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Abstract Fish habitat temperatures are increasing due to human impacts including climate change. For broadly distributed species, thermal tolerance can vary at the population level, making it challenging to predict which populations are most vulnerable to warming. Populations inhabiting warm range boundaries may be more resilient to these changes due to adaptation or acclimatization to warmer temperatures, or they may be more vulnerable as temperatures may already approach their physiological limits. We tested functional and critical thermal tolerance of two populations of wild Oncorhynchus mykiss near the species’ southern range limit and, as predicted, found population-specific responses to temperature. Specifically, the population inhabiting the warmer stream, Piru Creek, had higher critical thermal maxima and higher functional thermal tolerance compared to the population from the cooler stream, Arroyo Seco. Arroyo Seco O. mykiss are more likely to experience a limitation of aerobic scope with warming. Piru Creek O. mykiss, however, had higher resting metabolic rates and prolonged exercise recovery, meaning that they could be more vulnerable to warming if prey or dissolved oxygen become limited. Temperature varies widely between streams near the O. mykiss southern range limit and populations will likely have unique responses to warming based on their thermal tolerances and metabolic requirements.

Falling asleep at the wrong time can place an individual at risk of immediate physical harm. However, not sleeping degrades cognition and adaptive behavior. To understand how animals match sleep need with environmental demands, we used live-brain imaging to examine the physiological response properties of the dorsal fan-shaped body (dFB) following interventions that modify sleep (sleep deprivation, starvation, time-restricted feeding, memory consolidation) in Drosophila. We report that dFB neurons change their physiological response-properties to dopamine (DA) and allatostatin-A (AstA) in response to different types of waking. That is, dFB neurons are not simply passive components of a hard-wired circuit. Rather, the dFB neurons intrinsically regulate their response to the activity from upstream circuits. Finally, we show that the dFB appears to contain a memory trace of prior exposure to metabolic challenges induced by starvation or time-restricted feeding. Together, these data highlight that the sleep homeostat is plastic and suggests an underlying mechanism. Falling asleep at the wrong time can be dangerous. This study shows that both time-restricted feeding and acute starvation enhance subsequent waking by reducing sleep drive. Thus, internal state modulates sleep-promoting neurons to help animals maintain wakefulness in life-threatening conditions.

The Kuroshio Current System in the North Pacific displays path transitions on a decadal timescale. It is known that both internal variability involving barotropic and baroclinic instabilities and remote Rossby waves induced by North Pacific wind stress anomalies are involved in these path transitions. However, the precise coupling of both processes and its consequences for the dominant decadal transition timescale are still under discussion. Here, we analyse the output of a multi-centennial high-resolution global climate model simulation and study phase synchronisation between Pacific zonal wind stress anomalies and Kuroshio Current System path variability. We apply the Hilbert transform technique to determine the phase and find epochs where such phase synchronisation appears. The physics of this synchronisation are shown to occur through the effect of the vertical motion of isopycnals, as induced by the propagating Rossby waves, on the instabilities of the Kuroshio Current System.

Circadian rhythms help animals synchronize motivated behaviors to match environmental demands. Recent evidence indicates that clock neurons influence the timing of behavior by differentially altering the activity of a distributed network of downstream neurons. Downstream circuits can be remodeled by Hebbian plasticity, synaptic scaling, and, under some circumstances, activity-dependent addition of cell surface receptors; the role of this receptor respecification phenomena is not well studied. We demonstrate that high sleep pressure quickly reprograms the wake-promoting large ventrolateral clock neurons to express the pigment dispersing factor receptor (PDFR). The addition of this signaling input into the circuit is associated with increased waking and early mating success. The respecification of PDFR in both young and adult large ventrolateral neurons requires 2 dopamine (DA) receptors and activation of the transcriptional regulator nejire (cAMP response element-binding protein [CREBBP]). These data identify receptor respecification as an important mechanism to sculpt circuit function to match sleep levels with demand.

