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Background: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. Materials and methods: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. Results: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. Conclusions: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Jupiter's satellite auroral footprints are a consequence of the interaction between the Jovian magnetic field with co-rotating iogenic plasma and the Galilean moons. The disturbances created near the moons propagate as Alfv\'en waves along the magnetic field lines. The position of the moons is therefore "Alfv\'enically" connected to their respective auroral footprint. The angular separation from the instantaneous magnetic footprint can be estimated by the so-called lead angle. That lead angle varies periodically as a function of orbital longitude, since the time for the Alfv\'en waves to reach the Jovian ionosphere varies accordingly. Using spectral images of the Main Alfv\'en Wing auroral spots collected by Juno-UVS during the first forty-three orbits, this work provides the first empirical model of the Io, Europa and Ganymede equatorial lead angles for the northern and southern hemispheres. Alfv\'en travel times between the three innermost Galilean moons to Jupiter's northern and southern hemispheres are estimated from the lead angle measurements. We also demonstrate the accuracy of the mapping from the Juno magnetic field reference model (JRM33) at the completion of the prime mission for M-shells extending to at least 15RJ . Finally, we shows how the added knowledge of the lead angle can improve the interpretation of the moon-induced decametric emissions., Comment: 20 pages, 8 figures, Accepted for publication in Journal of Geophysical Research: Space Physics on 20 April 2023

An extended-release formulation of the NSAID meloxicam (MSR) is used to provide 72 h of continuous analgesia in many species, including rodents. Although standard formulations of meloxicam are frequently used in rats with no observable injection-site reactions, the potential adverse effects from MSR have not been characterized sufficiently nor has a prospective study of these effects been performed in rats. To address this deficiency, we evaluated injection-site reactions after a single subcutaneous administration of MSR (n = 16) or sterile saline (SC, n = 6) in the flank of age- and sex-matched Sprague–Dawley rats. Mass and erythema scores were measured daily for 2 wk, and injection sites were collected for histopathology after euthanasia. Rats were randomly selected for euthanasia at 7 d (n = 12) or 14 d (n = 10) after injection to capture the subacute and chronic phases of mass and erythematic lesion formation. No rats in the SC group developed lesions, whereas all 16 MSR-treated rats developed masses. The median time to first mass in the MSR treatment group was 3 d (95% CI, 2–3 d), and nearly 8 d for erythema (95% CI, 6.7–9.1 d). The trajectory of mass lesion severity showed rapid progression from score 1 at onset (day 2 or 3) to score 2 for almost all animals by day 5 or 6. Histopathology was characterized by localized inflammation with central necrosis and peripheral fibrosis, with some sections showing developing draining tracts. Given the high prevalence and severity of localized skin reactions, MSR analgesia should be considered carefully for Sprague–Dawley rats.

This paper reports on flow visualisation and surface pressure measurements over the upper surface of a blunt-edged delta wing model at high angles of attack. The flow structure above the upper surface of the blunt-edged delta wing was found to be different compared to delta wing with sharp leading edge. The flow becomes more complicated especially in the leading edge region of the wing. Currently, there is no data available to verify if the primary vortex could reach the apex of the wing when the angle of attack is further increased. Most prior experiments were performed at the angles of attack, α, below 23° with only a few experiments that had gone to α = 27°. These prior experiments and some CFD works stipulated that the attached flow continue to exist in the apex region of the delta wing even at very high angles of attack above 23°. In order to verify this hypothesis, several experiments at high angles of attack were conducted in Universiti Teknologi Malaysia Low Speed wind Tunnel (UTM–LST), using a specially constructed VFE2 wing model equipped with blunt leading edges. This series of experiments employed two measurement techniques; the first was the long tuft flow visualisation method, followed by surface pressure measurements. The experiments were performed at Reynolds numbers of 1.0×106 and 1.5×106. During these experiments, several interesting flow characteristics were observed at high angles of attack, mainly that the flow became more sensitive to changes in Reynolds number and the angles of attack of the wing. When the Reynolds number increased from 1×106 to 1.5×106, the upstream progression of the initial point of the main vortex was relatively delayed compared to the sharp-edged delta wing. The experiments also showed that the flow continued to be attached in the apex region up to α = 27º.

