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Skin dendritic cells (DCs) are divided into several subsets with distinctive functions. This study shows a previously unappreciated role of dermal CD11b-type Langerin− DCs in maintaining immunological self-tolerance after UVB exposure. After UVB exposure, dermal CD11b-type Langerin− DCs upregulated surface CD86 expression, induced proliferation of Foxp3+ regulatory T (Treg) cells without exogenous Ags, and upregulated a set of genes associated with immunological tolerance. This Treg-expansion activity was significantly hampered by CD80/CD86 blockade in vivo. These results indicate that CD11b-type Langerin− DCs from the UVB-exposed skin are specialized to expand Treg cells in the skin, which suppress autoimmunity.

Calcium ion (Ca2+) is one of the most important second messengers. However, conventional Ca2+ indicators cannot be applied in plant cells. In previous paper, we developed the first-generation protein-ligand tethered calcium indicator that can be applied for living plant cells. Here, we will report the development of second-generation indicator based on the detailed examination on physical properties of the first-generation to improve the drawbacks. Through the examination, we also found that cell permeability of the probe is strongly affected by their aggregation properties. Our findings will provide new strategy for the design of synthetic indicators.

Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein-a mutation that confers reduced susceptibility to baloxavir marboxil-from patients before and after treatment with baloxavir marboxil in Japan. These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.

Human influenza A(H2N2) viruses emerged in 1957 and were replaced by A(H3N2) viruses in 1968. The antigenicity of human H2N2 viruses has been tested by using ferret antisera or mouse and human monoclonal antibodies. Here, we examined the antigenicity of human H2N2 viruses by using human plasma samples obtained from 50 aged individuals who were born between 1928 and 1933 and from 33 younger adult individuals who were born after 1962. The aged individuals possessed higher neutralization titers against H2N2 viruses isolated in 1957 and 1963 than those against H2N2 viruses isolated in 1968, whereas the younger adults who were born between 1962 and 1968 possessed higher neutralization titers against H2N2 viruses isolated in 1963 than those against other H2N2 viruses. Antigenic cartography revealed the antigenic changes that occurred in human H2N2 viruses during circulation in humans for 11 years, as detected by ferret antisera. These results show that even though aged individuals were likely exposed to more recent H2N2 viruses that are antigenically distinct from the earlier H2N2 viruses, they did not possess high neutralizing antibody titers to the more recent viruses, suggesting immunological imprinting of these individuals with the first H2N2 viruses they encountered and that this immunological imprinting lasts for over 50 years.

The angular momentum compensation temperature $T_{\rm A}$ of ferrimagnets has attracted much attention because of high-speed magnetic dynamics near $T_{\rm A}$. We show that NMR can be used to investigate domain wall dynamics near $T_{\rm A}$ in ferrimagnets. We performed $^{57}$Fe-NMR measurements on the ferrimagnet Ho$_3$Fe$_5$O$_{12}$ with $T_{\rm A} = 245$ K. In a multi-domain state, the NMR signal is enhanced by domain wall motion. We found that the NMR signal enhancement shows a maximum at $T_{\rm A}$ in the multi-domain state. The NMR signal enhancement occurs due to increasing domain-wall mobility toward $T_{\rm A}$. We develop the NMR signal enhancement model involves domain-wall mobility. Our study shows that NMR in multi-domain state is a powerful tool to determine $T_{\rm A}$, even from a powder sample and it expands the possibility of searching for angular momentum-compensated materials., Comment: 5 pages, 4 figures

We demonstrate that the angular momentum compensation temperature $T_A$, at which the net angular momentum in the sample disappears, can be controlled in Ho$_3$Fe$_5$O$_{12}$ by partially substituting Dy for Ho. The $T_A$ can be detected using the Barnett effect, by which mechanical rotation magnetizes an object due to spin-rotation coupling. We found that $T_A$ increases with the Dy content and clarified that the $T_A$ of Ho$_{1.5}$Dy$_{1.5}$Fe$_5$O$_{12}$ coincides with room temperature. The Barnett effect enables us to explore materials applicable to magnetic devices utilizing the angular momentum compensation only by rotating the powder sample at room temperature., Comment: 5pages, 4figure

