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Abstract Inflammation can be an unwanted consequence or cause of debilitating diseases of infectious and non-infectious aetiologies. Current anti-inflammatory medications have several deficiencies including lack of specificity and undesirable side effects. Herein, the potential of non-ionic surfactant vesicles (NISV) comprised of monopalmityol glycerol, dicetyl phosphate and cholesterol) as an anti-inflammatory drug and their mode of action is investigated. NISV were able to inhibit LPS-induced IL-6 from BMD macrophages. The individual components of NISV, monopalmityol glycerol, dicetyl phosphate and cholesterol did not affect LPS induced IL-6 levels, proving that formulation of NISV is essential for their anti-inflammatory effects. Transcriptomic analyses showed NISV mediated down-regulation of transcripts for inflammatory mediators in LPS stimulated macrophages. Notably, NISV downregulate NF-κB transcripts in LPS stimulated macrophages. Measurement of inflammatory mediators by cytometric bead array validated a number of transcriptomic findings as NISV were found to inhibit LPS induced IL-6, IL-12, and multiple chemokines. Further investigation demonstrated that NISV inhibited Poly(I:C) or Pam3csk4 induced inflammatory mediators. This indicates that the effects of NISV are distal to both MyD88 and TRIF signalling. Overall, the data generated highlights the potential of NISV as an anti-inflammatory therapeutic.

Working with the 29 available data on the ratio of proton electric and magnetic form factors, μpGEp(Q2)/GMp(Q2), and independent of any model or theory of strong interactions, we use the Schlessinger point method to objectively address the question of whether the ratio possesses a zero and, if so, its location. Our analysis predicts that, with 50% confidence, the data are consistent with the existence of a zero in the ratio on Q2≤10.37 GeV2. The level of confidence increases to 99.9% on Q2≤13.06 GeV2. Significantly, the likelihood that existing data are consistent with the absence of a zero in the ratio on Q2≤14.49 GeV2 is 1/1-million.

A light-front holographic model is used to illustrate an algebraic scheme for constructing a representation of a hadron's zero-skewness generalised parton distribution (GPD) from its valence-quark distribution function (DF) and electromagnetic form factor, FH, without reference to deeply virtual Compton scattering data. The hadron's mass distribution gravitational form factor, AH, calculated from this GPD is harder than FH; and, for each hadron, the associated mass-density profile is more compact than the analogous charge profile, with each pion near-core density being larger than that of its proton partner. These features are independent of the scheme employed.

Abstract Using a symmetry-preserving formulation of a vector $$\,\times \,$$ × vector contact interaction (SCI) and treating the proton as a quark + interacting-diquark bound state, whose structure is obtained by solving a Poincaré-covariant Faddeev equation, we provide a comprehensive, coherent set of predictions for unpolarised and polarised proton parton distribution functions (DFs): valence, glue, and four-flavour separated sea. The results enable many themes to be addressed, including: the asymmetry of antimatter in the proton; the neutron:proton structure function ratio; helicity retention in hard scattering processes; the charm quark momentum fraction; the sign and size of the polarised gluon DF; and the origin of the proton spin. In all cases where sound analyses of data are available, SCI predictions are semiquantitatively in agreement with the results. Those mismatches which exist are typically attributable to the momentum-independence of the underlying interaction. Judiciously interpreted, the SCI delivers a sound and insightful explanation of proton structure as expressed in DFs.

A reaction model for γ+p→J/ψ+p photoproduction, which exposes the cc¯ content of the photon in making the transition γ→cc¯+P→J/ψ and couples the intermediate cc¯ system to the proton's valence quarks via Pomeron (P) exchange, is used to deliver a description of available data, viz. both differential and total cross sections from near threshold, where data has newly been acquired, to invariant mass W≈300GeV. The study suggests that it is premature to link existing γ+p→J/ψ+p data with, for instance, in-proton gluon distributions, the quantum chromodynamics trace anomaly, or pentaquark production. Further developments in reaction theory and higher precision data are necessary before the validity of any such connections can be assessed.

Using a symmetry-preserving truncation of the quantum field equations describing hadron properties, parameter-free predictions are delivered for pion and kaon elastic electromagnetic form factors, FP=π,K, thereby unifying them with kindred results for nucleon elastic electromagnetic form factors. Regarding positive-charge states, the analysis stresses that the presence of scaling violations in QCD entails that Q2FP(Q2) should exhibit a single maximum on Q2>0. Locating such a maximum is both necessary and sufficient to establish the existence of scaling violations. The study predicts that, for charged π, K mesons, the Q2FP(Q2) maximum lies in the neighbourhood Q2≃5 GeV2. Foreseeable experiments will test these predictions and, providing their Q2 reach meets expectations, potentially also provide details on the momentum dependence of meson form factor scaling violation.

Exploiting an evolution scheme for parton distribution functions (DFs) that is all-orders exact, contemporary lattice-QCD (lQCD) results for low-order Mellin moments of the pion valence quark DF are shown to be mutually consistent. The analysis introduces a means by which key odd moments can be obtained from the even moments in circumstances where only the latter are available. Combining these elements, one arrives at parameter-free lQCD-based predictions for the pointwise behaviour of pion valence, glue, and sea DFs, with sound uncertainty estimates. The behaviour of the pion DFs at large light-front momentum fraction, x≳0.85, is found to be consistent with QCD expectations and continuum analyses of pion structure functions, i.e., damping like (1−x)βparton, with βvalence≈2.4, βglue≈3.6, βsea≈4.6. It may be possible to test these predictions using data from forthcoming experiments.