Aging pet cats can spontaneously develop Ab deposition and tauopathy (including neurofibrillary tangle formation) with neuronal loss in a similar distribution and with similar characteristics to Alzheimer’s disease (AD) in humans. These three major pathologies that characterize AD rarely occur spontaneously in other nonhuman animals. In addition, cats develop cognitive impairment with increasing age, and some studies show an association with neuronal lesions. These features suggest that the aging pet cat may be a more reliable spontaneously occurring model to investigate pathogenesis of, and therapeutic interventions for, AD compared to other domestic animals such as pet dogs. This review describes the unique translational potential of the domestic cat as a natural model of AD, with reference to other animal models of AD. Keywords: Alzheimer’s disease, pet cats, feline neuropathology, aging, feline cognitive dysfunction syndrome

International audience; The low-altitude, polar orbit of the Juno mission allows the Jupiter Energetic Particle Detector Instrument to view into, and resolve, the loss cone of energetic ions comprising the low-altitude extension of Jupiter's ring current ions. For regions mapping from just inside Ganymede's orbit to well beyond Ganymede's orbit, energetic ions (>50 keV H+ and >130 keV Oxygen and Sulfur ions) are strongly scattered into the loss cone and lost to the magnetosphere at the "strong diffusion limit" at essentially all times. We conclude, by arguing against magnetic curvature scattering, that the cause is waves, perhaps associated with Alfvénic variations previously documented in this equatorial region. Scattering is generally weak or nonexistent near the orbits of the moons Europa and Io, except for the regions just downstream of the corotating plasmas. For Io, we sometimes observe moderate, but not saturated, scattering within roughly 60° downstream. Significantly, scattering is weak or nonexistent just upstream of Io's position, an asymmetry echoed in some previous wave observations. A preliminary accounting of the total (longitude-averaged) scattering losses near Io's orbit yields loss rates of order 4%-5% of the strong diffusion limit for H+ and 5%-7% for heavy ions (O + S). We conclude that near Io's orbit, charge exchange losses likely dominate over scattering losses for heavy ions and for the lower energy H+ ions (roughly

C. Vastel et al., [Aims] Methanol is a ubiquitous species commonly found in the molecular interstellar medium. It is also a crucial seed species for the build-up of chemical complexity in star forming regions. Thus, understanding how its abundance evolves during the star formation process and whether it enriches the emerging planetary system is of paramount importance., [Methods] We used new data from the ALMA Large Program FAUST (Fifty AU STudy of the chemistry in the disc/envelope system of solar protostars) to study the methanol line emission towards the [BHB2007] 11 protobinary system (sources A and B), where a complex structure of filaments connecting the two sources with a larger circumbinary disc has previously been detected., [Results] Twelve methanol lines have been detected with upper energies in the [45–537] K range along with one 13CH3OH transition and one methyl formate (CH3OCHO) line blended with one of the methanol transitions. The methanol emission is compact (FWHM ~ 0.5″) and encompasses both protostars, which are separated by only 0.2″ (28 au). In addition, the overall methanol line emission presents three velocity components, which are not spatially resolved by our observations. Nonetheless, a detailed analysis of the spatial origin of these three components suggests that they are associated with three different spatial regions, with two of them close to 11B and the third one associated with 11A. A radiative transfer analysis of the methanol lines gives a kinetic temperature of [100–140] K, an H2 volume density of 106–107 cm−3 and column density of a few 1018 cm−2 in all three components with a source size of ~0.15″. Thus, this hot and dense gas is highly enriched in methanol with an abundance as high as 10−5. Using previous continuum data, we show that dust opacity can potentially completely absorb the methanol line emission from the two binary objects., [Conclusions] Although we cannot firmly exclude other possibilities, we suggest that the detected hot methanol is resulting from the shocked gas from the incoming filaments streaming towards [BHB2007] 11A and B, respectively. Higher spatial resolution observations are necessary to confirm this hypothesis., This project has received funding within the European Union’s Horizon 2020 research and innovation program from the European Research Council (ERC) for the project The Dawn of Organic Chemistry (DOC), grant agreement no. 741002, and from the Marie Sklodowska-Curie for the project Astro-Chemical Origins (ACO), grant agreement no. 811312. I.J.-S. has received partial support from the Spanish State Research Agency (project number PID2019-105552RB-C41). D.J. is supported by NRC Canada and by an NSERC Discovery Grant. S.Y. thanks the support by Grant-in-Aids from Ministry of Education, Culture, Sports, Science, and Technologies of Japan (18H05222). This paper makes use of the following ALMA data: ADS/JAO.ALMA#2018.1.01205.L. ALMA is a partnership of ESO (representing its member states), NSF (USA) and NINS (Japan), together with NRC (Canada), MOST and ASIAA (Taiwan), and KASI (Republic of Korea), in cooperation with the Republic of Chile. The Joint ALMA Observatory is operated by ESO, AUI/NRAO and NAOJ. The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc.

