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Objective Atherosclerosis is a major cause of cardiovascular disease. Monocyte-endothelial cell interactions are partly mediated by expression of monocyte CX3CR1 and endothelial cell fractalkine (CX3CL1). Interrupting the interaction between this ligand–receptor pair should reduce monocyte binding to the endothelial wall and reduce atherosclerosis. We sought to reduce atherosclerosis by preventing monocyte-endothelial cell interactions through use of a long-acting CX3CR1 agonist. Methods In this study, the chemokine domain of CX3CL1 was fused to the mouse Fc region to generate a long-acting soluble form of CX3CL1 suitable for chronic studies. CX3CL1-Fc or saline was injected twice a week (30 mg/kg) for 4 months into Ldlr knockout (KO) mice on an atherogenic western diet. Results CX3CL1-Fc-treated Ldlr KO mice showed decreased en face aortic lesion surface area and reduced aortic root lesion size with decreased necrotic core area. Flow cytometry analyses of CX3CL1-Fc-treated aortic wall cell digests revealed a decrease in M1-like polarized macrophages and T cells. Moreover, CX3CL1-Fc administration reduced diet-induced atherosclerosis after switching from an atherogenic to a normal chow diet. In vitro monocyte adhesion studies revealed that CX3CL1-Fc treatment caused fewer monocytes to adhere to a human umbilical vein endothelial cell monolayer. Furthermore, a dorsal window chamber model demonstrated that CX3CL1-Fc treatment decreased in vivo leukocyte adhesion and rolling in live capillaries after short-term ischemia-reperfusion. Conclusion These results indicate that CX3CL1-Fc can inhibit monocyte/endothelial cell adhesion as well as reduce atherosclerosis., Highlights • Long-acting FKN-Fc reduced atherosclerosis in LDLR KO mice in a prevention model. • FKN-Fc administration accelerated diet-induced regression of established atherosclerosis. • Monocyte adhesion in vitro and in vivo is reduced in the presence of FKN-Fc.

Janus Kinases (JAKs) mediate activity of many asthma-relevant cytokines. GDC-0214, an inhaled small molecule JAK1 inhibitor, has previously been shown to reduce fractional exhaled nitric oxide (FeNO) in patients with mild asthma, but required an excessive number of inhalations.To assess whether GDC-4379, a new inhaled JAK inhibitor, reduces FeNO and peripheral biomarkers of inflammation.This study assessed the activity of GDC-4379 in a double-blind, randomized, placebo-controlled, Phase 1 study in patients with mild asthma. Participants included adults (18-65y) with a diagnosis of asthma for ≥6 months, forced expiratory volume in 1 s (FEVsub1/sub)gt; 70% predicted, FeNOgt;40 ppb, using as-needed short-acting beta-agonist medication only. Four sequential, 14-day, ascending-dose cohorts (10 mg QD, 30 mg QD, 40 mg BID, and 80 mg QD) of 12 participants each were randomized 2:1 to GDC-4379 or placebo. The primary activity outcome was percent change from baseline (CFB) in FeNO to Day 14 compared to the pooled placebo group. Safety, tolerability, pharmacokinetics, and pharmacodynamic biomarkers, including blood eosinophils, serum CCL17, and serum CCL18, were also assessed.Of 48 enrolled participants, the mean age was 25 years and 54% were female. Median (range) FeNO at baseline was 79 (41-222) ppb. GDC-4379 treatment led to dose-dependent reductions in FeNO. Compared to placebo, mean (95% CI) percent CFB in FeNO to Day 14 was: -6 (-43, 32) at 10 mg QD, -26 (-53, 2) at 30 mg QD, -55 (-78, -32) at 40 mg BID and -52 (-72, -32) at 80 mg QD. Dose-dependent reductions in blood eosinophils and serum CCL17 were also observed. Higher plasma drug concentrations corresponded with greater FeNO reductions. No serious AEs occurred. The majority of AEs were mild to moderate. The most common AEs were headache and oropharyngeal pain. Minor changes in neutrophils were noted at 80 mg QD, but were not considered clinically meaningful.In patients with mild asthma, 14-day treatment with GDC-4379 reduced FeNO levels and peripheral biomarkers of inflammation. Treatment was well tolerated without any major safety concerns.ACTRN12619000227190.