Summary: Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat’s oocyst shedding. Increased sporozoite/merozoite TgO/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with “Rosetta stone”-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in TgO/GABA-AT-related-pathways. These candidates potentially influence merozoite’s capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease.

Understanding the strong interaction dynamics that govern the emergence of hadron mass (EHM) represents a challenging open problem in the Standard Model. In this paper we describe new opportunities for gaining insight into EHM from results on nucleon resonance (N*) electroexcitation amplitudes (i.e., γvpN* electrocouplings) in the mass range up to 1.8 GeV for virtual photon four-momentum squared (i.e., photon virtualities Q2) up to 7.5 GeV2 available from exclusive meson electroproduction data acquired during the 6-GeV era of experiments at Jefferson Laboratory (JLab). These results, combined with achievements in the use of continuum Schwinger function methods (CSMs), offer new opportunities for charting the momentum dependence of the dressed quark mass from results on the Q2-evolution of the γvpN* electrocouplings. This mass function is one of the three pillars of EHM and its behavior expresses influences of the other two, viz. the running gluon mass and momentum-dependent effective charge. A successful description of the Δ(1232)3/2+ and N(1440)1/2+ electrocouplings has been achieved using CSMs with, in both cases, common momentum-dependent mass functions for the dressed quarks, for the gluons, and the same momentum-dependent strong coupling. The properties of these functions have been inferred from nonperturbative studies of QCD and confirmed, e.g., in the description of nucleon and pion elastic electromagnetic form factors. Parameter-free CSM predictions for the electrocouplings of the Δ(1600)3/2+ became available in 2019. The experimental results obtained in the first half of 2022 have confirmed the CSM predictions. We also discuss prospects for these studies during the 12-GeV era at JLab using the CLAS12 detector, with experiments that are currently in progress, and canvass the physics motivation for continued studies in this area with a possible increase of the JLab electron beam energy up to 22 GeV. Such an upgrade would finally enable mapping of the dressed quark mass over the full range of distances (i.e., quark momenta) where the dominant part of hadron mass and N* structure emerge in the transition from the strongly coupled to perturbative QCD regimes.

Visible matter is characterised by a single mass scale; namely, the proton mass. The proton’s existence and structure are supposed to be described by quantum chromodynamics (QCD); yet, absent Higgs boson couplings, chromodynamics is scale-invariant. Thus, if the Standard Model is truly a part of the theory of Nature, then the proton mass is an emergent feature of QCD; and emergent hadron mass (EHM) must provide the basic link between theory and observation. Nonperturbative tools are necessary if such connections are to be made; and in this context, we sketch recent progress in the application of continuum Schwinger function methods to an array of related problems in hadron and particle physics. Special emphasis is given to the three pillars of EHM—namely, the running gluon mass, process-independent effective charge, and running quark mass; their role in stabilising QCD; and their measurable expressions in a diverse array of observables.

Acanthamoeba keratitis (AK) is a severe infection of the cornea. Prevention and treatment are difficult due to the inefficacy of currently available compounds. The impact of many commonly used compounds for routine examinations of Acanthamoeba is unexplored but might offer insight useful in combatting AK. In this study, we demonstrate that sodium metabisulfite, a common preservation constituent of eye care solutions, was found to be active against Acanthamoeba trophozoites at concentrations lower than that commonly found in eye drops (IC50 0.03 mg/mL). We demonstrate that sodium metabisulfite depletes thiamine from growth medium and that Acanthamoeba is a thiamine auxotroph, requiring thiamine salvage for growth. The inhibitory effects of sodium metabisulfite can be overcome by thiamine supplementation. These results are consistent with the lack of key enzymes for thiamine biosynthesis in the genome of Acanthamoeba, an area which might prove exploitable using new or existing compounds. Indeed, this study highlights sodium metabisulfite as a useful inhibitor of Acanthamoeba castellanii trophozoites in vitro and that it acts, at least in part, by limiting available thiamine.

Abstract Using a symmetry-preserving regularisation of a vector $$\times $$ × vector contact interaction (SCI), we complete a systematic treatment of twelve semileptonic transitions with vector meson final states: $$D\rightarrow \rho $$ D → ρ , $$D_{(s)}\rightarrow K^*$$ D ( s ) → K ∗ , $$D_s\rightarrow \phi $$ D s → ϕ , $$B\rightarrow \rho $$ B → ρ , $$B_s\rightarrow K^*$$ B s → K ∗ , $$B_{(s)}\rightarrow D_{(s)}^*$$ B ( s ) → D ( s ) ∗ , $$B_c \rightarrow B_{(s)}^*, J/\psi , D^*$$ B c → B ( s ) ∗ , J / ψ , D ∗ ; and thereby finalise a unified analysis of semileptonic decays of heavy + heavy and heavy + light pseudoscalar mesons to both pseudoscalar and vector meson final states. The analysis is marked by algebraic simplicity, few parameters, and the ability to consistently describe systems from Nambu-Goldstone modes to heavy + heavy mesons. Regarding the behaviour of the transition form factors, the SCI results compare well wherever sound experimental or independent theory analyses are available; hence, the SCI branching fraction predictions should be a reasonable guide. Considering the ratios $$R(D_{(s)}^{(*)})$$ R ( D ( s ) ( ∗ ) ) , $$R(J/\psi )$$ R ( J / ψ ) , $$R(\eta _c)$$ R ( η c ) , whose values are key tests of lepton universality in weak interactions, the SCI values agree with Standard Model predictions. The $$B_{(s)}\rightarrow D_{(s)}^*$$ B ( s ) → D ( s ) ∗ transitions are used to predict the precursor functions that evolve into the universal Isgur–Wise function in the heavy-quark limit, with results that conform with those from other sources where such are available. The study also exposes effects on the transition form factors that flow from interference between emergent hadron mass from the strong interaction and Higgs boson couplings via current-quark masses, including flavour symmetry violation.

