent rates of decline in lung function in smokers would be a robust phenotype for detection of genes that contribute to COPD severity. We selected 283 rapid decliners (deltaFEV1 = -154 +/- 3 ml/yr) and 308 nondecliners (deltaFEV1 = +15 +/- 2 ml/yr) from among smokers followed for 5 yr in the NHLBI Lung Health Study. Rapid decline of FEV1 was associated with the MZ genotype of the alpha1-antitrypsin gene (odds ratio [OR] = 2.8, p = 0.03). This association was stronger for a combination of a family history of COPD with MZ (OR = 9.7, p = 0.03). These data suggest that the MZ genotype results in an increased rate of decline in lung function and interacts with other familial factors. Haplotype frequencies of the microsomal epoxide hydrolase (mEH) gene were significantly different between rapid decliners and nondecliners (p = 0.03). A combination of a family history of COPD with homozygosity for the His113/His139 mEH haplotype was also associated with rapid decline of lung function (OR = 4.9, p = 0.04). The alpha1-antitrypsin S and 3' polymorphisms, vitamin D-binding protein isoforms, and tumor necrosis factor (TNF-alpha G-308A and TNF-beta A252G) polymorphisms were not associated with rate of decline of lung function.

The effect of age and duration of disease on airway structure in fatal asthma.

We hypothesized that if airway remodeling is related to duration of asthma, that when matched for severity, the airways of older adults should show greater alterations than the airways of younger adults. Using standard morphometric techniques, we compared airways with basement membrane perimeters (Pbm) between 2 and 10 mm from young individuals who died of asthma (n = 14, range 17-23 yr), and older individuals with fatal asthma (n = 13, range 40-49 yr). Comparisons were also made with normal airways from age-matched adults. Wall area was increased in old individuals with fatal asthma compared with young individuals with fatal asthma, primarily due to greater adventitial area, whereas wall area in young individuals with fatal asthma was not different from control subjects. Within muscle bundles the connective tissue matrix was increased around individual cells in individuals with asthma, unrelated to age. After adjustment for this change, smooth muscle area in both asthma groups was still greater than in age-matched control subjects, in old individuals with fatal asthma 4-fold greater (p = 0.04), and in young individuals with fatal asthma 2-fold greater (p = 0.03). Airway narrowing was increased in old versus young individuals with fatal asthma, with both groups more narrowed than control subjects. Intralumenal obstruction and subepithelial collagen in the two asthma groups were significantly greater than in control subjects, but there was no age effect. These data provide support for the hypothesis that there is an increase in airway wall area, including smooth muscle, and airway narrowing with increasing duration of severe asthma or with older age. The observation that total wall thickness was not greater in young individuals with young fatal asthma than in control subjects suggests that factors other than airway wall geometry contribute to the pathogenesis of fatal attacks in this age group.

Polymorphisms in the IL4, IL4RA, and FCERIB genes and asthma severity.

BACKGROUND: Genetic polymorphisms have been associated with asthma and asthma severity. OBJECTIVE: We sought to determine whether 3 polymorphisms were associated with severe asthma indicated either by the occurrence of a fatal (or near-fatal) asthma attack or by severe airflow obstruction. METHODS: We obtained DNA and clinical data from asthmatic subjects who either died or nearly died during an asthma attack and from a group of subjects with mild-to-moderate asthma who had never experienced a fatal or near-fatal asthma episode. These groups were compared with a group of nonatopic nonasthmatic control subjects. The level of airflow obstruction (FEV(1) percent predicted) in the subjects with mild-to-moderate asthma was used as an additional measure of disease severity. The subjects were genotyped for the IL4*C-589T promoter polymorphism and the IL4RA*Q576R and the FCERIB*E237G amino acid substitutions. RESULTS: The results showed that the FCERIB*E237G and IL4RA*Q576R polymorphisms were not associated with fatal or near-fatal asthma. However, the IL4*-589T allele was significantly increased in the subjects with fatal or near-fatal asthma compared with nonasthmatic subjects (odds ratio [OR], 1.8; P =.02) and subjects with mild-to-moderate asthma (OR, 1.9; P =.02). There was no interaction between the IL4*-589T and IL4RA*576R alleles. Of the 3 polymorphisms, only the IL4RA*576R allele was associated with severe airflow obstruction (OR, 8.2; P =.01). CONCLUSION: These data suggest that the IL4*-589T allele is a risk factor for life-threatening asthma and that the IL4RA*576R allele is a risk factor for a low level of lung function in asthmatic subjects.

Leukemia inhibitory factor is synthesized and released by human eosinophils and modulates activation state and chemotaxis.