Extreme-ultraviolet to x-ray free-electron lasers (FELs) in operation for scientific applications are up to now single-user facilities. While most FELs generate around 100 photon pulses per second, FLASH at DESY can deliver almost two orders of magnitude more pulses in this time span due to its superconducting accelerator technology. This makes the facility a prime candidate to realize the next step in FELs—dividing the electron pulse trains into several FEL lines and delivering photon pulses to several users at the same time. Hence, FLASH has been extended with a second undulator line and self-amplified spontaneous emission (SASE) is demonstrated in both FELs simultaneously. FLASH can now deliver MHz pulse trains to two user experiments in parallel with individually selected photon beam characteristics. First results of the capabilities of this extension are shown with emphasis on independent variation of wavelength, repetition rate, and photon pulse length.

The evolution of the Antarctic Ice Sheet is of vital importance given the coastal and societal implications of ice loss, with a potential to raise sea level by up to 58 m if it melts entirely. However, future ice-sheet trajectories remain highly uncertain. One of the main sources of uncertainty is related to nonlinear processes and feedbacks between the ice sheet and the Earth System on different timescales. Due to these feedbacks and ice-sheet inertia, ice loss may already be triggered in the next decades or centuries and will then unfold thereafter on timescales on the order of multiple centuries to millennia. This committed Antarctic sea-level contribution is not reflected in typical sea-level projections based on mass balance changes of the Antarctic Ice Sheet, which often cover decadal-to-centennial timescales. Here, using two ice-sheet models, we systematically assess the long-term multi-millennial sea-level commitment from Antarctica in response to warming projected over the next centuries under low- and high-emission pathways. This allows us to bring together the time horizon of stakeholder planning and the much longer response times of the Antarctic Ice Sheet. Our results show that warming levels representative of the lower-emission pathway, SSP1-2.6, may already result in an Antarctic mass loss of up to 6 m of sea-level equivalent on multi-millennial timescales. This committed mass loss is due to a strong grounding-line retreat in the West Antarctic Amundsen Sea embayment as well as potential drainage from the Ross Ice Shelf catchment and onset of ice loss from Wilkes subglacial basin in East Antarctica. Beyond the warming levels reached by the end of this century under the higher-emission trajectory, SSP5-8.5, a collapse of the West Antarctic Ice Sheet is triggered in the entire ensemble of simulations from both ice-sheet models. Under enhanced warming, next to ice loss from the marine subglacial basins, we also find a substantial decline in ice volume grounded above sea level in East Antarctica. Over the next millennia, this gives rise to a sea-level increase of up to 40 m in our simulations, stressing the importance of including the committed Antarctic sea-level contribution in future projections.

The Greenland Ice Sheet (GIS) and Atlantic Meridional Overturning Circulation (AMOC) are considered tipping elements in the climate system, where global warming exceeding critical threshold levels in forcing can lead to large-scale and nonlinear reductions in ice volume and overturning strength, respectively. The positive–negative feedback loop governing their interaction with a destabilizing effect on the AMOC due to ice loss and subsequent freshwater flux into the North Atlantic as well as a stabilizing effect of a net cooling around Greenland with an AMOC weakening may determine the long-term stability of both tipping elements. Here we explore the potential dynamic regimes arising from this positive–negative tipping feedback loop in a physically motivated conceptual model. Under idealized forcing scenarios we identify conditions under which different kinds of tipping cascades can occur: herein, we distinguish between overshoot/bifurcation tipping cascades, leading to tipping of both GIS and AMOC, and rate-induced tipping cascades, where the AMOC, despite not having crossed its own intrinsic tipping point, tips nonetheless due to the fast rate of ice loss from Greenland. The occurrence of these different cascades is affected by the ice sheet disintegration time and thus eventually by the imposed forcing and its timescales. Our results suggest that it is necessary not only to avoid surpassing the respective critical levels of the environmental drivers for the Greenland Ice Sheet and Atlantic Meridional Overturning Circulation, but also to respect safe rates of environmental change to mitigate potential domino effects.