Acute mesenteric ischemia (AMI) is caused by considerable intestinal injury, which is associated with intestinal ischemia followed by reperfusion. To elucidate the mechanisms of ischemia/reperfusion injuries, a C5a inhibitory peptide termed AcPepA was used to examine the role of C5a anaphylatoxin, induction of inflammatory cells, and cell proliferation of the intestinal epithelial cells in an experimental AMI model. In this rat model, the superior mesenteric artery was occluded and subsequently reperfused (Induce-I/R). Other groups were treated with AcPepA before ischemia or reperfusion. Induce-I/R induced injuries in the intestine and AcPepA significantly decreased the proportion of severely injured villi. Induce-I/R induced secondary receptor for C5a-positive polymorphonuclear leukocytes in the vessels and CD204-positive macrophages near the injured site; this was correlated with hypoxia-induced factor 1-alpha-positive cells. Induction of these inflammatory cells was attenuated by AcPepA. In addition, AcPepA increased proliferation of epithelial cells in the villi, possibly preventing further damage. Therefore, Induce-I/R activates C5a followed by the accumulation of polymorphonuclear leukocyte and hypoxia-induced factor 1-alpha-producing macrophages, leading to villus injury. AcPepA, a C5a inhibitory peptide, blocks the deleterious effects of C5a, indicating it has a therapeutic effect on the inflammatory consequences of experimental AMI.

In plant biology, calcium ions are involved in a variety of intriguing biological phenomena as a secondary messenger. However, most conventional calcium indicators are not applicable for plant cells because of the difficulty with their localization control in plant cells. We here introduce a method to monitor spatiotemporal Ca(2+) dynamics in living plant cells based on linking the synthetic calcium indicator Calcium Green-1 to a natural product-based protein ligand. In a proof-of-concept study using cultured BY-2 cells overexpressing the target protein for the ligand, the ligand-tethered probe accumulated in the cytosol and nucleus, and enabled real-time monitoring of the cytosolic and nucleus Ca(2+) dynamics under the physiological condition. The present strategy using ligand-tethered fluorescent sensors may be successfully applied to reveal the spatiotemporal dynamics of calcium ions in living plant cells.

Ebola virus disease is a severe disease, often fatal, with a mortality rate of up to 90%. Presently, effective treatment and safe prevention options for Ebola virus disease are not available. Therefore, there is an urgent need to develop control measures to prevent or limit future Ebola virus outbreaks. Ebola virus protein-based virus-like particle (VLP) and inactivated whole virion vaccines have demonstrated efficacy in animal models, and the addition of appropriate adjuvants may provide additional benefits to these vaccines, including enhanced immune responses. In this study, we screened 24 compounds from injectable excipients approved for human use in Japan and identified six compounds that significantly enhanced the humoral response to Ebola VLP vaccine in a murine model. Our novel adjuvant candidates for Ebola VLP vaccine have already been demonstrated to be safe when administered intramuscularly or subcutaneously, and therefore, they are closer to clinical trials than adjuvants whose safety profiles are unknown.

Chronic low-grade inflammation can cause several metabolic syndromes. Patients with psoriasis, a chronic immunological skin inflammation, often develop diabetes. However, it is not clear to date how psoriasis leads to, or is correlated with, glucose intolerance. Here, we investigate whether psoriasis itself is correlated with hyperglycemia in humans and mice. In patients, the severity of psoriasis was correlated with high blood glucose levels, and treatment of psoriasis by phototherapy improved insulin secretion. Imiquimod-induced systemic and cutaneous inflammation in mice, with features of human psoriasis, also resulted in hyperglycemia. Although it should be determined if psoriasis-like cutaneous inflammation alone can induce hyperglycemia, imiquimod-treated mice showed impairment of insulin secretion without significant islet inflammation. Administration of anti-IL-17A monoclonal antibody improved hyperglycemia in patients with psoriasis and imiquimod-treated mice with psoriasiform features. These results suggest that hyperglycemia is highly associated with psoriasis, mainly through IL-17.

