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Abstract Pediatric low-grade gliomas (pLGGs) exhibit heterogeneous prognoses and variable responses to treatment, leading to tumor progression and adverse outcomes in cases where complete resection is unachievable. Early prediction of treatment responsiveness and suitability for immunotherapy has the potential to improve clinical management and outcomes. Here, we present a radiogenomic analysis of pLGGs, integrating MRI and RNA sequencing data. We identify three immunologically distinct clusters, with one group characterized by increased immune activity and poorer prognosis, indicating potential benefit from immunotherapies. We develop a radiomic signature that predicts these immune profiles with over 80% accuracy. Furthermore, our clinicoradiomic model predicts progression-free survival and correlates with treatment response. We also identify genetic variants and transcriptomic pathways associated with progression risk, highlighting links to tumor growth and immune response. This radiogenomic study in pLGGs provides a framework for the identification of high-risk patients who may benefit from targeted therapies.

Abstract The azimuthal correlation angle, $$\Delta \phi $$ Δ ϕ , between the scattered lepton and the leading jet in deep inelastic $$e^{\pm }p$$ e ± p scattering at HERA has been studied using data collected with the ZEUS detector at a centre-of-mass energy of $$\sqrt{s} = 318 {\,\text {Ge}\hspace{-0.66666pt}\text {V}}$$ s = 318 Ge V , corresponding to an integrated luminosity of $$326 \,\text {pb}^{-1}$$ 326 pb - 1 . A measurement of jet cross sections in the laboratory frame was made in a fiducial region corresponding to photon virtuality $$10 {\,\text {Ge}\hspace{-0.66666pt}\text {V}}^2< Q^2 < 350 {\,\text {Ge}\hspace{-0.66666pt}\text {V}}^2$$ 10 Ge V 2 < Q 2 < 350 Ge V 2 , inelasticity $$0.04< y < 0.7$$ 0.04 < y < 0.7 , outgoing lepton energy $$E_e > 10 {\,\text {Ge}\hspace{-0.66666pt}\text {V}}$$ E e > 10 Ge V , lepton polar angle $$140^\circ< \theta _e < 180^\circ $$ 140 ∘ < θ e < 180 ∘ , jet transverse momentum $$2.5 {\,\text {Ge}\hspace{-0.66666pt}\text {V}}< p_\textrm{T,jet} < 30 {\,\text {Ge}\hspace{-0.66666pt}\text {V}}$$ 2.5 Ge V < p T,jet < 30 Ge V , and jet pseudorapidity $$-1.5< \eta _\textrm{jet} < 1.8$$ - 1.5 < η jet < 1.8 . Jets were reconstructed using the $$k_\textrm{T}$$ k T algorithm with the radius parameter $$R = 1$$ R = 1 . The leading jet in an event is defined as the jet that carries the highest $$p_\textrm{T,jet}$$ p T,jet . Differential cross sections, $$d\sigma /d\Delta \phi $$ d σ / d Δ ϕ , were measured as a function of the azimuthal correlation angle in various ranges of leading-jet transverse momentum, photon virtuality and jet multiplicity. Perturbative calculations at $$\mathcal {O}(\alpha _{s}^2)$$ O ( α s 2 ) accuracy successfully describe the data within the fiducial region, although a lower level of agreement is observed near $$\Delta \phi \rightarrow \pi $$ Δ ϕ → π for events with high jet multiplicity, due to limitations of the perturbative approach in describing soft phenomena in QCD. The data are equally well described by Monte Carlo predictions that supplement leading-order matrix elements with parton showering.