We use an observationally calibrated ice-sheet model to investigate the future trajectory of the Antarctic ice sheet related to uncertainties in the future balance between sub-shelf melting and ice discharge, on the one hand, and the surface mass balance, on the other. Our ensemble of simulations, forced by a panel of climate models from the sixth phase of the Coupled Model Intercomparison Project (CMIP6), suggests that the ocean will be the primary driver of short-term Antarctic mass loss, initiating ice loss in West Antarctica already during this century. The atmosphere initially plays a mitigating role through increased snowfall, leading to an Antarctic contribution to global mean sea-level rise by 2100 of 6 (−8 to 15) cm under a low-emission scenario and 5.5 (−10 to 16) cm under a very high-emission scenario. However, under the very high-emission pathway, the influence of the atmosphere shifts beyond the end of the century, becoming an amplifying driver of mass loss as the ice sheet's surface mass balance decreases. We show that this transition occurs when Antarctic near-surface warming exceeds a critical threshold of +7.5 ∘C, at which the increase in surface runoff outweighs the increase in snow accumulation, a signal that is amplified by the melt–elevation feedback. Therefore, under the very high-emission scenario, oceanic and atmospheric drivers are projected to result in a complete collapse of the West Antarctic ice sheet along with significant grounding-line retreat in the marine basins of the East Antarctic ice sheet, leading to a median global mean sea-level rise of 2.75 (6.95) m by 2300 (3000). Under a more sustainable socio-economic pathway, we find that the Antarctic ice sheet may still contribute to a median global mean sea-level rise of 0.62 (1.85) m by 2300 (3000). However, the rate of sea-level rise is significantly reduced as mass loss is likely to remain confined to the Amundsen Sea Embayment, where present-day climate conditions seem sufficient to commit to a continuous retreat of Thwaites Glacier.

Climate tipping elements are large-scale subsystems of the Earth that may transgress critical thresholds (tipping points) under ongoing global warming, with substantial impacts on the biosphere and human societies. Frequently studied examples of such tipping elements include the Greenland Ice Sheet, the Atlantic Meridional Overturning Circulation (AMOC), permafrost, monsoon systems, and the Amazon rainforest. While recent scientific efforts have improved our knowledge about individual tipping elements, the interactions between them are less well understood. Also, the potential of individual tipping events to induce additional tipping elsewhere or stabilize other tipping elements is largely unknown. Here, we map out the current state of the literature on the interactions between climate tipping elements and review the influences between them. To do so, we gathered evidence from model simulations, observations, and conceptual understanding, as well as examples of paleoclimate reconstructions where multi-component or spatially propagating transitions were potentially at play. While uncertainties are large, we find indications that many of the interactions between tipping elements are destabilizing. Therefore, we conclude that tipping elements should not only be studied in isolation, but also more emphasis has to be put on potential interactions. This means that tipping cascades cannot be ruled out on centennial to millennial timescales at global warming levels between 1.5 and 2.0 ∘C or on shorter timescales if global warming surpassed 2.0 ∘C. At these higher levels of global warming, tipping cascades may then include fast tipping elements such as the AMOC or the Amazon rainforest. To address crucial knowledge gaps in tipping element interactions, we propose four strategies combining observation-based approaches, Earth system modeling expertise, computational advances, and expert knowledge.

Streptococcus suis ( S. suis ) is a major porcine pathogen. Some strains have a substantial zoonotic potential such as serotype ( cps ) 14 as the second most important cps in human infections. To this date no licensed S. suis vaccine is available in Europe though subunit vaccines and bacterins have been examined by several scientific groups worldwide. Objectives of this study were to determine protective efficacy of rIde Ssuis vaccination against intranasal S. suis cps 14 challenge in conventional weaned piglets and to investigate additionally immunogenicity of rIde Ssuis vaccination in cesarean-derived colostrum-deprived (CDCD) piglets. Immunization led to reduction of bacterial multiplicity in porcine blood and delayed onset of clinical signs of cps 14 disease in conventional rIde Ssuis -vaccinated piglets. However, significant differences were not recorded which might be related to comparable low anti-Ide Ssuis antibody levels and insufficient neutralization of IgM protease activity in this animal experiment. In contrast, immunization of cesarean-derived colostrum-deprived piglets with rIde Ssuis resulted in high α-rIde Ssuis IgG antibody levels and a highly significant reduction of the survival factor of the cps 14 challenge strain in porcine blood in vitro . In conclusion, the results of this study indicate bactericidal immunity against S. suis cps 14 by Ide Ssuis specific immunity., Competing Interests: Research of CGB was funded by CEVA Innovations GmbH. CGB is the inventor of a patent for a vaccine composition including IdeSsuis (e.g. US Patent # 12,036,275). The assignee of this patent is Ceva Santé Animale S.A. (Libourne)., (© 2024 The Authors. Published by Elsevier Ltd.)