International audience; Jupiter's satellite auroral footprints are a manifestation of the satellite-magnetosphere interaction of the Galilean moons. Juno's polar elliptical orbit enables crossing the magnetic flux tubes connecting each Galilean moon with their associated auroral emission. Its payload allows measuring the fields and particle population in the flux tubes while remotely sensing their associated auroral emissions. During its thirtieth perijove, Juno crossed the flux tube directly connected to Ganymede's leading footprint spot, a unique event in the entire Juno prime mission. Juno revealed a highly-structured precipitating electron flux, up to 316 mW/m2, while measuring both a small perturbation in the magnetic field azimuthal component and small Poynting flux with an estimated total downward current of 4.2 ± 1.2 kA. Based on the evolution of the footprint morphology and the field and particle measurements, Juno transited for the first time through a region connected to the transhemispheric electron beam of the Ganymede footprint.

Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs each targeting different but overlapping processes. In order to determine if combining drugs previously shown to improve lifespan would have greater impact than any individuyal drug, a diet containing rapamycin at 14 ppm, acarbose at 1000 ppm, and phenylbutyrate at 1000 ppm was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice fed the cocktail diet showed a strain and gender-dependent phenotype consistent with healthy aging including decreased body fat and blood glucose, improved cognition, and increased grip strength and walking ability compared to mice fed individual drug or control diets. A cocktail diet containing ½ dosing of each compound was overall less effective than the full dose. The composite age-related lesion score of heart, lungs, liver and kidney was decreased in mice fed the cocktail diet compared to mice fed individual drug or control diets suggesting an interactive advantage of the three drugs. Senescence and inflammatory cytokine levels in kidneys from mice fed the cocktail diet were lower than in kidneys from mice fed control diet, and consistent with low expression levels in kidneys from young untreated mice, suggesting the cocktail diet delayed aging partly by senolytic and anti-inflammatory effects.

Aging is a complex process driven by seven intertwined pillars that functionally decline with increasing chronologic age. These pillars of aging include stem cell function, mitochondrial function, proteostasis, autophagy, nutrient sensing, metabolism, epigenetic control, and adaptation to stress, macromolecular damage and inflammation. All of the pillars appear to be interconnected such that a change in one, impinges upon others. With so many pillars of aging, it makes drug development to target aging processes equally complex. This leads to the notion that multiple pathways or biological processes need to be targeted to effectively prevent, delay or attenuate aging. The concept of drug combinations as a powerful anti-aging platform is intriguing but has yet to be tested systematically. Insulin function, mTOR (mammalian target of rapamycin) signaling and epigenetic regulation are well-established molecular pathways involved in the pathobiology of aging. Existing drugs that target these pathways include acarbose, rapamycin, and phenylbutyrate, respectively. Acarbose and rapamycin, used as single agents, extend the lifespan of mice. Thus, a cocktail of these drugs with different mechanisms of action would be expected to complement one another and robustly enhance a delay of aging and age-related disease not achievable with mono-therapeutic approaches. Studies to test this concept will be helpful in the development of clinical trials to enhance healthy aging.