Cloud properties are strongly influenced by ice formation; hence, we need to understand the sources of ice-nucleating particles (INPs) around the globe. Boreal forests are known as sources of bioaerosol, and recent work indicates that these dominate the INP spectra above −24 °C. To quantify the INP population at temperatures below −24 °C, we deployed a portable cloud expansion chamber (PINE) in a Finnish boreal forest from 13 March 2018 to 11 May 2018. Using the 6 min time resolution PINE data, we present several lines of evidence that INPs below −24 °C in this location are also from biological sources: (i) an INP parameterization developed for a pine forest site in Colorado, where many INPs were shown to be biological, produced a good fit to our measurements; a moderate correlation of INPs with aerosol concentration larger than 0.5 µm and the fluorescent bioaerosol concentration; (ii) a negative correlation with relative humidity that may relate to enhanced release of bioaerosol at low humidity from local sources such as the prolific lichen population in boreal forests; and (iii) the absence of correlation with ultra-fine particles (3.5 to 50 nm), indicating that new particle formation events are not sources of INPs. This study should motivate further work to establish whether the commonality in bioaerosol ice-nucleating properties between spring in Finland and summer in Colorado is more generally applicable to different coniferous forest locations and times and also to determine to what extent these bioaerosols are transported to locations where they may affect clouds.

Children are biologically predisposed to develop language, but learning to read requires years of instruction on the associations and conventions inherent to culturally specific writing systems. This does not come easily to all students. Dyslexia is a specific type of reading disability that impacts millions of learners in the K-12 school system. This article reviews contemporary neuroscience research about dyslexia and reading in the English language and how school psychologists can apply findings to their assessment, consultation, and intervention practices.

Abstract Radio-frequency particle accelerators are engines of discovery, powering high-energy physics and photon science, but are also large and expensive due to their limited accelerating fields. Plasma-wakefield accelerators (PWFAs) provide orders-of-magnitude stronger fields in the charge-density wave behind a particle bunch travelling in a plasma, promising particle accelerators of greatly reduced size and cost. However, PWFAs can easily degrade the beam quality of the bunches they accelerate. Emittance, which determines how tightly beams can be focused, is a critical beam quality in for instance colliders and free-electron lasers, but is particularly prone to degradation. We demonstrate, for the first time, emittance preservation in a high-gradient and high-efficiency PWFA while simultaneously preserving charge and energy spread. This establishes that PWFAs can accelerate without degradation—an essential step toward energy boosters in photon science and multistage facilities for compact high-energy particle colliders.

For plasma-wakefield accelerators to fulfill their potential for cost effectiveness, it is essential that their energy-transfer efficiency be maximized. A key aspect of this efficiency is the near-complete transfer of energy, or depletion, from the driver electrons to the plasma wake. Achieving full depletion is limited by the process of re-acceleration, which occurs when the driver electrons decelerate to nonrelativistic energies, slipping backward into the accelerating phase of the wakefield and being subsequently re-accelerated. Such re-acceleration is unambiguously observed here for the first time. At this re-acceleration limit, we measure a beam driver depositing (57 ± 3)% of its energy into a 195-mm-long plasma. This suggests that the energy-transfer efficiency of plasma accelerators could approach that of conventional accelerators.

Abstract A new measurement of inclusive-jet cross sections in the Breit frame in neutral current deep inelastic scattering using the ZEUS detector at the HERA collider is presented. The data were taken in the years 2004–2007 at a centre-of-mass energy of $$318\,\,\textrm{GeV}$$ 318 GeV and correspond to an integrated luminosity of $$347\,\,\textrm{pb}^{-1}$$ 347 pb - 1 . The jets were reconstructed using the $$k_t$$ k t -algorithm in the Breit reference frame. They have been measured as a function of the squared momentum transfer, $$Q^2$$ Q 2 , and the transverse momentum of the jets in the Breit frame, $$p_{\perp ,\text {Breit}}$$ p ⊥ , Breit . The measured jet cross sections are compared to previous measurements and to perturbative QCD predictions. The measurement has been used in a next-to-next-to-leading-order QCD analysis to perform a simultaneous determination of parton distribution functions of the proton and the strong coupling, resulting in a value of $$\alpha _s(M_Z^2) = 0.1142 \pm 0.0017 \text {~(experimental/fit)}$$ α s ( M Z 2 ) = 0.1142 ± 0.0017 (experimental/fit) $${}_{-0.0007}^{+0.0006} \text {~(model/parameterisation)}$$ - 0.0007 + 0.0006 (model/parameterisation) $${}_{-0.0004}^{+0.0006} \text {~(scale)}$$ - 0.0004 + 0.0006 (scale) , whose accuracy is improved compared to similar measurements. In addition, the running of the strong coupling is demonstrated using data obtained at different scales.