Cuttlefish are highly efficient predators, which strongly rely on their anterior binocular visual field for hunting and prey capture. Their complex eyes possess adaptations for low light conditions. Recently, it was discovered that they display camouflaging behavior at night, perhaps to avoid detection by predators, or to increase their nighttime hunting success. This raises the question whether cuttlefish are capable of foraging during nighttime. In the present study, prey capture of the common cuttlefish (Sepia officinalis) was filmed with a high-speed video camera in different light conditions. Experiments were performed in daylight and with near-infrared light sources in two simulated nightlight conditions, as well as in darkness. The body of the common cuttlefish maintained a velocity of less than 0.1 m/s during prey capture, while the tentacles during the seizing phase reached velocities of up to 2.5 m/s and accelerations reached more than 450 m/s2 for single individuals. There was no significant difference between the day and nighttime trials, respectively. In complete darkness, the common cuttlefish was unable to catch any prey. Our results show that the common cuttlefish are capable of catching prey during day- and nighttime light conditions. The common cuttlefish employ similar sensory motor systems and prey capturing techniques during both day- and nighttime conditions.

Present study evaluated the impacts of adult density on key biological parameters of a tropical estuarine calanoid copepod A. tropica. Egg production, egg hatching success (EHS), adult mortality (%), nauplii cannibalism (% hour−1), population growth and intrinsic rate of population increase in response to five different adult densities viz. 125, 250, 500, 1000 and 2000 adults/L were assessed. The highest individual egg production (IEP, eggs/female/day) was recorded at 125 adults/L treatment while relative egg production (REP, eggs/L/day) was highest at 1000 adults/L. EHS (24 h and 48 h) showed significant difference (p

Methadone maintenance is currently the predominant form of opioid substitution treatment available in the Republic of Ireland. Prescribing decisions currently involve urine testing for drug use. Urine testing may involve provision of a supervised sample in some circumstances, despite recommendations made in 2010 to abandon this practice. This project aims to evaluate the accuracy and acceptability of oral fluid testing for patients on methadone maintenance and also gather patient views on their treatment. Patients attending for methadone maintenance at 4 general practices were invited to take part in this study, which involved taking an additional oral fluid test and a questionnaire. Fifty-five patients agreed to participate. Fifty-two (95%) found the oral fluid test acceptable, and almost two-thirds would prefer to see it used instead of urine testing. Oral fluid provided similar results to urine testing for all drugs except benzodiazepines. Self-report identified cocaine and opiate use not detected by oral fluid or urine testing. This study presents evidence that oral fluid testing is acceptable to most patients. While oral fluid testing was inferior to urine testing for benzodiazepines, it may have an adjunctive role to play in methadone maintenance provision. Patients reported more negative than positive aspects of methadone maintenance.

The emergence of SARS-CoV-2 variants will change the landscape of what we already know about COVID-19, making it important to understand the immunological and molecular mechanism of this illness. The virulent nature of the virus, disease outcomes and lack of suitable facilities for studying virus-infected samples has made the need for small animal models urgent. Staphylococcus enterotoxin B (SEB)-induced Acute Respiratory Distress Syndrome (ARDS) mimics the cytokine storm presented in patients with severe COVID-19 and is a safer alternative than working with infected samples. To identify pathways in pulmonary cells that potentially cause ARDS, we utilized single-cell RNA sequencing (scRNASeq) to profile the whole lung cells of C3H/HeJ mice treated with SEB and healthy controls. While it is well established that SEB induces robust proliferation of CD4+ T cells with the receptor Vβ8.2 by binding of these cells with antigen presenting cells, effects in other cell types is not well described. We found that intranasal administration of SEB induced the proliferation of three subsets of macrophages, neutrophils, and cytotoxic T cells in the lungs. Our data also illustrated a loss of multiple cell types including resident macrophages, multiple subsets of B cells, and club cells. Macrophage subsets displayed increased expression of genes related to interferon signaling and lipid metabolism. This data emphasizes the importance of understanding the role of macrophages in ARDS, and can further provide insights into elucidating the mechanisms not only in SEB-induced ARDS but also in severe COVID-19. This may serve as a model for severe case of the disease. (Supported by NIH P01AT003961, P20GM103641, R01AI129788, R01 ES030144 and R01AI123947)

Over thirty percent of individuals infected with human immunodeficiency virus type 1 (HIV) worldwide suffer from HIV-associated neurocognitive disorder (HAND). GFAP-gp120 transgenic (Tg) mice serve as an excellent model system for HAND because they manifest the same neuropathological attributes observed in the brains of AIDS patients. In this study, we sought to identify novel genes associated with the GFAP-gp120 neurodegenerative mouse model. Von Frey filament and hot plate tests on 8 month old GFAP-gp120 mice resulted in a significant increase in mechanical and thermal nociception in Tg versus wild-type mice. Neuropathology was confirmed via immunohistochemistry of MAP2, Synaptophysin, Iba-1, and GFAP. The MAP2 and Synaptophysin allowed us to visualize dendritic density and synaptic loss. Infiltration of macrophages was observed with anti-Iba-1 and astrocytosis with anti-GFAP Abs. Additionally, single cell RNA sequencing (scRNASeq) of encephalitogenic mononuclear cells illustrated 10 distinct clusters of cells. These clusters included: astrocytes, neurons, oligodendrocytes, endothelial cells, microglia, and macrophages. Differential expression analysis showed decreased expression of GM42031 in Tg macrophages and microglia. This locus is currently unclassified and thought to be either a long non coding RNA (lncRNA) or a gene for a NYNRIN-like protein. Until now, this particular RNA has not been associated with the GFAP-gp120 disease model. However, there has been some association of GM42031 with macrophage regulation in Parkinson’s disease and colitis models. Together our study provides novel insights into the immunopathology of HAND that may form the basis for development of effective therapeutics.