Veronaea botryosa is a ubiquitous, dematiaceous mold capable of causing cutaneous and subcutaneous lesions in humans. In the last decade, V. botryosa has been associated with emergent systemic fungal infections in aquatic animals, including cultured sturgeon (Acipenser spp.), captive amphibians, and wild reptiles. Recently, repetitive extragenic palindromic PCR (rep-PCR) fingerprinting has demonstrated intraspecific variability among V. botryosa isolates from different clinically affected hosts and geographic regions. However, little is known regarding the pathogenic potential of the different genetic clades, and no mammalian model currently exists to investigate V. botryosa phaeohyphomycosis. In this study, we inoculated immunocompetent heterozygotic (nu/+) and immunodeficient homozygotic (nu/nu) Hsd:Athymic Nude-Fox1nu mice subcutaneously or through orogastric gavage with 1 of 3 representative V. botryosa strains that had been recovered from white sturgeon (Acipenser transmontanus), green sea turtle (Chelonia mydas), and human hosts and typed by using rep-PCR analysis. Daily mortality and morbidity were recorded, and dissemination of the fungus was investigated through culture of splenic samples and histologic analysis of the injection site, regional lymph nodes, salivary gland, spleen, liver, mesenteric lymph node, and gastrointestinal tract. No differences in survival, fungal burden, or dissemination were observed between fungal strains, routes of inoculation, or host immune status. Fungal infection was observed after subcutaneous inoculation only, was localized to the inoculation site, and was identified in both nu/nu and nu/+ mice. Fungal strain variability was not associated with virulence in a murine model of infection, and this novel mouse model of V. botryosa phaeohyphomycosis recapitulates the human clinical condition.

An understanding of early-onset mechanisms underlying age-related changes can be obtained by evaluating changes that precede frailty and end of life using histological characterization of age-related lesions. Histopathology-based information as a component of aging studies in mice can complement and add context to molecular, cellular, and physiologic data, but there is a lack of information regarding scoring criteria and lesion grading guidelines. This report describes the validation of a grading system, designated as the geropathology grading platform (GGP), which generated a composite lesion score (CLS) for comparison of histological lesion scores in tissues from aging mice. To assess reproducibility of the scoring system, multiple veterinary pathologists independently scored the same slides from the heart, lung, liver, and kidney from two different strains (C57BL/6 and CB6F1) of male mice at 8, 16, 24, and 32 months of age. There was moderate to high agreement between pathologists, particularly when agreement within a 1-point range was considered. CLS for all organs was significantly higher in older versus younger mice, suggesting that the GGP was reliable for detecting age-related pathology in mice. The overall results suggest that the GGP guidelines reliably distinguish between younger and older mice and may therefore be accurate in distinguishing between experimental groups of mice with more, or less, age-related pathology.

Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants1,2. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1-knockout mice displayed phenotypes similar to those observed upon ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes.

Naked mole-rats are highly valuable research models and popular exhibition animals at zoos worldwide. Here, we provide comprehensive descriptions of common postmortem findings of naked mole-rats from both research colonies and populations managed in zoological institutions. Included are brief reviews of their natural history and related physiologic adaptations, unique anatomical features, gross and histologic lesions of common as well as rarely reported disease processes, and discussions of possible pathogeneses with recommendations for future investigations to fill knowledge gaps. Based on postmortem data of several hundreds of naked mole-rats in managed care, it is clear that cancer is extremely rare and infectious disease is infrequently reported. However, despite relatively benign aging phenotypes in this species, several degenerative processes have been nevertheless observed in older populations of naked mole-rats. As such, some potential diet and husbandry-related issues are discussed in addition to the one of the most prominent causes of morbidity and mortality, conspecific aggression and traumas. From this review of lesions and disease, it is clear that pathology, including histopathology, is integral to better understanding mechanisms of healthy aging and cancer resistance of these extraordinary rodents.

Autophagy is essential to cell function, as it enables the recycling of intracellular constituents during starvation and in addition functions as a quality control mechanism by eliminating spent organelles and proteins that could cause cellular damage if not properly removed. Recently, we reported on Wdfy3’s role in mitophagy, a clinically relevant macroautophagic scaffold protein that is linked to intellectual disability, neurodevelopmental delay, and autism spectrum disorder. In this study, we confirm our previous report that Wdfy3 haploinsufficiency in mice results in decreased mitophagy with accumulation of mitochondria with altered morphology, but expanding on that observation, we also note decreased mitochondrial localization at synaptic terminals and decreased synaptic density, which may contribute to altered synaptic plasticity. These changes are accompanied by defective elimination of glycogen particles and a shift to increased glycogen synthesis over glycogenolysis and glycophagy. This imbalance leads to an age-dependent higher incidence of brain glycogen deposits with cerebellar hypoplasia. Our results support and further extend Wdfy3’s role in modulating both brain bioenergetics and synaptic plasticity by including glycogen as a target of macroautophagic degradation.