We report direct observation of gyromagnetic reversal, which is the sign change of gyromagnetic ratio in a ferrimagnet Ho$_3$Fe$_5$O$_{12}$, by using the Barnett effect measurement technique at low temperatures. The Barnett effect is a phenomenon in which magnetization is induced by mechanical rotation through the coupling between rotation and total angular momentum $J$ of electrons. The magnetization of Ho$_3$Fe$_5$O$_{12}$ induced by mechanical rotation disappears at 135~K and 240~K. The temperatures correspond to the magnetization compensation temperature $T_{\rm M}$ and the angular momentum compensation temperature $T_{\rm A}$, respectively. Between $T_{\rm M}$ and $T_{\rm A}$, the magnetization flips over to be parallel against the angular momentum due to the sign change of gyromagnetic ratio. This study provides an unprecedented technique to explore the gyromagnetic properties., 4pages,4figures

A unifying mechanism for the origin of ferromagnetism which takes into account both well-known and polar extreme theories, namely, the localized- and itinerant-electron regimes, remains a longstanding mystery. Here, we study a particularly interesting system of FeGa3−yGey, within which the magnetic orderings can be adjusted by the Ge-electron filling control, turning from itinerancy to adequate localized through a ferromagnetic quantum critical transition with increasing y. By involving the effects of the spin fluctuations in general, the theoretical estimations of the magnetic properties at the intermediate state of magnetic orderings formulated in terms of the correlation between itinerancy electrons and the spin fluctuations are in quantitative agreements with experimental observations. Our analysis shows a potential universality to all itinerant ferromagnets.

During December 2016–February 2017, influenza A viruses of the H7N2 subtype infected ≈500 cats in animal shelters in New York, NY, USA, indicating virus transmission among cats. A veterinarian who treated the animals also became infected with feline influenza A(H7N2) virus and experienced respiratory symptoms. To understand the pathogenicity and transmissibility of these feline H7N2 viruses in mammals, we characterized them in vitro and in vivo. Feline H7N2 subtype viruses replicated in the respiratory organs of mice, ferrets, and cats without causing severe lesions. Direct contact transmission of feline H7N2 subtype viruses was detected in ferrets and cats; in cats, exposed animals were also infected via respiratory droplet transmission. These results suggest that the feline H7N2 subtype viruses could spread among cats and also infect humans. Outbreaks of the feline H7N2 viruses could, therefore, pose a risk to public health.

We investigated the expression of membrane complement regulators (CRegs), CD46, CD55 and CD59 in human mesothelial cells, and correlated with clinical background and level of complement (C) activation products in peritoneal dialysis (PD) fluids (PDF) to clarify influence of the C activation system in PD patients. Expression of CRegs was assessed on primary cultures of mesothelial cells (HPMC) harvested from PD fluid of 31 PD patients. Because expression of CD55 but not CD46 and CD59 in mesothelial cells was significantly correlated to value of dialysate-to-plasma creatinine concentration ratio (D/P Cre) (p

Soft X-ray micro-ARPES measurements have successfully been applied to band mapping of the strongly correlated metallic V2O3., Soft X-ray angle-resolved photoemission has been performed for metallic V2O3. By combining a microfocus beam (40 µm × 65 µm) and micro-positioning techniques with a long-working-distance microscope, it has been possible to observe band dispersions from tiny cleavage surfaces with a typical size of several tens of µm. The photoemission spectra show a clear position dependence, reflecting the morphology of the cleaved sample surface. By selecting high-quality flat regions on the sample surface, it has been possible to perform band mapping using both photon-energy and polar-angle dependences, opening the door to three-dimensional angle-resolved photoemission spectroscopy for typical three-dimensional correlated materials where large cleavage planes are rarely obtained.