We have previously reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and β cell function. Here, we demonstrate that chronic administration of a long-acting form of FKN, FKN-Fc, can exert durable effects to improve glucose tolerance with increased glucose-stimulated insulin secretion and decreased β cell apoptosis in obese rodent models. Unexpectedly, chronic FKN-Fc administration also led to decreased α cell glucagon secretion. In islet cells, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism, which triggered β cell action potential (AP) firing and decreased α cell AP amplitude. This results in increased glucose-stimulated insulin secretion and decreased glucagon secretion. Beyond its islet effects, FKN-Fc also exerted peripheral effects to enhance hepatic insulin sensitivity due to inhibition of glucagon action. In hepatocytes, FKN treatment reduced glucagon-stimulated cAMP production and CREB phosphorylation in a pertussis toxin-sensitive manner. Together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.

The objective of this systematic review is to extract and study evidences available toassess the effectiveness of low level laser therapy (LLLT) on acceleration of Orthodontic tooth movement. The data sources used were electronic data bases including EMBASE, PubMed, Scopus and Google Scholar. References from collectedarticles were hand searched. Search was not bound with any time limits. Randomized control and clinical trials were also included. Search terms included were orthodontic movement speed/accelerated tooth movement/ LLLT/ Cold-soft diode laser/ Ga-Al-As laser/ low intensity laser/ light therapy/ phototherapy/ photobiostimulation. Only those studies which falls in the moderate to high category on assessment with Cericato et al. method for bias assessment were included. Double extractors did the data collection and at the time of controversies a blinded expert were approached for final decision. Nine studies seemed to be eligible for this study. An energy input of 4.2-8J sq.cm, wavelength of 780-904 nm applied for 80-100 sec/tooth within a time period of 4-6 days per month was found to be effective in demonstrating accelerated orthodontic tooth movement. Some scientific evidence for low level laser therapy causing accelerated orthodontic tooth movement was demonstrated. Those high evidence studies which came up with laser having no benefits on tooth movement explained their pit falls in the discussion, giving reason why they failed to observe any benefit in tooth movement.

Attacks by aquatic predators generate frontal water disturbances characterised by low-frequency gradients in pressure and particle motion. Low-frequency hearing is highly developed in cephalopods. Thus, we examined behavioural responses in juvenile cuttlefish to infrasonic accelerations mimicking main aspects of the hydrodynamic signals created by predators. In the experimental set-up, animals and their surrounding water moved as a unit to minimise lateral line activation and to allow examination of the contribution by the inner ear. Behavioural responses were tested in light versus darkness and after food deprivation following a ‘simulated’ hunting opportunity. At low acceleration levels, colour change threshold at 3, 5 and 9 Hz was 0.028, 0.038 and 0.035 m s−2, respectively. At higher stimulus levels, jet-propulsed escape responses thresholds in daylight were 0.043, 0.065 and 0.069 m s−2 at 3, 5 and 9 Hz, respectively, and not significantly different from the corresponding darkness thresholds of 0.043, 0.071 and 0.064 m s−2. In a simulated hunting mode, escape thresholds were significantly higher at 3 Hz (0.118 m s−2) but not at 9 Hz (0.134 m s−2). Escape responses were directional, and overall followed the direction of the initial particle acceleration, with mean escape angles from 313 to 33 deg for all three experiments. Thus, in the wild, particle acceleration might cause escape responses directed away from striking predators but towards suction-feeding predators. We suggest that cuttlefish jet-propulsed escape behaviour has evolved to be elicited by the early hydrodynamic disturbances generated during predator encounters, and that the inner ear plays an essential role in the acoustic escape responses.