Aging is a complex multidimensional process of progressive decline affecting multiple organ systems by a number of processes that are still not well understood. While many studies have focused on the approach of studying aging across multiple organs, assessment of the contribution of individual organs to overall aging processes is under appreciated. The ability to study and compare organs in the context of organismal aging has been documented recently using a geropathology grading platform in laboratory mice. This concept consists of identifying and grading age-related histologic lesions within organs to generate a quantitative lesion score for each organ, which is representative of the presence and degree of organ-related pathology, and can be compared to scores from other organs examined. This geropathology approach provides a powerful tool to elucidate the basic mechanisms of aging in multiple organs, as well as the response of organs to therapeutic interventions. Furthermore, ongoing work with the concept has expanded and adapted the geropathology grading system to other preclinical animal model species that are commonly used to understand disease associated phenotypes in aging humans, ultimately adding to the utility of the concept.

Lactococcus garvieae is an emergent bacterial pathogen of salmonid fish in North America that causes acute infections particularly at water temperatures above 15°C. During 2020, L. garvieae was detected in rainbow trout, Onchorhyncus mykiss, cultured in Southern California and the Eastern Sierras. Infected fish exhibited high mortalities and nonspecific clinical signs of lethargy, erratic swimming, dark skin pigmentation, and exophthalmia. Macroscopic changes included external and internal hemorrhages, mainly in the eyes, liver, coelomic fat, intestine, and brain. Histological examination revealed splenitis, branchitis, panophthalmitis, hepatitis, enteritis, and coelomitis, with variable degrees of tissue damage among evaluated fish. Pure colonies of L. garvieae were isolated from infected trout and specific PCR primers for L. garvieae confirmed the preliminary diagnosis. Multilocus sequence analysis showed that the strains recovered from diseased trout represent a novel genetic group. Isolates were able to form biofilms within 24 h that increased their resistance to disinfection by hydrogen peroxide. Laboratory challenge methods for inducing lactococcosis in steelhead trout, O. mykiss, were evaluated by intracoelomic injection with serial dilutions of L. garvieae. The median lethal dose 21 days post challenge was ∼20 colony-forming units/fish. Experimentally infected trout presented similar clinical signs, gross changes, and microscopic lesions as those with natural disease, fulfilling Koch's postulates and demonstrating the high virulence of the recovered strains.

The sustained-release formulation of meloxicam (MSR) is a compounded NSAID that may provide pain relief for as long as 72 h after administration. MSR injection-site skin reactions have occurred in several species but have not previously been observed in mice. We investigated the development and progression of localized skin reactions after a single injection of MSR in Crl:CD1(ICR), C57BL/6J, and BALB/cJ mice. Each mouse received a subcutaneous injection of MSR (n = 60), standard-formulation meloxicam (MEL; n = 24) or saline (control; SC; n = 24) and was scored daily according to a 5-point system for erythema and mass characteristics. Mice were euthanized at either 7 or 14 d after injection and underwent postmortem analysis. MSR-treated mice had more erythematous and mass reactions than did MEL and SC mice. Mass lesions developed in 49 MSR mice (82%; 95% CI, 70% to 90%), 5 MEL animals (21%; 95% CI, 7% to 42%), and 1 SC mouse. MSR-treated BALB/cJ developed erythematous lesions less frequently than similarly treated Crl:CD1(ICR) or C57BL/6J. Lesions often were ventrolateral to the injection site. The median times to the appearance of mass and erythematous lesions were 2 d and 3 d, respectively. Histologically, the erythematous and mass reactions correlated with necrotizing to pyogranulomatous injection-site panniculitis. Inflammation severity scores at 7 and 14 d after injection were greater in the MSR-treated group than the other 2 groups. No strain- or sex-associated differences emerged except that inflammation severity scores at day 14 were higher in Crl:CD1(ICR) females than males. The character of the inflammatory response in MSR-treated mice did not differ between 7 and 14 d after injection, indicating that MSR-induced inflammation is slow to resolve. The ventral migration and delayed onset of MSR injection-site reactions could result in their being attributed to another cause or not being identified. Researchers and clinicians should be aware of the potential for slowly resolving injection-site reactions with MSR.