Abstract The exclusive photoproduction reactions γp → J/ψ(1S)p and γp → ψ(2S)p have been measured at an ep centre-of-mass energy of 318 GeV with the ZEUS detector at HERA using an integrated luminosity of 373 pb −1. The measurement was made in the kinematic range 30 < W < 180 GeV, Q 2 < 1 GeV2 and |t| < 1 GeV2, where W is the photon-proton centre-of-mass energy, Q 2 is the photon virtuality and t is the squared four-momentum transfer at the proton vertex. The decay channels used were J/ψ(1S) → μ + μ − , ψ(2S) → μ + μ − and ψ(2S) → J/ψ(1S)π + π − with subsequent decay J/ψ(1S) → μ + μ − . The ratio of the production cross sections, R = σ ψ(2S) /σ J/ψ(1S), has been measured as a function of W and |t| and compared to previous data in photoproduction and deep inelastic scattering and with predictions of QCD-inspired models of exclusive vector-meson production, which are in reasonable agreement with the data.

Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition syndrome associated with the development of hypermutant pediatric high-grade glioma, and confers a poor prognosis. While therapeutic histone deacetylase (HDAC) inhibition of diffuse intrinsic pontine glioma (DIPG) has been reported; here, we use a clinically relevant biopsy-derived hypermutant DIPG model (PBT-24FH) and a CRISPR-Cas9 induced genetic model to evaluate the efficacy of HDAC inhibition against hypermutant DIPG. We screened PBT-24FH cells for sensitivity to a panel of HDAC inhibitors (HDACis) in vitro, identifying two HDACis associated with low nanomolar IC50s, quisinostat (27 nM) and romidepsin (2 nM). In vivo, quisinostat proved more efficacious, inducing near-complete tumor regression in a PBT-24FH flank model. RNA sequencing revealed significant quisinostat-driven changes in gene expression, including upregulation of neural and pro-inflammatory genes. To validate the observed potency of quisinostat in vivo against additional hypermutant DIPG models, we tested quisinostat in genetically-induced mismatch repair (MMR)-deficient DIPG flank tumors, demonstrating that loss of MMR function increases sensitivity to quisinostat in vivo. Here, we establish the preclinical efficacy of quisinostat against hypermutant DIPG, supporting further investigation of epigenetic targeting of hypermutant pediatric cancers with the potential for clinical translation. These findings support further investigation of HDAC inhibitors against pontine high-grade gliomas, beyond only those with histone mutations, as well as against other hypermutant central nervous system tumors.

While immunotherapy for pediatric cancer has made great strides in recent decades, including the FDA approval of agents such as dinutuximab and tisgenlecleucel, these successes have rarely impacted children with pediatric central nervous system (CNS) tumors. As our understanding of the biological underpinnings of these tumors evolves, new immunotherapeutics are undergoing rapid clinical translation specifically designed for children with CNS tumors. Most recently, there have been notable clinical successes with oncolytic viruses, vaccines, adoptive cellular therapy, and immune checkpoint inhibition. In this article, the immunotherapy working group of the Pacific Pediatric Neuro-Oncology Consortium (PNOC) reviews the current and future state of immunotherapeutic CNS clinical trials with a focus on clinical trial development. Based on recent therapeutic trials, we discuss unique immunotherapy clinical trial challenges, including toxicity considerations, disease assessment, and correlative studies. Combinatorial strategies and future directions will be addressed. Through internationally collaborative efforts and consortia, we aim to direct this promising field of immuno-oncology to the next frontier of successful application against pediatric CNS tumors.