In order to elucidate the dependence of the magnetic ground state on the Ca content (x) in Sr1-xCaxCo2P2 (0 ≤x ≤1, ThCr2Si2-type structure), we have performed muon spin rotation− and relaxation (μ+SR) experiments on Sr1-xCax Co2P2 powder samples mainly in a zero applied field. The end member compound, SrCo2P2, is found to be paramagnetic down to 19 mK. As x increases, such a paramagnetic ground state is observed down to 1.8K until x = 0.45. Then, as x increases further, a short-range antiferromagnetic (AF) ordered phase appears at low temperatures for 0.48 ≤ x ≤ 0.75, and finally, a long-range AF ordered phase is stabilized for x > 0.75. The internal magnetic field of the other end member compound, CaCo2P2, is well consistent with that of the A-type AF order state, which was proposed from neutron scattering experiments. The phase diagram determined with μ+SR is different from that proposed by macroscopic measurements. For an isostructural compound, LaCo2P2, static magnetic order is found to be formed below

The ThCr2Si2-type layered compound SrCo2P2 shows an itinerant-electron metamagnetic transition at high magnetic field. To investigate substitution effects on the itinerant metamagnetic transition, we synthesized Sr[1-x]LaxCo2P2 and SrCo2(P[1-x]Gex)2 and measured their magnetic properties, including magnetizations under pulsed high magnetic fields. We have revealed a strong x dependence of the metamagnetic transition which is consistent with the band theory describing the physical properties in metals., 20th International Conference on Magnetism, ICM 2015

The development of modern medicine has allowed us to conquer numerous infectious diseases; however, we human beings constantly face threats from novel infectious diseases that have been previously unrecognized. These so-called “emerging infectious diseases” are often caused by zoonotic pathogens, which mostly originate in wild animals (1, 2). Human diseases, such as AIDS, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), Ebola viral disease, and pandemic influenza are all caused by such pathogens. To cause zoonosis, the pathogens that originate in animals must cross the species barrier and transmit to humans. If these pathogens are able to efficiently transmit from human to human, a pandemic would result, endangering the lives of humans globally. Aquatic wild birds harbor a large gene pool of influenza A viruses that have been the source of influenza pandemics. Although influenza A viruses can infect a wide range of species, host restriction usually constrains their interspecies transmission; however, some mammalian-adaptive mutations have been identified in hemagglutinin (HA) and Polymerase Basic 2 (PB2) that allow avian influenza viruses to overcome the species barrier and become transmissible via the airborne route among ferrets (3). In addition, PB1 has been shown to confer to airborne transmission to H5N1 viruses (4). For over 25 y, Webster’s group has conducted surveillance of avian viruses at Delaware Bay, New Jersey, and has investigated the biological properties of the isolated H1N1 avian viruses in mammalian models (5, 6). Surprisingly, some of the H1N1 avian isolates transmitted via the airborne route in a ferret model without prior adaptation (5⇓–7), suggesting no adaptive mutations were required for these viruses to become transmissible. By comparing the genomes of the transmissible and nontransmissible viruses, Zanin et al. (7) identify differences in the PB2, PB1, PB1-F2, PA-X, NS1, and NEP genes … [↵][1]1To whom correspondence should be addressed. Email: yoshihiro.kawaoka{at}wisc.edu. [1]: #xref-corresp-1-1

Skin dendritic cells (DCs) are divided into several subsets with distinctive functions. This study shows a previously unappreciated role of dermal CD11b-type Langerin

Antiviral compounds (eg, the neuraminidase inhibitor oseltamivir) are invaluable for the treatment of individuals infected with influenza A viruses of the H7N9 subtype (A[H7N9]), which have infected and killed hundreds of persons. However, oseltamivir treatment often leads to the emergence of resistant viruses in immunocompromised individuals. To better understand the emergence and properties of oseltamivir-resistant A(H7N9) viruses in immunosuppressed individuals, we infected immunosuppressed cynomolgus macaques with an A(H7N9) virus and treated them with oseltamivir. Disease severity and mortality were higher in immunosuppressed than in immunocompetent animals. Oseltamivir treatment at 2 different doses reduced A(H7N9) viral titers in infected animals, but even high-dose oseltamivir did not block viral replication sufficiently to suppress the emergence of resistant variants. Some resistant variants were not appreciably attenuated in cultured cells, but an oseltamivir-resistant A(H7N9) virus did not transmit among ferrets. These findings are useful for the control of A(H7N9) virus infections in clinical settings.

