High-force catch bonds between the <i>Staphylococcus aureus</i> surface protein SdrE and complement regulator factor H drive immune evasion

The invasive bacterial pathogen Staphylococcus aureus recruits the complement regulatory protein factor H (fH) to its surface to evade the human immune system. Here, we report the identification of an extremely high-force catch bond used by the S. aureus surface protein SdrE to efficiently capture fH under mechanical stress. We find that increasing the external force applied to the SdrE-fH complex prolongs the lifetime of the bond at an extraordinary high force, 1,400 pN, above which the bond lifetime decreases as an ordinary slip bond. This catch-bond behavior originates from a variation of the dock, lock and latch interaction, where the SdrE ligand binding domains undergo conformational changes under stress, enabling the formation of long-lived hydrogen bonds with fH. The binding mechanism dissected here represents a potential target for new therapeutics against multidrug-resistant S. aureus strains. © 2023, The Author(s)

The universal functorial equivariant Lefschetz invariant

We introduce the universal functorial equivariant Lefschetz invariant for endomorphisms of finite proper G-CW-complexes, where G is a discrete group. We use K_0 of the category of "phi-endomorphisms of finitely generated free RPi(G,X)-modules". We derive results about fixed points of equivariant endomorphisms of cocompact proper smooth G-manifolds.Comment: 33 pages; shortened version of the author's PhD thesis, supervised by Wolfgang Lueck, Westfaelische Wilhelms-Universitaet Muenster, 200

Modelling nasal high flow therapy effects on upper airway resistance and resistive work of breathing

Aim The goal of this paper is to quantify upper airway resistance with and without nasal high flow (NHF) therapy. For adults, NHF therapy feeds 30–60 L/min of warm humidified air into the nose through short cannulas which do not seal the nostril. NHF therapy has been reported to increase airway pressure, increase tidal volume (Vt) and decrease respiratory rate (RR), but it is unclear how these findings affect the work done to overcome airway resistance to air flow during expiration. Also, there is little information on how the choice of nasal cannula size may affect work of breathing. In this paper, estimates of airway resistance without and with different NHF flow (applied via different cannula sizes) were made. The breathing efforts required to overcome airway resistance under these conditions were quantified. Method NHF was applied via three different cannula sizes to a 3-D printed human upper airway. Pressure drop and flow rate were measured and used to estimate inspiratory and expiratory upper airway resistances. The resistance information was used to compute the muscular work required to overcome the resistance of the upper airway to flow. Results NHF raises expiratory resistance relative to spontaneous breathing if the breathing pattern does not change but reduces work of breathing if peak expiratory flow falls. Of the cannula sizes used, the large cannula produced the greatest resistance and the small cannula produced the least. The work required to cause tracheal flow through the upper airway was reduced if the RR and minute volume are reduced by NHF. NHF has been observed to do so in COPD patients (Bräunlich et al., 2013). A reduction in I:E ratio due to therapy was found to reduce work of breathing if the peak inspiratory flow is less than the flow below which no inspiratory effort is required to overcome upper airway resistance. Conclusion NHF raises expiratory resistance but it can reduce the work required to overcome upper airway resistance via a fall in inspiratory work of breathing, RR and minute volume

Thermally activated escape rates of uniaxial spin systems with transverse field

Classical escape rates of uniaxial spin systems are characterized by a prefactor differing from and much smaller than that of the particle problem, since the maximum of the spin energy is attained everywhere on the line of constant latitude: theta=const, 0 =< phi =< 2*pi. If a transverse field is applied, a saddle point of the energy is formed, and high, moderate, and low damping regimes (similar to those for particles) appear. Here we present the first analytical and numerical study of crossovers between the uniaxial and other regimes for spin systems. It is shown that there is one HD-Uniaxial crossover, whereas at low damping the uniaxial and LD regimes are separated by two crossovers.Comment: 4 PR pages, 3 figures, final published versio

Infectious Pancreatic Necrosis Virus and its impact on the Irish Salmon Aquaculture and Wild Fish sectors