IntroductionWe previously discovered a pyridazine derivative compound series that can improve cognitive functions in mouse models of Alzheimer’s disease. One of the advanced compounds from this series, LDN/OSU-0215111-M3, was selected as the preclinical development candidate. This compound activates local protein translation at the perisynaptic astrocytic process (PAP) and enhances synaptic plasticity sequentially. While biochemical evidence supports the hypothesis that the compound enhances the structural plasticity of the tripartite synapse, its direct structural impact has not been investigated.MethodsVolume electron microscopy was used to study the hippocampal tripartite synapse three-dimensional structure in 3-month-old wild-type FVB/NJ mice after LDN/OSU-0215111-M3 treatment.ResultsLDN/OSU-0215111-M3 increased the size of tertiary apical dendrites, the volume of mushroom spines, the proportion of mushroom spines containing spine apparatus, and alterations in the spine distribution across the surface area of tertiary dendrites. Compound also increased the number of the PAP interacting with the mushroom spines as well as the size of the PAP in contact with the spines. Furthermore, proteomic analysis of the isolated synaptic terminals indicated an increase in dendritic and synaptic proteins as well as suggested a possible involvement of the phospholipase D signaling pathway. To further validate that LDN/OSU-0215111-M3 altered synaptic function, electrophysiological studies showed increased long-term potentiation following compound treatment.DiscussionThis study provides direct evidence that pyridazine derivatives enhance the structural and functional plasticity of the tripartite synapse.

MagAO-X is a recently commissioned extreme adaptive optics instrument for the Magellan Clay 6.5 m telescope at Las Campanas Observatory in Chile. MagAO-X had first light in 2019 and subsequent commissioning observations in 2022 and 2023. An essential step for the commissioning of any new instrument is the calibration of the conversion of detector coordinates to angular sky coordinates, which we accomplish with observations of HD 165054. The background stars adjacent to HD 165054 in Baade’s Window are in a fortuitous configuration for the astrometric calibration of natural-guide-star high-contrast imaging instruments. We extend past work to connect these stars’ positions to absolute astrometry for HD 165054 itself using Gaia Data Release 3 data, and bootstrap the creation of an astrometric solution for our new high-contrast imaging instrument. Through Markov Chain Monte Carlo analysis of the historical data and position measurements from MagAO-X, we obtain updated astrometric parameters for the seven background stars and an astrometric calibration of the MagAO-X science cameras.

Abstract The HERAPDF2.0 ensemble of parton distribution functions (PDFs) was introduced in 2015. The final stage is presented, a next-to-next-to-leading-order (NNLO) analysis of the HERA data on inclusive deep inelastic ep scattering together with jet data as published by the H1 and ZEUS collaborations. A perturbative QCD fit, simultaneously of $$\alpha _s(M_Z^2)$$ α s ( M Z 2 ) and the PDFs, was performed with the result $$\alpha _s(M_Z^2)= 0.1156 \pm 0.0011~\mathrm{(exp)}~ ^{+0.0001}_{-0.0002}~ \mathrm{(model}$$ α s ( M Z 2 ) = 0.1156 ± 0.0011 ( exp ) - 0.0002 + 0.0001 ( model $$\mathrm{+ parameterisation)}~ \pm 0.0029~\mathrm{(scale)}$$ + parameterisation ) ± 0.0029 ( scale ) . The PDF sets of HERAPDF2.0Jets NNLO were determined with separate fits using two fixed values of $$\alpha _s(M_Z^2)$$ α s ( M Z 2 ) , $$\alpha _s(M_Z^2)=0.1155$$ α s ( M Z 2 ) = 0.1155 and 0.118, since the latter value was already chosen for the published HERAPDF2.0 NNLO analysis based on HERA inclusive DIS data only. The different sets of PDFs are presented, evaluated and compared. The consistency of the PDFs determined with and without the jet data demonstrates the consistency of HERA inclusive and jet-production cross-section data. The inclusion of the jet data reduced the uncertainty on the gluon PDF. Predictions based on the PDFs of HERAPDF2.0Jets NNLO give an excellent description of the jet-production data used as input.