Extracellular histones promote platelet aggregation and thrombosis; this is followed by induction of coagulation disorder, which results in exhaustion of coagulation factors. Complement component 5 (C5) is known to be associated with platelet aggregation and coagulation system activation. To date, the pathological mechanism underlying liver injury has remained unclear. Here, we investigated whether C5 promotes liver injury associated with histone-induced lethal thrombosis. C5-sufficient and C5-deficient mice received single tail vein injections of purified, unfractionated histones obtained from calf thymus (45–75 μg/g). Subsequently, the mice were monitored for survival for up to 72 h. Based on the survival data, the 45 μg/g dose was used for analysis of blood cell count, liver function, blood coagulation ability, and promotion of platelet aggregation and platelet/leukocyte aggregate (PLA) production by extracellular histones. C5-deficient mice were protected from lethal thrombosis and had milder thrombocytopenia, consumptive coagulopathy, and liver injury with embolism and lower PLA production than C5-sufficient mice. These results indicate that C5 is associated with coagulation disorders, PLA production, and embolism-induced liver injury. In conclusion, C5 promotes liver injury associated with histone-induced lethal thrombosis.

We took $^{31}\text{P}$ NMR measurements of mainly paramagnetic phase ${\mathrm{Sr}}_{1\ensuremath{-}x}{\mathrm{Ca}}_{x}{\mathrm{Co}}_{2}{\mathrm{P}}_{2}$ ($0\ensuremath{\le}x\ensuremath{\le}0.5$) to reveal the itinerant-electron metamagnetic transition, and of its magnetically ordered phase ($0.7\ensuremath{\le}x\ensuremath{\le}1$), and characterized their spin fluctuations by estimating the spin fluctuation parameter ${T}_{0}$ corresponding to the width of the spin fluctuation in the spectrum in frequency space. ${\mathrm{SrCo}}_{2}{\mathrm{P}}_{2}$ has a quasi-two-dimensional uncollapsed tetragonal (ucT) cell without interlayer P-P bonds, whereas ${\mathrm{CaCo}}_{2}{\mathrm{P}}_{2}$ has a three-dimensional collapsed tetragonal (cT) cell with P-P bonds. The $ab$-in-plane component of ${T}_{0}$ is much larger than the out-of-plane component in ${\mathrm{SrCo}}_{2}{\mathrm{P}}_{2}$. As $x$ increases from 0 to 0.5, the in-plane component of ${T}_{0}$ decreases proportionally with the metamagnetic transition field. In the antiferromagnetic cT phase ($0.7\ensuremath{\le}x\ensuremath{\le}1$), ${T}_{0}$ is constant and spin fluctuations show an isotropic character in contrast to their behavior in the paramagnetic ucT phase ($0\ensuremath{\le}x\ensuremath{\le}0.5$). These results indicate that the in-plane spin fluctuations due to the quasi-two-dimensional crystal structure play a significant role in the metamagnetic transition of this system.

The quasi-skutterudite superconductors $A_3T_4$Sn$_{13}$ ($A$=Sr, Ca; $T$=Ir, Rh, Co) are highly tunable featuring a structural quantum critical point. We construct a temperature-lattice constant phase diagram for these isovalent compounds, establishing Ca$_{3}$Rh$_4$Sn$_{13}$ and Ca$_{3}$Co$_4$Sn$_{13}$ as members close to and far away from the structural quantum critical point, respectively. Deconvolution of the lattice specific heat and the electrical resistivity provide an approximate phonon density of states $F(\omega)$ and the electron-phonon transport coupling function $\alpha_{tr}^2F(\omega)$ for Ca$_{3}$Rh$_4$Sn$_{13}$ and Ca$_{3}$Co$_4$Sn$_{13}$, enabling us to investigate the influence of the structural quantum critical point. Our results support the scenario of phonon softening close to the structural quantum critical point, and explain the enhancement of the coupling strength on approaching structural instability., Comment: 6 pages, 4 figures. Accepted by Phys. Rev. B