Theory suggests that in high-energy elastic hadron+hadron scattering, t-channel exchange of a family of colourless crossing-odd states – the odderon – may generate differences between pp¯ and pp cross-sections in the neighbourhood of the diffractive minimum. Using a mathematical approach based on interpolation via continued fractions enhanced by statistical sampling, we develop robust comparisons between pp¯ elastic differential cross-sections measured at √s=1.96 TeV by the D0 Collaboration at the Tevatron and function-form-unbiased extrapolations to this energy of kindred pp measurements at √s/TeV=2.76,7,8,13 by the TOTEM Collaboration at the LHC and a combination of these data with earlier cross-section measurements at √s/GeV=23.5,30.7,44.7,52.8,62.5 made at the intersecting storage rings. Focusing on a domain that straddles the diffractive minimum in the pp¯ and pp cross-sections, we find that these two cross-sections differ at the (2.2−2.6)σ level; hence, supply evidence with this level of significance for the existence of the odderon. If combined with evidence obtained through different experiment-theory comparisons, whose significance is reported to lie in the range (3.4−4.6)σ, one arrives at a (4.0−5.2)σ signal for the odderon.

Abstract A symmetry-preserving regularisation of a vector $$\times $$ × vector contact interaction (SCI) is used to deliver a unified treatment of semileptonic transitions involving $$\pi $$ π , K, $$D_{(s)}$$ D ( s ) , $$B_{(s,c)}$$ B ( s , c ) initial states. The framework is characterised by algebraic simplicity, few parameters, and the ability to simultaneously treat systems from Nambu–Goldstone modes to heavy+heavy mesons. Although the SCI form factors are typically somewhat stiff, the results are comparable with experiment and rigorous theory results. Hence, predictions for the five unmeasured $$B_{s,c}$$ B s , c branching fractions should be a reasonable guide. The analysis provides insights into the effects of Higgs boson couplings via current-quark masses on the transition form factors; and results on $$B_{(s)}\rightarrow D_{(s)}$$ B ( s ) → D ( s ) transitions yield a prediction for the Isgur–Wise function in fair agreement with contemporary data.

Abstract A symmetry-preserving treatment of a vector $$\times $$ × vector contact interaction is used to compute spectra of ground-state $$J^P = 0^\pm , 1^\pm $$ J P = 0 ± , 1 ± $$(f{\bar{g}})$$ ( f g ¯ ) mesons, their partner diquark correlations, and $$J^P=1/2^\pm , 3/2^\pm $$ J P = 1 / 2 ± , 3 / 2 ± (fg h) baryons, where $$f,g,h \in \{u,d,s,c,b\}$$ f , g , h ∈ { u , d , s , c , b } . Results for the leptonic decay constants of all mesons are also obtained, including scalar and pseudovector states involving heavy quarks. The spectrum of baryons produced by this chiefly algebraic approach reproduces the 64 masses known empirically or computed using lattice-regularised quantum chromodynamics with an accuracy of 1.4(1.2)%. It also has the richness of states typical of constituent-quark models and predicts many baryon states that have not yet been observed. The study indicates that dynamical, nonpointlike diquark correlations play an important role in all baryons; and, typically, the lightest allowed diquark is the most important component of a baryon’s Faddeev amplitude.

Working with proton and pion valence distribution functions (DFs) determined consistently at the same, unique hadron scale and exploiting the possibility that there is an effective charge which defines an evolution scheme for DFs that is all-orders exact, we obtain a unified body of predictions for all proton and pion DFs – valence, glue, and four-flavour-separated sea. Whilst the hadron light-front momentum fractions carried by identifiable parton classes are the same for the proton and pion at any scale, the pointwise behaviour of the DFs is strongly hadron-dependent. All calculated distributions comply with quantum chromodynamics constraints on low- and high-x scaling behaviour and, owing to emergent hadron mass, pion DFs are the most dilated. These results aid in elucidating the sources of similarities and differences between proton and pion structure.

Abstract The visible Universe is largely characterised by a single mass scale, namely, the proton mass, m p . Contemporary theory suggests that m p emerges as a consequence of gluon self-interactions, which are a defining characteristic of quantum chromodynamics (QCD), the theory of strong interactions in the Standard Model. However, the proton is not elementary. Its mass appears as a corollary of other, more basic emergent phenomena latent in the QCD Lagrangian, e.g. generation of nuclear-size gluon and quark mass-scales, and a unique effective charge that may describe QCD interactions at all accessible momentum scales. These remarks are explained herein, and focusing on the distribution amplitudes and functions of π and K mesons, promising paths for their empirical verification are elucidated. Connected therewith, in anticipation that production of J/ψ-mesons using π and K beams can provide access to the gluon distributions in these pseudo-Nambu-Goldstone modes, predictions for all π and K distribution functions are provided at the scale ζ=m J/ψ .