During the early twentieth century, industrial-era European immigrants entered the United States with lower levels of education than the U.S. average. However, empirical research has yielded unclear and inconsistent evidence about the extent and pace of their integration, leaving openings for arguments that contest the narrative that these groups experienced rapid integration and instead assert that educational deficits among lower-status groups persisted across multiple generations. Here, we advance another argument, that European immigrants may have "leapfrogged" or exceeded U.S.-born non-Hispanic white attainment by the third generation. To assess these ideas, we reconstituted three-generation families by linking individuals across the 1940 census; years 1973, 1979, and 1981 to 1990 of the Current Population Survey; the 2000 census; and years 2001 to 2017 of the American Community Survey. Results show that most European immigrant groups not only caught up with U.S.-born whites by the second generation but surpassed them, and this advantage further increased in the third generation. This research provides a new understanding of the time to integration for twentieth-century European immigrant groups by showing that they integrated at a faster pace than previously thought, indicative of a process of accelerated upward mobility.

Abstract Collective behaviour of final-state hadrons, and multiparton interactions are studied in high-multiplicity ep scattering at a centre-of-mass energy s $$ \sqrt{s} $$ = 318 GeV with the ZEUS detector at HERA. Two- and four-particle azimuthal correlations, as well as multiplicity, transverse momentum, and pseudorapidity distributions for charged-particle multiplicities N ch ≥ 20 are measured. The dependence of two-particle correlations on the virtuality of the exchanged photon shows a clear transition from photoproduction to neutral current deep inelastic scattering. For the multiplicities studied, neither the measurements in photoproduction processes nor those in neutral current deep inelastic scattering indicate significant collective behaviour of the kind observed in high-multiplicity hadronic collisions at RHIC and the LHC. Comparisons of PYTHIA predictions with the measurements in photoproduction strongly indicate the presence of multiparton interactions from hadronic fluctuations of the exchanged photon.

Central nervous system (CNS) tumors are the most common solid malignancy in the pediatric population. Based on adoptive cellular therapy's clinical success against childhood leukemia and the preclinical efficacy against pediatric CNS tumors, chimeric antigen receptor (CAR) T cells offer hope of improving outcomes for recurrent tumors and universally fatal diseases such as diffuse intrinsic pontine glioma (DIPG). However, a major obstacle for tumors of the brain and spine is ineffective T cell chemotaxis to disease sites. Locoregional CAR T cell delivery via infusion through an intracranial catheter is currently under study in multiple early phase clinical trials. Here, we describe the Seattle Children's single-institution experience including the multidisciplinary process for the preparation of successful, repetitive intracranial T cell infusion for children and the catheter-related safety of our 307 intracranial CAR T cell doses.

Background Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target.Methods We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing.Results We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2–4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed.Conclusion Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

Abstract Background Epidemiological surveillance data indicate that a majority of HIV-infected in the United States (U.S.) military are African-Americans and men who have sex with men. There is limited research about barriers to HIV prevention among military service members and the unique factors that contribute to HIV stigma. Methods A convenience sample of 30 U.S. service members were recruited from an infectious disease clinic. In depth interviews were conducted and data analyzed using a thematic coding process. Results Two broad categories were identified: 1) Outcomes of HIV Stigma: Fear of Rejection, Shame, and Embarrassment; and 2) Strategies for combating stigma which include increasing HIV education and prevention resources. Military policies and institutional culture regarding sexuality were found to contribute to stigma. Conclusions Participants identified a need for HIV education and suggested individuals living with HIV serve as mentors. A peer-to-peer intervention for delivering HIV prevention education may address these needs and reduce HIV stigma.