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are enzootic in poultry populations in different parts of the world, and have caused numerous human infections in recent years, particularly in Egypt. However, no sustained human-to-human transmission of these viruses has yet been reported. We tested nine naturally occurring Egyptian H5N1 viruses (isolated in 2014–2015) in ferrets and found that three of them transmitted via respiratory droplets, causing a fatal infection in one of the exposed animals. All isolates were sensitive to neuraminidase inhibitors. However, these viruses were not transmitted via respiratory droplets in three additional transmission experiments in ferrets. Currently, we do not know if the efficiency of transmission is very low or if subtle differences in experimental parameters contributed to these inconsistent results. Nonetheless, our findings heighten concern regarding the pandemic potential of recent Egyptian H5N1 influenza viruses.

In peritoneal dialysis (PD) therapy, physical stresses such as exposure to peritoneal dialysate, catheter trauma, and peritonitis may induce peritoneal injury that can prevent continued long-term PD therapy. Therefore, protection of the peritoneum is an important target to enable long-term PD therapy in patients with end-stage renal disease. We previously showed that neutralization of the membrane complement regulators (CRegs) Crry and CD59 in rat peritoneum provokes development of acute peritoneal injury due to uncontrolled complement activation. C5a is a key effecter molecule of the complement system released during acute inflammation. Control of C5a has been proposed as a strategy to suppress inflammatory reactions and, because peritoneal injury is accompanied by inflammation, we hypothesized that C5a targeted therapy might be an effective way to suppress peritoneal injury. In the present study we used an established acute peritonitis model induced by neutralization of CRegs to investigate the effects on acute peritoneal injury of inhibiting C5a. Intravenous administration of an anti-C5a complementary peptide (AcPepA) up to 4 h after induction of injury significantly and dose-dependently prevented accumulation of inflammatory cells and reduced tissue damage in the model, accompanied by decreased C3b deposition. We show that C5a contributed to the development of peritoneal injury. Our results suggest that C5a is a target for preventing or treating peritoneal injury in patients undergoing prolonged PD therapy or with infectious complications.

Avian influenza A viruses rarely infect humans; however, when human infection and subsequent human-to-human transmission occurs, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern owing to the appreciable case fatality rate associated with these infections (more than 25%), potential instances of human-to-human transmission, and the lack of pre-existing immunity among humans to viruses of this subtype. Here we characterize two early human A(H7N9) isolates, A/Anhui/1/2013 (H7N9) and A/Shanghai/1/2013 (H7N9); hereafter referred to as Anhui/1 and Shanghai/1, respectively. In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011 (H7N9); Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/4/2009 (H1N1pdm09); CA04). Anhui/1, Shanghai/1 and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates, Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs after intranasal inoculation. Critically, Anhui/1 transmitted through respiratory droplets in one of three pairs of ferrets. Glycan arrays showed that Anhui/1, Shanghai/1 and A/Hangzhou/1/2013 (H7N9) (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was found to be less sensitive in mice to neuraminidase inhibitors than a pandemic H1N1 2009 virus, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets and nonhuman primates and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.

T helper (Th) 17 cells are reportedly effector T cells that produce interleukin (IL)-17A and play a significant role in the development of autoimmune diseases and immune responses for antimicrobial host defense. Production of IL-17A in chronic active Epstein–Barr virus infection (CAEBV) was studied to investigate its contribution to pathogenesis of this disease. Significantly more IL-17A-producing cells were detected in the peripheral blood of CAEBV patients than in that of healthy controls, although a significant difference in serum IL-17A production was not confirmed. Of the IL-17A-producing cells, 91.8% were cluster of differentiation (CD)4-positive Th17 cells. Moreover, there were significantly more IL-17A-producing cells among CD4+ cells in peripheral blood of CAEBV patients than in that of controls (1.97 ± 0.69% vs. 1.09 ± 0.53%, P = 0.0073). These data suggest that IL-17A-producing cells may influence the pathophysiology of CAEBV.