To improve conservation strategies for threatened sea turtles, more knowledge on their ecology, behavior, and how they cope with severe and changing weather conditions is needed. Satellite and animal motion datalogging tags were used to study the inter-nesting behavior of two female loggerhead turtles in the Gulf of Mexico, which regularly has hurricanes and tropical storms during nesting season. We contrast the behavioral patterns and swimming energetics of these two turtles, the first tracked in calm weather and the second tracked before, during and after a tropical storm. Turtle 1 was highly active and swam at the surface or submerged 95% of the time during the entire inter-nesting period, with a high estimated specific oxygen consumption rate (0.95 ml min-1 kg-0.83). Turtle 2 was inactive for most of the first 9 days of the inter-nesting period, during which she rested at the bottom (80% of the time) with low estimated oxygen consumption (0.62 ml min-1 kg-0.83). Midway through the internesting period, turtle 2 encountered a tropical storm and became highly active (swimming 88% of the time during and 95% after the storm). Her oxygen consumption increased significantly to 0.97 ml min-1 kg-0.83 during and 0.98 ml min-1 kg-0.83 after the storm. However, despite the tropical storm, turtle 2 returned to the nesting beach, where she successfully re-nested 75 m from her previous nest. Thus, the tropical storm had a minor effect on this female's individual nesting success, even though the storm caused 90% loss nests at Casey Key.

To improve conservation strategies for threatened sea turtles, more knowledge on their ecology, behavior, and how they cope with severe and changing weather conditions is needed. Satellite and animal motion datalogging tags were used to study the inter-nesting behavior of two female loggerhead turtles in the Gulf of Mexico, which regularly has hurricanes and tropical storms during nesting season. We contrast the behavioral patterns and swimming energetics of these two turtles, the first tracked in calm weather and the second tracked before, during and after a tropical storm. Turtle 1 was highly active and swam at the surface or submerged 95% of the time during the entire inter-nesting period, with a high estimated specific oxygen consumption rate (0.95 ml min

The last several decades of research have seen a burgeoning of data on the morphology, physiology, and evolutionary history of vertebrate auditory organs. This chapter briefly describes the status of our understanding of ear structure and function and their origins in fish, which hear using their vestibular epithelia, and land vertebrates that early evolved dedicated hearing structures. The various major lineages of land vertebrates—amphibians, lepidosaurs, archosaurs, and mammals—each have unique hearing organs. From humble beginnings as a small epithelium in their common ancestor, each lineage evolved specialized hair-cell populations and divisions of labor that led to highly sensitive and frequency-selective hearing. This chapter covers the origins, morphology, and physiological characteristics of the ears of all major groups.

Field work in Norway was funded by the Carlsberg Foundation and the National Danish Research Council to PTM. The NMFS study was funded by the U.S. Mineral Management Service. MJ is funded by the Marine Alliance for Science and Technology, Scotland, and by a Marie Curie Career Integration Grant. MW was funded by the Danish Council for Independent Research, Natural Science and NAS is currently funded by a EU Horizon 2020 MSC Fellowship. The sperm whale carries a hypertrophied nose that generates powerful clicks for long-range echolocation. However, it remains a conundrum how this bizarrely shaped apex predator catches its prey. Several hypotheses have been advanced to propose both active and passive means to acquire prey, including acoustic debilitation of prey with very powerful clicks. Here we test these hypotheses by using sound and movement recording tags in a fine-scale study of buzz sequences to relate the acoustic behaviour of sperm whales with changes in acceleration in their head region during prey capture attempts. We show that in the terminal buzz phase, sperm whales reduce inter-click intervals and estimated source levels by 1-2 orders of magnitude. As a result, received levels at the prey are more than an order of magnitude below levels required for debilitation, precluding acoustic stunning to facilitate prey capture. Rather, buzzing involves high-frequency, low amplitude clicks well suited to provide high-resolution biosonar updates during the last stages of capture. The high temporal resolution helps to guide motor patterns during occasionally prolonged chases in which prey are eventually subdued with the aid of fast jaw movements and/or buccal suction as indicated by acceleration transients (jerks) near the end of buzzes. Publisher PDF

The application of three-dimensional computational fluid dynamics in twin-screw compressors provides an outstanding opportunity for developers to gain an understanding of the complex internal flow phenomena occurring within the machine. Equipped with this knowledge, design parameters, such as clearances and port geometry, can be optimised, to enhance performance. However, as with all modelling, be it numerical or analytical, a high degree of certainty in the accuracy of the results is necessary. This paper presents the results of a study of oil-free twin screw compressor in which the results of two modelling techniques are compared. The modelling techniques used are an analytical non-dimensional thermodynamic chamber model and a numerical computational fluid dynamic model. The paper presents an overview of an oil-free twin screw compressor machine, before describing important operating characteristics and the modelling techniques used. To validate, both models are compared against historical test data, this validation indicated the chamber model is more accurate. Following this, the focus will be on the comparison of key performance indicators, including, volume flow rate, volumetric efficiency, indicated power, and discharge temperature at varying duty points. The paper concludes that the difference between both models decreases as the compressor operating speed increases, although the level of variance is dependent on pressure ratio.