Among legumes, the lentil (Lens culinaris) is a major dietary component in many Mediterranean and Asian countries due to its high nutritional value, especially protein. However, allergic reactions triggered by lentil consumption have also been documented in many countries. Complete allergens profiling is critical for better management of lentil food allergies. Earlier studies suggested Len c 1, a 47 kDa vicilin, Len c 2, a seed-specific-biotinylated 66-kDa protein, and Len c 3, low molecular weight lipid transfer proteins (LTPs) were major allergenic proteins in lentils. Recently, mass-spectrometry-based proteomic platforms successfully identified proteins from lentil samples homologous to known plant allergens. Furthermore, in silico analysis using 337 protein sequences revealed lentil allergens that have not previously been identified as potential allergens in lentil. Herein, we discuss the feasibility of omics platforms utilized for lentil allergens profiling and quantification. In addition, we propose some future strategies that might be beneficial for profiling and development of precise assays for lentil allergens and could facilitate identification of the low allergen-containing lentil cultivars.

Abstract Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly primarily affecting the mediastinum with high mortality rate. We present a patient with KLA and significant disease burden harboring a somatic point mutation in the Casitas B lineage lymphoma (CBL) gene. She was treated with MEK inhibition with complete resolution of symptoms, near‐complete resolution of lymphatic fluid burden, and remodeling of her lymphatic system. While patients with KLA have been reported to harbor mutations in NRAS, here we report for the first time a causative mutation in the CBL gene in a patient with KLA, successfully treated with Ras pathway inhibition.

Abstract Two-particle azimuthal correlations have been measured in neutral current deep inelastic ep scattering with virtuality Q 2 > 5 GeV2 at a centre-of-mass energy s $$ \sqrt{s} $$ = 318 GeV recorded with the ZEUS detector at HERA. The correlations of charged particles have been measured in the range of laboratory pseudorapidity −1.5 < η < 2.0 and transverse momentum 0.1 < p T < 5.0 GeV and event multiplicities N ch up to six times larger than the average 〈N ch〉 ≈ 5. The two-particle correlations have been measured in terms of the angular observables c n{2} = 〈〈cosnΔφ〉〉, where n is between 1 and 4 and ∆φ is the relative azimuthal angle between the two particles. Comparisons with available models of deep inelastic scattering, which are tuned to reproduce inclusive particle production, suggest that the measured two-particle correlations are dominated by contributions from multijet production. The correlations observed here do not indicate the kind of collective behaviour recently observed at the highest RHIC and LHC energies in high-multiplicity hadronic collisions.

The construction of an electron–positron collider ‘Higgs factory’ has been stalled for a decade, not because of feasibility but because of the cost of conventional radio-frequency (RF) acceleration. Plasma-wakefield acceleration promises to alleviate this problem via significant cost reduction based on its orders-of-magnitude higher accelerating gradients. However, plasma-based acceleration of positrons is much more difficult than for electrons. We propose a collider scheme that avoids positron acceleration in plasma, using a mixture of beam-driven plasma-wakefield acceleration to high energy for the electrons and conventional RF acceleration to low energy for the positrons. We emphasise the benefits of asymmetric energies, asymmetric bunch charges and asymmetric transverse emittances. The implications for luminosity and experimentation at such an asymmetric facility are explored and found to be comparable to conventional facilities; the cost is found to be much lower. Some of the areas in which R&D is necessary to make HALHF a reality are highlighted, including estimates for the improvement required in key technologies. These range from a factor of 10 to a factor of 1000.

Abstract Background The lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice—an aggressive tauopathy model. Methods rTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation. Results At both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3β. Conclusions The results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer’s disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer’s disease.

Abstract Charm production in charged current deep inelastic scattering has been measured for the first time in e ± p collisions, using data collected with the ZEUS detector at HERA, corresponding to an integrated luminosity of 358 pb−1. Results are presented separately for e + p and e − p scattering at a centre-of-mass energy of s $$ \sqrt{s} $$ = 318 GeV within a kinematic phase-space region of 200 GeV2 < Q 2 < 60000 GeV2 and y < 0.9, where Q 2 is the squared four-momentum transfer and y is the inelasticity. The measured cross sections of electroweak charm production are consistent with expectations from the Standard Model within the large statistical uncertainties.