BACKGROUND: The cytokine leukemia inhibitory factor (LIF) is known to be produced by both inflamed peripheral autonomic nerves and several cell types involved in the regulation of the immune response. We have recently demonstrated that several structural cell types in human airways produce LIF in response to inflammatory stimuli and that LIF augments contractile responses to tachykinins in airway explants. Because the eosinophil is a major effector cell in asthma and often found adjacent to the nerves, we hypothesized that eosinophils produce LIF and that LIF primes and upregulates eosinophil recruitment and function, allowing bidirectional neuroimmune interactions and augmentation of eosinophil-mediated injury. OBJECTIVE: The purpose of this study was to demonstrate that human eosinophils synthesize and release LIF, to determine the effects of LIF on eosinophil functions (ie, chemotaxis, granule protein release, expression of the activation marker CD69, and apoptosis), and to compare serum LIF levels between atopic and nonatopic individuals. METHODS: Reverse-transcription PCR, ELISA, immunocytochemistry, chemotaxis assay, and flow cytometry were used. RESULTS: Peripheral blood eosinophils express LIF and messenger RNA for LIF and LIF receptor. Serum LIF levels were higher in atopic patients with mild asthma than in nonatopic normal donors. Eosinophils from nonatopic donors were stimulated by calcium ionophore to release small amounts of LIF (from almost none to 5.3 +/- 1.8 pg/10(6) cells). Eosinophils from atopic donors showed a 10-fold increase (from 45.1 +/- 38.7 pg/106 cells to 414.5 +/- 189.9 pg/10(6) cells). Preincubation of eosinophils with LIF increased eosinophil peroxidase release 4-fold. LIF was not chemotactic for eosinophils but augmented chemotaxis mediated by substance P by 82% and by platelet-activating factor by 31%. LIF did not effect eosinophil apoptosis but increased CD69 expression. CONCLUSION: LIF has proinflammatory roles in eosinophil-dependent airway disorders.

Prevalence of tumor necrosis factor-alpha and angiotensin converting enzyme polymorphisms in mild/moderate and fatal/near-fatal asthma.

Allele 2 of the polymorphism at position -308 in the promoter of the tumor necrosis factor alpha (TNF-alpha) gene, and the D allele of the angiotensin converting enzyme (ACE) gene, have been associated with asthma. We hypothesized that genotypes containing these alleles would show an increased prevalence in asthmatic as compared with nonasthmatic individuals, and would be associated with asthma severity. Polymerase chain reaction-based assays were developed to determine TNF-alpha and ACE genotypes among subjects with mild/moderate asthma (n = 92), fatal/near-fatal asthma (n = 159), no asthma (n = 43), and random population controls (n = 252). The TNF-alpha -308 polymorphism was increased in both subjects with mild/moderate (p = 0.03) and those with fatal/near fatal asthma (p = 0.02) versus those without asthma, and in all subjects with asthma versus random population controls (p = 0.02). The mild/moderate group was subdivided into subjects with mild (n = 43) and those with moderate (n = 33) asthma. TNF-alpha -308 was increased in the moderately asthmatic versus the nonasthmatic subjects (p = 0.003), and in the mildly asthmatic subjects (p = 0.01). However, TNF-alpha -308 was not significantly more prevalent in the fatal/near-fatal than in the mild/moderate asthmatic group. The ACE-D allele did not show an association with either asthma or asthma severity. We conclude that the TNF-alpha -308 polymorphism may be a risk factor for asthma but does not increase the risk of a fatal or a near-fatal asthma attack, whereas the ACE polymorphism is not associated with asthma in this population.

Leukemia inhibitory factor (LIF) and LIF receptor in human lung. Distribution and regulation of LIF release.

The distribution and regulation of leukemia inhibitory factor (LIF) and its receptor (LIFR) in human lung tissue is unknown. We recently found that LIF was immunolocalized to several cell types in human airways, and that exogenous LIF modulated neural and contractile responses of explanted airways. The present study aimed to determine the cellular distribution and regulation of gene transcripts for LIF and LIFR in human lung, and measured the release of LIF in response to anti-immunoglobulin (Ig)E, interleukin (IL)-1beta, and IL-6. Exposure of human lung to IL-1beta (100 pg/ml) resulted in the rapid induction of LIF messenger RNA (mRNA) (1 h) and subsequent protein release (6 h). Similar results were observed when lung tissue was exposed to anti-IgE (6 U/ml). Gene transcripts for LIF were observed in nine pulmonary cell types, with the greatest expression occurring in fibroblasts. LIFR transcripts were also widely expressed in these cell types. In cultures of nontransformed epithelial cells, lung fibroblasts, and airway smooth-muscle cells, IL-1beta (100 pg/ml) induced the rapid accumulation of LIF mRNA and protein release, with fibroblasts liberating the greatest amount. IL-6 also induced the expression of LIF mRNA and release of LIF in airway smooth-muscle cells, whereas exogenous LIF itself had no effect. Expression of LIFR mRNA was not influenced by exposure to IL-1beta or LIF in any of the cell lines used. These results highlight the widespread distribution and rapid release of LIF in human lung tissue and, in conjunction with our previous report, suggest that this cytokine may play an important role in lung inflammatory processes and neuroimmune interactions.

Z and S mutations of the alpha1-antitrypsin gene and the risk of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) has been associated with heterozygosity for the Z and S alleles of the alpha1-antitrypsin gene in some studies, but these observations have not been confirmed by others. Cigarette smoking is the major risk factor for COPD and may have been a confounding factor in many of the previous studies. We investigated whether the Z or S alleles were more prevalent in a group of heavy smokers with COPD than in a group of nonobstructed smokers. Forced expiratory volume in 1 s and forced vital capacity were derived for 266 patients undergoing lobar or lung resection. These lung-function measurements were used to divide the patients into a COPD group and a group of nonobstructed control subjects. The subjects were typed for the Z and S alleles of the alpha1-antitrypsin gene using a polymerase chain reaction-based technique. In the COPD patients, 12 of 193 (6%) were heterozygous for the Z allele (MZ) compared with 0 of 73 control subjects, which gave a P value of 0.04 after correction for age, gender, and smoking history. There was no association of the S allele with COPD. The results indicate that the Z, but not the S, allele is a risk factor for COPD in the heterozygous state.