Abstract A contact interaction is used to calculate an array of pion twist-two, -three and -four generalised transverse light-front momentum dependent parton distribution functions (GTMDs). Despite the interaction’s simplicity, many of the results are physically relevant, amongst them a statement that GTMD size and shape are largely prescribed by the scale of emergent hadronic mass. Moreover, proceeding from GTMDs to generalised parton distributions, it is found that the pion’s mass distribution form factor is harder than its electromagnetic form factor, which is harder than the gravitational pressure distribution form factor; the pressure in the neighbourhood of the pion’s core is commensurate with that at the centre of a neutron star; the shear pressure is maximal when confinement forces become dominant within the pion; and the spatial distribution of transversely polarised quarks within the pion is asymmetric. Regarding transverse momentum dependent distribution functions, their magnitude and domain of material support decrease with increasing twist. The simplest Wigner distribution associated with the pion’s twist-two dressed-quark GTMD is sharply peaked on the kinematic domain associated with valence-quark dominance; has a domain of negative support; and broadens as the transverse position variable increases in magnitude.

An algebraic Ansatz for the proton's Poincaré-covariant wave function, which includes both scalar and pseudovector diquark correlations, is used to calculate proton valence, sea, and glue distribution functions (DFs). Regarding contemporary data, a material pseudovector diquark component in the proton is necessary for an explanation of the neutron-proton structure function ratio; and a modest Pauli blocking effect in the gluon splitting function is sufficient to explain the proton's light-quark antimatter asymmetry. In comparison with pion DFs, the light-front momentum fractions carried by all identifiable parton classes are the same; on the other hand, the higher moments are different. Understanding these features may provide insights that explain distinctions between Nambu-Goldstone bosons and seemingly less complex hadrons.

Continuum Schwinger function methods for the strong-interaction bound-state problem are used to arrive at a unified set of parameter-free predictions for the semileptonic K→π, D→π,K and Ds→K, B(s)→π(K) transition form factors and the associated branching fractions. The form factors are a leading source of uncertainty in all such calculations: our results agree quantitatively with available data and provide benchmarks for the hitherto unmeasured Ds→K0, B¯s→K+ form factors. The analysis delivers a value of |Vcs|=0.974(10) and also predictions for all branching fraction ratios in the pseudoscalar meson sector that can be used to test lepton flavour universality. Quantitative comparisons are provided between extant theory and the recent measurement of BBs0→K−μ+νμ. Here, further, refined measurements would be useful in moving toward a more accurate value of |Vub|.

With the aim of extracting the pion charge radius, we analyse extant precise pion+electron elastic scattering data on Q2∈[0.015,0.144] GeV2 using a method based on interpolation via continued fractions augmented by statistical sampling. The scheme avoids any assumptions on the form of function used for the representation of data and subsequent extrapolation onto Q2≃0. Combining results obtained from the two available data sets, we obtain rπ=0.640(7) fm, a value 2.4σ below today's commonly quoted average. The tension may be relieved by collection and similar analysis of new precise data that densely cover a domain which reaches well below Q2=0.015 GeV2. Considering available kaon+electron elastic scattering data sets, our analysis reveals that they contain insufficient information to extract an objective result for the charged-kaon radius, rK. New data with much improved precision, low-Q2 reach and coverage are necessary before a sound result for rK can be recorded.

Abstract Background Varicella is a highly contagious childhood disease. Generally benign, serious complications necessitating antibiotic use may occur. The objective of this study was to characterize the rate, appropriateness and patterns of real-world antibiotic prescribing for management of varicella-associated complications, prior to universal varicella vaccination (UVV) implementation. Methods Pooled, post-hoc analysis of 5 international, multicenter, retrospective chart reviews studies (Argentina, Hungary, Mexico, Peru, Poland). Inpatient and outpatient primary pediatric (1–14 years) varicella cases, diagnosed between 2009 and 2016, were eligible. Outcomes, assessed descriptively, included varicella-associated complications and antibiotic use. Three antibiotic prescribing scenarios were defined based on complication profile in chart: evidence of microbiologically confirmed bacterial infection (Scenario A); insufficient evidence confirming microbiological confirmation (Scenario B); no evidence of microbiological confirmation (Scenario C). Stratification was performed by patient status (inpatient vs. outpatient) and country. Results Four hundred one outpatients and 386 inpatients were included. Mean (SD) outpatient age was 3.6 (2.8) years; inpatient age was 3.1 (2.8) years. Male gender was predominant. Overall, 12.2% outpatients reported ≥1 infectious complication, 3.7% ≥1 bacterial infection, and 0.5% ≥1 microbiologically confirmed infection; inpatient complication rates were 78.8, 33.2 and 16.6%, respectively. Antibiotics were prescribed to 12.7% of outpatients and 68.9% of inpatients. Among users, β-lactamases (class), and clindamycin (agent), dominated prescriptions. Scenario A was assigned to 3.9% (outpatients) vs 13.2% (inpatients); Scenario B: 2.0% vs. 6.0%; Scenario C: 94.1% vs. 80.8%. Conclusions High rates of infectious complications and antibiotic use are reported, with low rates of microbiological confirmation suggesting possible antibiotic misuse for management of varicella complications.

Using a systematic, symmetry-preserving continuum approach to the Standard Model strong-interaction bound-state problem, we deliver parameter-free predictions for all semileptonic Bc→ηc,J/ψ transition form factors on the complete domains of empirically accessible momentum transfers. Working with branching fractions calculated therefrom, the following values of the ratios for τ over μ final states are obtained: Rηc=0.313(22) and RJ/ψ=0.242(47). Combined with other recent results, our analysis confirms a 2σ discrepancy between the Standard Model prediction for RJ/ψ and the single available experimental result.