Infectious pancreatic necrosis (IPN) is an economically significant viral disease of salmonid fish worldwide. Infectious pancreatic necrosis is categorised as a List III disease under Annex A of EU Council Directive 91/67/EEC. List III diseases are present within the EU and up to 2004 were regulated under national control programmes within each member state. The disease was first described in freshwater trout in North America in the 1950’s (Wood et al., 1955) and has been reported in Europe since the early 1970’s (Ball et al., 1971). Initially, IPN was regarded as a serious disease affecting rainbow trout fry and fingerlings (Roberts & Pearson, 2005). However as the salmon farming industry began to expand during the 1970’s, incidence of IPN disease in salmon also increased with the result that IPN is now widespread in the salmon farming industry in both Norway and Scotland. The economic loss due to the disease is large and outbreaks may occur in Atlantic salmon juveniles in fresh-water and in post-smolts after transfer to sea-water. Historically in Ireland, isolations of the IPN virus have been rare and occasional outbreaks have occurred in both rainbow trout and Atlantic salmon facilities. The Marine Institute and its predecessor, the Fisheries Research Centre, have been testing farmed and wild fish for disease pathogens since the mid 1980’s. The first reported clinical outbreak of IPN in Atlantic salmon occurred in 2003. However in 2006 severe outbreaks in a number of freshwater salmon hatcheries occurred which were all linked to imports from a specific single source. To date, clinical outbreaks of IPN in Ireland have been associated with imports of infected ova and their subsequent movement within the country. This report reviews the prevalence of the IPN virus in the Irish salmon farming industry and also in wild fish from selected rivers. It describes the steps taken by the industry to control the disease in 2006 and aims to provide some practical solutions to reduce the prevalence of the virus in farmed and wild fish and to prevent future outbreaks of the disease.Funder: Marine Institut

Field dependence of the temperature at the peak of the ZFC magnetization

The effect of an applied magnetic field on the temperature at the maximum of the ZFC magnetization, $M_{ZFC}$, is studied using the recently obtained analytic results of Coffey et al. (Phys. Rev. Lett. {\bf 80}(1998) 5655) for the prefactor of the N\'{e}el relaxation time which allow one to precisely calculate the prefactor in the N\'{e}el-Brown model and thus the blocking temperature as a function of the coefficients of the Taylor series expansion of the magnetocrystalline anisotropy. The present calculations indicate that even a precise determination of the prefactor in the N\'{e}el-Brown theory, which always predicts a monotonic decrease of the relaxation time with increasing field, is insufficient to explain the effect of an applied magnetic field on the temperature at the maximum of the ZFC magnetization. On the other hand, we find that the non linear field-dependence of the magnetization along with the magnetocrystalline anisotropy appears to be of crucial importance to the existence of this maximum.Comment: 14 LaTex209 pages, 6 EPS figures. To appear in J. Phys.: Condensed Matte

Fabrication and Assessment of 3D Printed Anatomical Models of the Lower Limb for Anatomical Teaching and Femoral Vessel Access Training in Medicine

For centuries, cadaveric dissection has been the touchstone of anatomy education. It offers a medical student intimate access to his or her first patient. In contrast to idealized artisan anatomical models, it presents the natural variation of anatomy in fine detail. However, a new teaching construct has appeared recently in which artificial cadavers are manufactured through three-dimensional (3D) printing of patient specific radiological data sets. In this article, a simple powder based printer is made more versatile to manufacture hard bones, silicone muscles and perfusable blood vessels. The approach involves blending modern approaches (3D printing) with more ancient ones (casting and lost-wax techniques). These anatomically accurate models can augment the approach to anatomy teaching from dissection to synthesis of 3D-printed parts held together with embedded rare earth magnets. Vascular simulation is possible through application of pumps and artificial blood. The resulting arteries and veins can be cannulated and imaged with Doppler ultrasound. In some respects, 3D-printed anatomy is superior to older teaching methods because the parts are cheap, scalable, they can cover the entire age span, they can be both dissected and reassembled and the data files can be printed anywhere in the world and mass produced. Anatomical diversity can be collated as a digital repository and reprinted rather than waiting for the rare variant to appear in the dissection room. It is predicted that 3D printing will revolutionize anatomy when poly-material printing is perfected in the early 21st century. (C) 2015 American Association of Anatomists

Fabrication and Assessment of 3D Printed Anatomical Models of the Lower Limb for Anatomical Teaching and Femoral Vessel Access Training in Medicine

For centuries, cadaveric dissection has been the touchstone of anatomy education. It offers a medical student intimate access to his or her first patient. In contrast to idealized artisan anatomical models, it presents the natural variation of anatomy in fine detail. However, a new teaching construct has appeared recently in which artificial cadavers are manufactured through three-dimensional (3D) printing of patient specific radiological data sets. In this article, a simple powder based printer is made more versatile to manufacture hard bones, silicone muscles and perfusable blood vessels. The approach involves blending modern approaches (3D printing) with more ancient ones (casting and lost-wax techniques). These anatomically accurate models can augment the approach to anatomy teaching from dissection to synthesis of 3D-printed parts held together with embedded rare earth magnets. Vascular simulation is possible through application of pumps and artificial blood. The resulting arteries and veins can be cannulated and imaged with Doppler ultrasound. In some respects, 3D-printed anatomy is superior to older teaching methods because the parts are cheap, scalable, they can cover the entire age span, they can be both dissected and reassembled and the data files can be printed anywhere in the world and mass produced. Anatomical diversity can be collated as a digital repository and reprinted rather than waiting for the rare variant to appear in the dissection room. It is predicted that 3D printing will revolutionize anatomy when poly-material printing is perfected in the early 21st century. (C) 2015 American Association of Anatomists