Highly pathogenic avian influenza viruses of the H5N1 subtype continue to circulate in poultry in Asia, Africa, and the Middle East. Recently, outbreaks of novel reassortant H5 viruses have also occurred in North America. Although the number of human infections with highly pathogenic H5N1 influenza viruses continues to rise, these viruses remain unable to efficiently transmit between humans. However, we and others have identified H5 viruses capable of respiratory droplet transmission in ferrets. Two experimentally introduced mutations in the viral hemagglutinin (HA) receptor-binding domain conferred binding to human-type receptors but reduced HA stability. Compensatory mutations in HA (acquired during virus replication in ferrets) were essential to restore HA stability. These stabilizing mutations in HA also affected the pH at which HA undergoes an irreversible switch to its fusogenic form in host endosomes, a crucial step for virus infectivity. To identify additional stabilizing mutations in an H5 HA, we subjected a virus library possessing random mutations in the ectodomain of an H5 HA (altered to bind human-type receptors) to three rounds of treatment at 50°C. We isolated several mutants that maintained their human-type receptor-binding preference but acquired an appreciable increase in heat stability and underwent membrane fusion at a lower pH; collectively, these properties may aid H5 virus respiratory droplet transmission in mammals. IMPORTANCE We have identified mutations in HA that increase its heat stability and affect the pH that triggers an irreversible conformational change (a prerequisite for virus infectivity). These mutations were identified in the genetic background of an H5 HA protein that was mutated to bind to human cells. The ability to bind to human-type receptors, together with physical stability and an altered pH threshold for HA conformational change, may facilitate avian influenza virus transmission via respiratory droplets in mammals.

Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to hostspecific cellular receptors 1–3 . Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals. We identified a reassortant H5 HA/H1N1 virus—comprising H5 HA (from an H5N1 virus) with four mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virus—that was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality. These results indicate that H5 HA can convert to an HA that supports efficient viral transmission in mammals; however, we do not know whether the four mutations in the H5 HA identified here would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral gene segments may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avian–human reassortant viruses as tested here, may emerge. Our findings emphasize the need to prepare for potential pandemics caused by influenza viruses possessing H5 HA, and will help individuals conducting surveillance in regions with circulating H5N1 viruses to

Influenza A virus infection begins with the binding of the hemagglutinin (HA) glycoprotein to sialic acid-containing receptors on the surface of the target cell. Avian influenza viruses, including avian H5N1, H7, and H9N2 viruses, can occasionally cross the species barrier and infect humans; however, these viruses do not spread efficiently from person to person, perhaps, partly, owing to differences in the receptor-binding specificities of human and avian influenza viruses. The HAs of avian influenza viruses must adapt to receptors in humans to acquire efficient human-to-human transmissibility. In this review, we discuss the receptor binding specificity of influenza A viruses and its role in interspecies transmission.

The family of the superconducting quasiskutterudites (Ca(x)Sr(1-x))(3)Rh(4)Sn(13) features a structural quantum critical point at x(c)=0.9, around which a dome-shaped variation of the superconducting transition temperature T(c) is found. Using specific heat, we probe the normal and the superconducting states of the entire series straddling the quantum critical point. Our analysis indicates a significant lowering of the effective Debye temperature on approaching x(c), which we interpret as a result of phonon softening accompanying the structural instability. Furthermore, a remarkably large enhancement of 2Δ/k(B)T(c) and ΔC/γT(c) beyond the Bardeen-Cooper-Schrieffer values is found in the vicinity of the structural quantum critical point. The phase diagram of (Ca(x)Sr(1-x))(3)Rh(4)Sn(13) thus provides a model system to study the interplay between structural quantum criticality and strong electron-phonon coupling superconductivity.