A symmetry-preserving Poincaré-covariant quark+diquark Faddeev equation treatment of the nucleon is used to deliver parameter-free predictions for the nucleon's axial and induced pseudoscalar form factors, GA and GP, respectively. The result for GA can reliably be represented by a dipole form factor characterised by an axial charge gA=GA(0)=1.25(3) and a mass-scale MA=1.23(3)mN, where mN is the nucleon mass; and regarding GP, the induced pseudoscalar charge gp⁎=8.80(23), the ratio gp⁎/gA=7.04(22), and the pion pole dominance Ansatz is found to provide a reliable estimate of the directly computed result. The ratio of flavour-separated quark axial charges is also calculated: gAd/gAu=−0.16(2). This value expresses a marked suppression of the size of the d-quark component relative to that found in nonrelativistic quark models and owes to the presence of strong diquark correlations in the nucleon Faddeev wave function – both scalar and axial-vector, with the scalar diquark being dominant. The predicted form for GA should provide a sound foundation for analyses of the neutrino-nucleus and antineutrino-nucleus cross-sections that are relevant to modern accelerator neutrino experiments.

BackgroundThe World Health Organization (WHO)-defined radiological pneumonia is a preferred endpoint in pneumococcal vaccine efficacy and effectiveness studies in children. Automating the WHO methodology may support more widespread application of this endpoint.MethodsWe trained a deep learning model to classify pneumonia CXRs in children using the World Health Organization (WHO)'s standardized methodology. The model was pretrained on CheXpert, a dataset containing 224,316 adult CXRs, and fine-tuned on PERCH, a pediatric dataset containing 4,172 CXRs. The model was then tested on two pediatric CXR datasets released by WHO. We also compared the model's performance to that of radiologists and pediatricians.ResultsThe average area under the receiver operating characteristic curve (AUC) for primary endpoint pneumonia (PEP) across 10-fold validation of PERCH images was 0.928; average AUC after testing on WHO images was 0.977. The model's classification performance was better on test images with high inter-observer agreement; however, the model still outperformed human assessments in AUC and precision-recall spaces on low agreement images.ConclusionA deep learning model can classify pneumonia CXR images in children at a performance comparable to human readers. Our method lays a strong foundation for the potential inclusion of computer-aided readings of pediatric CXRs in vaccine trials and epidemiology studies.

A symmetry-preserving approach to the continuum bound-state problem in quantum field theory is used to calculate the masses, leptonic decay constants and light-front distribution amplitudes of empirically accessible heavy-light mesons. The inverse moment of the B-meson distribution is particularly important in treatments of exclusive B-decays using effective field theory and the factorisation formalism; and its value is therefore computed: λB(ζ=2GeV)=0.54(3)GeV. As an example and in anticipation of precision measurements at new-generation B-factories, the branching fraction for the rare B→γ(Eγ)ℓνℓ radiative decay is also calculated, retaining 1/mB2 and 1/Eγ2 corrections to the differential decay width, with the result ΓB→γℓνℓ/ΓB=0.47(15) on Eγ>1.5GeV. Keywords: B-meson decays, Heavy-light mesons, Nonperturbative continuum methods in quantum field theory, Parton distribution amplitudes, Quantum chromodynamics

Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome b inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces Toxoplasma gondii tachyzoites and encysted bradyzoites in vitro, and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant Plasmodium falciparum in vitro. Causal prophylaxis and radical cure are achieved after P. berghei sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria.

The formation of a protein layer “corona” on the nanoparticle surface upon entry into a biological environment was shown to strongly influence the interactions with cells, especially affecting the uptake of nanomedicines. In this work, we present the impact of the protein corona on the uptake of PEGylated zein micelles by cancer cells, macrophages, and dendritic cells. Zein was successfully conjugated with poly(ethylene glycol) (PEG) of varying chain lengths (5K and 10K) and assembled into micelles. Our results demonstrate that PEGylation conferred stealth effects to the zein micelles. The presence of human plasma did not impact the uptake levels of the micelles by melanoma cancer cells, regardless of the PEG chain length used. In contrast, it decreased the uptake by macrophages and dendritic cells. These results therefore make PEGylated zein micelles promising as potential drug delivery systems for cancer therapy.

Abstract The soil amoebae Acanthamoeba causes Acanthamoeba keratitis, a severe sight-threatening infection of the eye and the almost universally fatal granulomatous amoebic encephalitis. More effective treatments are required. Sterol biosynthesis has been effectively targeted in numerous fungi using azole compounds that inhibit the cytochrome P450 enzyme sterol 14α-demethylase. Herein, using Gas Chromatography Mass Spectrometry (GCMS), we demonstrate that the major sterol of Acanthamoeba castellanii is ergosterol and identify novel putative precursors and intermediate sterols in its production. Unlike previously reported, we find no evidence of 7-dehydrostigmasterol or any other phytosterol in Acanthamoeba. Of five azoles tested, we demonstrate that tioconazole and voriconazole have the greatest overall inhibition for all isolates of Acanthamoeba castellanii and Acanthamoeba polyphaga tested. While miconazole and sulconazole have intermediate activity econazole is least effective. Through GCMS, we demonstrate that voriconazole inhibits 14α-demethylase as treatment inhibits the production of ergosterol, but results in the accumulation of the lanosterol substrate. These data provide the most complete description of sterol metabolism in Acanthamoeba, provide a putative framework for their further study and validate 14α-demethylase as the target for azoles in Acanthamoeba.