An Epidemiological Investigation of the Re-Emergence of Pancreas Disease in Irish Farmed Atlantic Salmon (Salmo salar L.) in 2002

In the early 1990’s pancreas disease (PD) was shown to be the most significant cause of mortality in Irish farmed salmon (Wheatley et al., 1995, Menzies et al., 1996, Crockford et al., 1999). At that time the aetiology of PD was uncertain but in 1995 it was conclusively shown that PD was caused by a virus subsequently named salmon pancreas disease virus (SPDV), (Nelson et al., 1995, McLoughlin et al., 1996). It has since been further classified and named salmonid alphavirus (Weston et al., 1999, Weston et al., 2002). The clinical and histopathological features of naturally occurring pancreas disease in farmed Atlantic salmon in Ireland were described by Murphy et al., 1992 and McLoughlin et al., 2002. The original epidemiological studies of PD in Ireland indicated that mortality rates up to 48% have occurred in farmed Atlantic salmon in their first year in the sea on some individual fish farms (Menzies et al., 1996). PD was recorded in over 70% of marine sites monitored and the majority of PD outbreaks occurred during August to October (Crockford et al., 1999). A serological survey for the presence of SPDV antibody in 1996 revealed 53% of the sites (9/17) were positive and that not all positive sites had recognised clinical signs of PD. This indicated a relatively low incidence and severity of PD at that time (McLoughlin et al., 1998). This pattern persisted until 2002 when there was a serious increase in both the incidence and severity of PD reported on farmed Atlantic salmon marine sites in Ireland. In order to identify factors associated with this re-emergence of PD in Irish farmed salmon, an in-depth epidemiological investigation was carried out on all marine sites. In trying to identify the cause of a disease from epidemiological studies the concept of time, place and individual is paramount, i.e. why did a particular disease occur in a particular animal or group of animals at a particular time in a particular place? Epidemiological study designs are chosen so that predictor variables are measured in affected and non-affected “units”. These “units” may be cells, animals, pens, farms or countries. The association between these predictor variables and disease is then examined. Where associations are demonstrated then risk factors for disease can be identified. A risk factor is a predictor variable associated with the disease. However the identification of a risk factor does not imply causation. The strength, consistency, temporality and dose response effect of the risk factor add weight to it being causal but only an intervention study where the risk factor is added or omitted can confirm this. Individual or univariate analysis of the relationship between a predictor variable and disease may result in an association being demonstrated. However it is dangerous to read too much into univariate analyses as factors which have been ignored, not measured or not seen as important may have a confounding effect. Multivariate analysis is used to try to provide estimates of association adjusted for the effect of confounding factors is a much more accurate and powerful epidemiological tool, but was of limited application in this snapshot survey of a single production cycle. This report aims to describe the occurrence and severity of PD in Irish farmed salmon in 2002-2003 and to identify risk factors associated with the re-emergence of severe PD. Finally, recommendations are made on how PD can be managed to reduce its serious impact on the health, welfare and productivity of Irish farmed salmon.Funder: Marine Institut

Host-specialized fibrinogen-binding by a bacterial surface protein promotes biofilm formation and innate immune evasion

Fibrinogen is an essential part of the blood coagulation cascade and a major component of the extracellular matrix in mammals. The interface between fibrinogen and bacterial pathogens is an important determinant of the outcome of infection. Here, we demonstrate that a canine host-restricted skin pathogen, Staphylococcus pseudintermedius, produces a cell wall-associated protein (SpsL) that has evolved the capacity for high strength binding to canine fibrinogen, with reduced binding to fibrinogen of other mammalian species including humans. Binding occurs via the surface-expressed N2N3 subdomains, of the SpsL A-domain, to multiple sites in the fibrinogen α-chain C-domain by a mechanism analogous to the classical dock, lock, and latch binding model. Host-specific binding is dependent on a tandem repeat region of the fibrinogen α-chain, a region highly divergent between mammals. Of note, we discovered that the tandem repeat region is also polymorphic in different canine breeds suggesting a potential influence on canine host susceptibility to S. pseudintermedius infection. Importantly, the strong host-specific fibrinogen-binding interaction of SpsL to canine fibrinogen is essential for bacterial aggregation and biofilm formation, and promotes resistance to neutrophil phagocytosis, suggesting a key role for the interaction during pathogenesis. Taken together, we have dissected a bacterial surface protein-ligand interaction resulting from the co-evolution of host and pathogen that promotes host-specific innate immune evasion and may contribute to its host-restricted ecology