Acute mesenteric ischemia (AMI) is caused by considerable intestinal injury, which is associated with intestinal ischemia followed by reperfusion. To elucidate the mechanisms of ischemia/reperfusion injuries, a C5a inhibitory peptide termed AcPepA was used to examine the role of C5a anaphylatoxin, induction of inflammatory cells, and cell proliferation of the intestinal epithelial cells in an experimental AMI model. In this rat model, the superior mesenteric artery was occluded and subsequently reperfused (Induce‐I/R). Other groups were treated with AcPepA before ischemia or reperfusion. Induce‐I/R induced injuries in the intestine and AcPepA significantly decreased the proportion of severely injured villi. Induce‐I/R induced secondary receptor for C5a‐positive polymorphonuclear leukocytes in the vessels and CD204‐positive macrophages near the injured site; this was correlated with hypoxia‐induced factor 1‐alpha‐positive cells. Induction of these inflammatory cells was attenuated by AcPepA. In addition, AcPepA increased proliferation of epithelial cells in the villi, possibly preventing further damage. Therefore, Induce‐I/R activates C5a followed by the accumulation of polymorphonuclear leukocyte and hypoxia‐induced factor 1‐alpha‐producing macrophages, leading to villus injury. AcPepA, a C5a inhibitory peptide, blocks the deleterious effects of C5a, indicating it has a therapeutic effect on the inflammatory consequences of experimental AMI.

The first influenza pandemic of the 21st century was caused by novel H1N1 viruses that emerged in early 2009. An Asp-to-Gly change at position 222 of the receptor-binding protein hemagglutinin (HA) correlates with more-severe infections in humans. The amino acid at position 222 of HA contributes to receptor-binding specificity with Asp (typically found in human influenza viruses) and Gly (typically found in avian and classic H1N1 swine influenza viruses), conferring binding to human- and avian-type receptors, respectively. Here, we asked whether binding to avian-type receptors enhances influenza virus pathogenicity. We tested two 2009 pandemic H1N1 viruses possessing HA-222G (isolated from severe cases) and two viruses that possessed HA-222D. In glycan arrays, viruses possessing HA-222D preferentially bound to human-type receptors, while those encoding HA-222G bound to both avian- and human-type receptors. This difference in receptor binding correlated with efficient infection of viruses possessing HA-222G, compared to those possessing HA-222D, in human lung tissue, including alveolar type II pneumocytes, which express avian-type receptors. In a nonhuman primate model, infection with one of the viruses possessing HA-222G caused lung damage more severe than did infection with a virus encoding HA-222D, although these pathological differences were not observed for the other virus pair with either HA-222G or HA-222D. These data demonstrate that the acquisition of avian-type receptor-binding specificity may result in more-efficient infection of human alveolar type II pneumocytes and thus more-severe lung damage. Collectively, these findings suggest a new mechanism by which influenza viruses may become more pathogenic in mammals, including humans.

Anaphylatoxins (C5a, C4a, and C3a) are fragments of activated complement and are leading mediators of the inflammatory response for controlling viral infection. However, an excessive response may increase the severity of infectious diseases. Serum concentrations of proinflammatory mediators, including cytokines, high-mobility group box 1 and anaphylatoxins, were measured in pediatric 2009 H1N1 influenza patients in order to investigate the pathology of this new influenza. The concentrations of all three anaphylatoxins were significantly enhanced by 2009 H1N1 influenza infection. However, there were no significant differences in anaphylatoxin concentrations between 2009 H1N1 influenza patients with and without severe complications during the early stages of the disease. C3a concentrations dropped significantly during the recovery phase, whereas there were no significant differences between the acute and recovery phases in C5a and C4a concentrations. There was a correlation between C5a and IL-2. C4a was associated with IL-1ra, eotaxin, MCP-1, PDGFbb, and VEGF. C3a was correlated with IL-2 and IFN-γ. Taken together, these findings indicate that complement activation occurs in patients infected with 2009 H1N1 influenza virus and demonstrate that anaphylatoxins are involved in increased production of proinflammatory mediators in this new influenza.

The Curie temperature TC of the weakly ferromagnetic system FeGa3−yGey is investigated by means of isothermal magnetization experiments. The critical temperature of the ferromagnetic phase transition is estimated by the so-called M4 plots rather than the Arrott plots technique. The M4 plots are exploited from the sixth power term of the expanded free energy, which is neglected by the Arrott plots. The magnetic properties are analyzed by taking into account the effects of spin fluctuations in terms of related spin-fluctuation theories.

To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model. Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR-P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-α, and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP. Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-α, NOx, and HMGB1. ETR-P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-α, NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 ± 2.3 h vs. 9.0 ± 0.8 h, p