The well-known Toll like receptor 9 (TLR9) agonist CpG ODN has shown promising results as vaccine adjuvant in preclinical and clinical studies, however its in vivo stability and potential systemic toxicity remain a concern. In an effort to overcome these issues, different strategies have been explored including conjugation of CpG ODN with proteins or encapsulation/adsorption of CpG ODN into/onto liposomes. Although these methods have resulted in enhanced immunopotency compared to co-administration of free CpG ODN and antigen, we believe that this effect could be further improved. Here, we designed a novel delivery system of CpG ODN based on its conjugation to serve as anchor for liposomes. Thiol-maleimide chemistry was utilised to covalently ligate model protein with the CpG ODN TLR9 agonist. Due to its negative charge, the protein conjugate readily electrostatically bound cationic liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol and dimethyldioctadecylammonium bromide (DDA) in a very high degree. The novel cationic liposomes-protein conjugate complex shared similar vesicle characteristics (size and charge) compared to free liposomes. The conjugation of CpG ODN to protein in conjunction with adsorption on cationic liposomes, could promote co-delivery leading to the induction of immune response at low antigen and CpG ODN doses. • The CpG ODN Toll-like receptor (TLR) 9 agonist was conjugated to protein antigens via thiol-maleimide chemistry. • Due to their negative charge, protein conjugates readily electrostatically bound cationic liposomes composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol and dimethyldioctadecylammonium bromide (DDA) resulting to the design of novel cationic liposomes-protein conjugate complexes. • The method is suited for the liposomal delivery of a variety of adjuvant-protein conjugates.

Toxoplasma gondii is capable of actively invading almost any mammalian cell type including phagocytes. Early events in phagocytic cells such as dendritic cells are not only key to establishing parasite infection, but conversely play a pivotal role in initiating host immunity. It is now recognized that in addition to changes in canonical immune markers and mediators, alteration in metabolism occurs upon activation of phagocytic cells. These metabolic changes are important for supporting the developing immune response, but can affect the availability of nutrients for intracellular pathogens including T. gondii. However, the interaction of T. gondii with these cells and particularly how infection changes their metabolism has not been extensively investigated. Herein, we use a multi-omics approach comprising transcriptomics and metabolomics validated with functional assays to better understand early events in these cells following infection. Analysis of the transcriptome of T. gondii infected bone marrow derived dendritic cells (BMDCs) revealed significant alterations in transcripts associated with cellular metabolism, activation of T cells, inflammation mediated chemokine and cytokine signaling pathways. Multivariant analysis of metabolomic data sets acquired through non-targeted liquid chromatography mass spectroscopy (LCMS) identified metabolites associated with glycolysis, the TCA cycle, oxidative phosphorylation and arginine metabolism as major discriminants between control uninfected and T. gondii infected cells. Consistent with these observations, glucose uptake and lactate dehydrogenase activity were upregulated in T. gondii infected BMDC cultures compared with control BMDCs. Conversely, BMDC mitochondrial membrane potential was reduced in T. gondii-infected cells relative to mitochondria of control BMDCs. These changes to energy metabolism, similar to what has been described following LPS stimulation of BMDCs and macrophages are often termed the Warburg effect. This metabolic reprogramming of cells has been suggested to be an important adaption that provides energy and precursors to facilitate phagocytosis, antigen processing and cytokine production. Other changes to BMDC metabolism are evident following T. gondii infection and include upregulation of arginine degradation concomitant with increased arginase-1 activity and ornithine and proline production. As T. gondii is an arginine auxotroph the resultant reduced cellular arginine levels are likely to curtail parasite multiplication. These results highlight the complex interplay of BMDCs and parasite metabolism within the developing immune response and the consequences for adaptive immunity and pathogen clearance.

Studies indicate that female mice are more susceptible to T. gondii infection, as defined by higher mortality rates in comparison to male mice. However, whether this is due to an inability to control initial parasite multiplication or due to detrimental effects of the immune system has not been determined. Therefore, the following studies were undertaken to determine the influence of sex on early parasite multiplication and the immune response during T. gondii infection and to correlate this with disease outcome. Early parasite replication was studied through applying an in vivo imaging system (IVIS) with luciferase expressing T. gondii. In parallel immunological events were studied by cytometric bead array to quantify key immunological mediators. The results confirmed the previous findings that female mice are more susceptible to acute infection, as determined by higher mortality rates and weight loss compared with males. However, conflicting with expectations, female mice had lower parasite burdens during the acute infection than male mice. Female mice also exhibited significantly increased production of Monocyte Chemoattractant Protein-1 (MCP-1), Interferon (IFN)-γ, and Tumour Necrosis Factor (TNF)-α than male mice. MCP-1 was found to be induced by T. gondii in a dose dependent manner suggesting that the observed increased levels detected in female mice was due to a host-mediated sex difference rather than due to parasite load. However, MCP-1 was not affected by physiological concentration of estrogen or testosterone, indicating that MCP-1 differences observed between the sexes in vivo are due to an as yet unidentified intermediary factor that in turn influences MCP-1 levels. These results suggest that a stronger immune response in female mice compared with male mice enhances their ability to control parasite replication but increases their morbidity and mortality.