Maple Syrup Urine Disease (MSUD) is a rare inherited disorder of branched chain amino acid metabolism characterized by cerebral edema and death in uncorrected metabolic crisis. It is conventionally treated with intensive nutritional therapy to prevent and correct metabolic crisis. This paper reports the use of growth hormone as a pharmacologic rescue agent in the case of an 11-year-old male with MSUD and metabolic crisis refractory to standard interventions. The initiation of short courses of growth hormone correlated with corrected mental status, resolution of metabolic acidosis, and improvement in plasma leucine levels on two occasions during an admission to the pediatric intensive care unit. This is the first known case report of the use of growth hormone in MSUD since contemporary dietary management became available. The discussion includes a literature review of the use of growth hormone in inherited diseases of amino acid metabolism and a brief discussion of protein anabolic pharmacotherapeutic agents shown to improve net protein balance in pediatric burn patients. We propose that growth hormone and other protein anabolic agents may be valuable adjuvants to standard therapy in children with inherited metabolic disease.

Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness.

Abstract Organic semiconductors (OSCs) promise to deliver next‐generation electronic and energy devices that are flexible, scalable and printable. Unfortunately, realizing this opportunity is hampered by increasing concerns about the use of volatile organic compounds (VOCs), particularly toxic halogenated solvents that are detrimental to the environment and human health. Here, a cradle‐to‐grave process is reported to achieve high performance p‐ and n‐type OSC devices based on indacenodithiophene and diketopyrrolopyrrole semiconducting polymers that utilizes aqueous‐processes, fewer steps, lower reaction temperatures, a significant reduction in VOCs (>99%) and avoids all halogenated solvents. The process involves an aqueous mini‐emulsion polymerization that generates a surfactant‐stabilized aqueous dispersion of OSC nanoparticles at sufficient concentration to permit direct aqueous processing into thin films for use in organic field‐effect transistors. Promisingly, the performance of these devices is comparable to those prepared using conventional synthesis and processing procedures optimized for large amounts of VOCs and halogenated solvents. Ultimately, the holistic approach reported addresses the environmental issues and enables a viable guideline for the delivery of future OSC devices using only aqueous media for synthesis, purification and thin‐film processing.

Abstract Measurements of open charm and beauty production cross sections in deep inelastic ep scattering at HERA from the H1 and ZEUS Collaborations are combined. Reduced cross sections are obtained in the kinematic range of negative four-momentum transfer squared of the photon $$2.5~\hbox {GeV}^2\le Q^2 \le 2000\, \hbox {GeV}^2$$ 2.5GeV2≤Q2≤2000GeV2 and Bjorken scaling variable $$3 \cdot 10^{-5} \le x_\mathrm{Bj} \le 5 \cdot 10^{-2}$$ 3·10-5≤xBj≤5·10-2 . The combination method accounts for the correlations of the statistical and systematic uncertainties among the different datasets. Perturbative QCD calculations are compared to the combined data. A next-to-leading order QCD analysis is performed using these data together with the combined inclusive deep inelastic scattering cross sections from HERA. The running charm- and beauty-quark masses are determined as $$m_c(m_c) = 1.290^{+0.046}_{-0.041} \mathrm{(exp/fit)}$$ mc(mc)=1.290-0.041+0.046(exp/fit) $${}^{+0.062}_{-0.014} \mathrm{(model)}$$ -0.014+0.062(model) $${}^{+0.003}_{-0.031} \mathrm{(parameterisation)}$$ -0.031+0.003(parameterisation) GeV and $$m_b(m_b) = 4.049^{+0.104}_{-0.109} \mathrm{(exp/fit)}$$ mb(mb)=4.049-0.109+0.104(exp/fit) $${}^{+0.090}_{-0.032} \mathrm{(model)}$$ -0.032+0.090(model) $${}^{+0.001}_{-0.031} \mathrm{(parameterisation)}~\mathrm{GeV}$$ -0.031+0.001(parameterisation)GeV .