Toxoplasma gondii, an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized. Crystallography revealed insights into the overall structure, protein oligomeric states and molecular details of active sites important for ligand recognition. Literature and molecular modeling suggested potential inhibitors and druggability. The targets were further studied with vivoPMO to interrupt enzyme synthesis, identifying the targets as potentially important to parasitic replication and, therefore, of therapeutic interest. Targeted vivoPMO resulted in statistically significant perturbation of parasite replication without concomitant host cell toxicity, consistent with a previous CRISPR/Cas9 screen showing PGM, RPE, and RPI contribute to parasite fitness. PGM, RPE, and RPI have the greatest promise for affecting replication in tachyzoites. These targets are shared between other medically important parasites and may have wider therapeutic potential.

The leading-twist parton distribution amplitudes (PDAs) of ground-state S01 and S13 cc¯- and bb¯-quarkonia are calculated using a symmetry-preserving continuum treatment of the meson bound-state problem which unifies the properties of these heavy-quark systems with those of light-quark bound-states, including QCD's Goldstone modes. Analysing the evolution of S01 and S13 PDAs with current-quark mass, mˆq, increasing away from the chiral limit, it is found that in all cases there is a value of mˆq for which the PDA matches the asymptotic form appropriate to QCD's conformal limit and hence is insensitive to changes in renormalisation scale, ζ. This mass lies just above that associated with the s-quark. At current-quark masses associated with heavy-quarkonia, on the other hand, the PDAs are piecewise convex–concave–convex. They are much narrower than the asymptotic distribution on a large domain of ζ; but nonetheless deviate noticeably from φQQ¯(x)=δ(x−1/2), which is the result in the static-quark limit. There are also material differences between S01 and S13 PDAs, and between the PDAs for different vector-meson polarisations, which vanish slowly with increasing ζ. An analysis of moments of the root-mean-square relative-velocity, 〈v2m〉, in S01 and S13 systems reveals that 〈v4〉-contributions may be needed in order to obtain a reliable estimate of matrix elements using such an expansion, especially for processes involving heavy pseudoscalar quarkonia.

Analyses of the three valence-quark bound-state problem in relativistic quantum field theory predict that the nucleon may be understood primarily as a Borromean bound-state, in which binding arises mainly from two separate effects. One originates in non-Abelian facets of QCD that are expressed in the strong running coupling and generate confined but strongly-correlated colour-antitriplet diquark clusters in both the scalar–isoscalar and pseudovector–isotriplet channels. That attraction is magnified by quark exchange associated with diquark breakup and reformation. Diquark clustering is driven by the same mechanism which dynamically breaks chiral symmetry in the Standard Model. It has numerous observable consequences, the complete elucidation of which requires a framework that also simultaneously expresses the running of the coupling and masses in the strong interaction. Planned experiments are capable of validating this picture.

Acanthamoeba is normally free-living, but sometimes facultative and occasionally opportunistic parasites. Current therapies are, by necessity, arduous and yet poorly effective due to their inabilities to kill cyst stages or in some cases to actually induce encystation. Acanthamoeba can therefore survive as cysts and cause disease recurrence. Herein, in pursuit of better therapies and to understand the biochemistry of this understudied organism, we characterize its histidine biosynthesis pathway and explore the potential of targeting this with antimicrobials. We demonstrate that Acanthamoeba is a histidine autotroph, but with the ability to scavenge preformed histidine. It is able to grow in defined media lacking this amino acid, but is inhibited by 3-amino-1,2,4-triazole (3AT) that targets Imidazoleglycerol-Phosphate Dehydratase (IGPD) the rate limiting step of histidine biosynthesis. The structure of Acanthamoeba IGPD has also been determined in complex with 2-hydroxy-3-(1,2,4-triazol-1-yl) propylphosphonate [(R)-C348], a recently described novel inhibitor of Arabidopsis thaliana IGPD. This compound inhibited the growth of four Acanthamoeba species, having a 50% inhibitory concentration (IC50) ranging from 250-526 nM. This effect could be ablated by the addition of 1 mM exogenous free histidine, but importantly not by physiological concentrations found in mammalian tissues. The ability of 3AT and (R)-C348 to restrict the growth of four strains of Acanthamoeba spp. including a recently isolated clinical strain, while not inducing encystment, demonstrates the potential therapeutic utility of targeting the histidine biosynthesis pathway in Acanthamoeba.

Within contemporary hadron physics there are two common methods for determining the momentum-dependence of the interaction between quarks: the top-down approach, which works toward an ab initio computation of the interaction via direct analysis of the gauge-sector gap equations; and the bottom-up scheme, which aims to infer the interaction by fitting data within a well-defined truncation of those equations in the matter sector that are relevant to bound-state properties. We unite these two approaches by demonstrating that the renormalisation-group-invariant running-interaction predicted by contemporary analyses of QCD's gauge sector coincides with that required in order to describe ground-state hadron observables using a nonperturbative truncation of QCD's Dyson–Schwinger equations in the matter sector. This bridges a gap that had lain between nonperturbative continuum-QCD and the ab initio prediction of bound-state properties. Keywords: Dyson–Schwinger equations, Confinement, Dynamical chiral symmetry breaking, Fragmentation, Gribov copies

Background: Micronemal proteins of the thrombospondin-related anonymous protein (TRAP) family are believed to play essential roles during gliding motility and host cell invasion by apicomplexan parasites, and currently represent major vaccine candidates against Plasmodium falciparum, the causative agent of malaria. However, recent evidence suggests that they play multiple and different roles than previously assumed. Here, we analyse a null mutant for MIC2, the TRAP homolog in Toxoplasma gondii. Methods: We performed a careful analysis of parasite motility in a 3D-environment, attachment under shear stress conditions, host cell invasion and in vivo virulence. Results: We verified the role of MIC2 in efficient surface attachment, but were unable to identify any direct function of MIC2 in sustaining gliding motility or host cell invasion once initiated. Furthermore, we find that deletion of mic2 causes a slightly delayed infection in vivo, leading only to mild attenuation of virulence; like with wildtype parasites, inoculation with even low numbers of mic2 KO parasites causes lethal disease in mice. However, deletion of mic2 causes delayed host cell egress in vitro, possibly via disrupted signal transduction pathways. Conclusions: We confirm a critical role of MIC2 in parasite attachment to the surface, leading to reduced parasite motility and host cell invasion. However, MIC2 appears to not be critical for gliding motility or host cell invasion, since parasite speed during these processes is unaffected. Furthermore, deletion of MIC2 leads only to slight attenuation of the parasite.

Background: Micronemal proteins of the thrombospondin-related anonymous protein (TRAP) family are believed to play essential roles during gliding motility and host cell invasion by apicomplexan parasites, and currently represent major vaccine candidates against Plasmodium falciparum, the causative agent of malaria. However, recent evidence suggests that they play multiple and different roles than previously assumed. Here, we analyse a null mutant for MIC2, the TRAP homolog in Toxoplasma gondii. Methods: We performed a careful analysis of parasite motility in a 3D-environment, attachment under shear stress conditions, host cell invasion and in vivo virulence. Results: We verified the role of MIC2 in efficient surface attachment, but were unable to identify any direct function of MIC2 in sustaining gliding motility or host cell invasion once initiated. Furthermore, we find that deletion of mic2 causes a slightly delayed infection in vivo, leading only to mild attenuation of virulence; like with wildtype parasites, inoculation with even low numbers of mic2 KO parasites causes lethal disease in mice. However, deletion of mic2 causes delayed host cell egress in vitro, possibly via disrupted signal transduction pathways. Conclusions: We confirm a critical role of MIC2 in parasite attachment to the surface, leading to reduced parasite motility and host cell invasion. However, MIC2 appears to not be critical for gliding motility or host cell invasion, since parasite speed during these processes is unaffected. Furthermore, deletion of MIC2 leads only to slight attenuation of the parasite.

We compute the kaon's valence-quark (twist-two parton) distribution amplitude (PDA) by projecting its Poincaré-covariant Bethe–Salpeter wave-function onto the light-front. At a scale ζ=2 GeV, the PDA is a broad, concave and asymmetric function, whose peak is shifted 12–16% away from its position in QCD's conformal limit. These features are a clear expression of SU(3)-flavour-symmetry breaking. They show that the heavier quark in the kaon carries more of the bound-state's momentum than the lighter quark and also that emergent phenomena in QCD modulate the magnitude of flavour-symmetry breaking: it is markedly smaller than one might expect based on the difference between light-quark current masses. Our results add to a body of evidence which indicates that at any energy scale accessible with existing or foreseeable facilities, a reliable guide to the interpretation of experiment requires the use of such nonperturbatively broadened PDAs in leading-order, leading-twist formulae for hard exclusive processes instead of the asymptotic PDA associated with QCD's conformal limit. We illustrate this via the ratio of kaon and pion electromagnetic form factors: using our nonperturbative PDAs in the appropriate formulae, FK/Fπ=1.23 at spacelike-Q2=17 GeV2, which compares satisfactorily with the value of 0.92(5) inferred in e+e− annihilation at s=17 GeV2. Keywords: Dynamical chiral symmetry breaking, Dyson–Schwinger equations, Factorisation in heavy-meson decays, Flavour symmetry breaking, Light pseudoscalar mesons, Parton distribution amplitudes, Strange quarks

The impulse-approximation expression used hitherto to define the pion's valence-quark distribution function is flawed because it omits contributions from the gluons which bind quarks into the pion. A corrected leading-order expression produces the model-independent result that quarks dressed via the rainbow–ladder truncation, or any practical analogue, carry all the pion's light-front momentum at a characteristic hadronic scale. Corrections to the leading contribution may be divided into two classes, responsible for shifting dressed-quark momentum into glue and sea-quarks. Working with available empirical information, we use an algebraic model to express the principal impact of both classes of corrections. This enables a realistic comparison with experiment that allows us to highlight the basic features of the pion's measurable valence-quark distribution, qπ(x); namely, at a characteristic hadronic scale, qπ(x)∼(1−x)2 for x≳0.85; and the valence-quarks carry approximately two-thirds of the pion's light-front momentum.

Objectives: The goal of this study was to provide a comprehensive analysis of the potential health impact of universal vaccination of infants with the 7-valent pneumococcal conjugate vaccine (PCV7) in China. Methods: A decision-analytic model designed for pneumococcal disease and outcomes of pneumococcal infection was populated with local age-specific incidence and mortality data to estimate the expected health benefits of vaccinating birth cohorts of approximately 16 million infants per year over a 10-year time horizon in China. The model incorporates both the direct impact on vaccinated children and the indirect effect of herd protection on unvaccinated children and adults. Results: The model predicts that more than 16.2 million cases of pneumococcal disease and 709 411 deaths could be prevented in China over the initial 10-year period following the introduction of the PCV7 vaccine. The majority of these health benefits are due to the indirect effectiveness of the vaccine on the unvaccinated population, resulting in approximately 10.8 million cases prevented and 636 371 lives saved over 10 years. Conclusions: The results suggest that a policy of universal PCV7 vaccination among infants in China would have a substantial positive public health impact on the population of China.