Abstract Isolated photons with high transverse energy have been studied in deep inelastic ep scattering with the ZEUS detector at HERA, using an integrated luminosity of 326 pb−1 in the range of exchanged-photon virtuality 10-350 GeV2. Outgoing isolated photons with transverse energy 4

Electron beams to be accelerated in beam-driven plasma wakes are commonly formed by a photocathode and externally injected into the wakefield of a preceding bunch. Alternatively, using the plasma itself as a cathode offers the possibility of generating ultrashort, low-emittance beams by trapping and accelerating electrons from the ambient plasma background. Here, we present a beam-driven plasma cathode realized via laser-triggered density-downramp injection, showing stable beam formation over more than a thousand consecutive events with an injection probability of 95%. The plasma cathode is highly tunable, resulting in the injection of electron bunches of tens of pC of charge, energies of up to 79 MeV, and relative energy spreads as low as a few percent. The stability of the injected beams was sufficiently high to experimentally determine their normalized emittance of 9.3 μm rms with a multishot method.

Combined HERA data on charm production in deep-inelastic scattering have previously been used to determine the charm-quark running mass mc(mc) in the MSâ¾ renormalisation scheme. Here, the same data are used as a function of the photon virtuality Q2 to evaluate the charm-quark running mass at different scales to one-loop order, in the context of a next-to-leading order QCD analysis. The scale dependence of the mass is found to be consistent with QCD expectations.

Two infants treated for syphilis born to at risk mothers who screened negative at their first prenatal visit but were not rescreened at delivery are described. The first presented with classic, but unrecognized, features of congenital syphilis. In the second case, possible early maternal syphilis was diagnosed soon after delivery using the treponemal first reverse-screening algorithm. Although the child’s physical exam was normal and the maternal rapid plasma reagin (RPR) negative, the child was treated for syphilis because maternal confirmatory treponemal tests suggested recent seroconversion. Given the re-emergence of congenital syphilis, our report aims to demonstrate the importance of rescreening women at increased risk and improve awareness of common manifestations of the syphilis disease in the newborn. For women at increased risk, repeat syphilis testing early in the third trimester and again at delivery in communities and populations with a high prevalence of syphilis is recommended.

A search for a narrow baryonic state in the pKS0 and p‾KS0 system has been performed in ep collisions at HERA with the ZEUS detector using an integrated luminosity of 358pb−1 taken in 2003–2007. The search was performed with deep inelastic scattering events at an ep centre-of-mass energy of 318GeV for exchanged photon virtuality, Q2, between 20 and 100GeV2. Contrary to evidence presented for such a state around 1.52 GeV in a previous ZEUS analysis using a sample of 121 pb−1 taken in 1996–2000, no resonance peak was found in the p(p‾)KS0 invariant-mass distribution in the range 1.45–1.7 GeV. Upper limits on the production cross section are set.

The exclusive deep inelastic electroproduction of ψ(2S) and J/ψ(1S) at an ep centre-of-mass energy of 317 GeV has been studied with the ZEUS detector at HERA in the kinematic range 2

The purpose of this quantitative, quasi-experimental study was to analyze whether the education of radiology personnel mandated by the American Registry of Radiologic Technologists (ARRT) affects the quality of care delivered to radiology patients. One area of radiology quality of care was focused on the findings presented in this study: radiation dosage. Three groups of study participants were used. The participants were chosen and divided into groups based on their radiology background, non-radiology medical background, or lack of medical background. All study participants were required to complete an assessment asking participants what radiation dosage and shields they would use for a standard set of radiographic examinations. A training video was shown to those participants with no radiology background prior to the assessment. The data provided by each group was compared to determine similarities and variances between the groups and ANOVA calculations were completed. Differences were found between the assessments completed by members of all three groups. The results support the perception that ARRT-mandated education does affect radiation dosage chosen in the care of radiology patients.