Introduction: Barriers to pre-exposure prophylaxis (PrEP) access have limited its reach to priority populations. Community-based mobile clinics have potential to broaden PrEP engagement. We evaluated reach and persistence for fixed and mobile clinic cohorts in Miami-Dade County, Florida., Methods: This observational cohort study analysed data from 1896 clients engaged through our fixed or mobile clinic from August 2018 to March 2023. Services were offered at no cost to clients. The same staff and package of barrier-lowering strategies was deployed across fixed and mobile clinic sites. Chi-square and Fisher's exact test or the Kruskal-Wallis test were used to test for differences in characteristics across sites as well as across services sought. Kaplan-Meier curves were generated to evaluate persistence on PrEP and in care, defined as completion of at least one clinic visit (including PrEP prescribing, for PrEP persistence, or for any reason, for persistence in care) within 24 weeks of the prior visit. Cox proportional hazards models were used to evaluate risk factors for discontinuation of PrEP or clinic care by 48 weeks by gender, race, ethnicity, insurance status and site., Results: The fixed and mobile clinics reached 781 and 1109 clients, respectively, during the study period. The median client age was 35 years; the majority (70.4%) of clients were cisgender men, identified as Hispanic/Latino (62.5%) and were men who have sex with men (54.5%). The mobile clinic extended reach to a higher proportion of cisgender women (32.1% mobile vs. 12.9% for fixed clinic), Black clients (34.5% vs. 13.1%) and older clients (median 37 vs. 33 years) compared with the fixed setting. Uninsured individuals, men and those who initiated services in the mobile clinic were more likely to continue PrEP to 48 weeks (HR: 1.20, p = 0.01; HR: 2.02, p<0.01; HR: 1.68, p<0.01, respectively). Persistence did not differ by race or ethnicity., Conclusions: A mobile clinic strategy for PrEP engagement can increase reach to key populations underrepresented in HIV prevention care including cisgender women and Black clients. Persistence in PrEP was increased for the mobile clinic cohort, suggesting an additional benefit to this modality beyond other barrier-lowering strategies employed in our fixed and mobile clinics., (© 2024 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of International AIDS Society.)

The prognosis for children with recurrent and/or refractory neuroblastoma (NB) is dismal. The receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is highly expressed on the surface of NB cells, provides a potential target for novel immunotherapeutics. Anti-ROR1 chimeric antigen receptor engineered ex vivo expanded peripheral blood natural killer (anti-ROR1 CAR exPBNK) cells represent this approach. N-803 is an IL-15 superagonist with enhanced biological activity. In this study, we investigated the in vitro and in vivo anti-tumor effects of anti-ROR1 CAR exPBNK cells with or without N-803 against ROR1 + NB models. Compared to mock exPBNK cells, anti-ROR1 CAR exPBNK cells had significantly enhanced cytotoxicity against ROR1 + NB cells, and N-803 further increased cytotoxicity. High-dimensional analysis revealed that N-803 enhanced Stat5 phosphorylation and Ki67 levels in both exPBNK and anti-ROR1 CAR exPBNK cells with or without NB cells. In vivo, anti-ROR1 CAR exPBNK plus N-803 significantly ( p  < 0.05) enhanced survival in human ROR1 + NB xenografted NSG mice compared to anti-ROR1 CAR exPBNK alone. Our results provide the rationale for further development of anti-ROR1 CAR exPBNK cells plus N-803 as a novel combination immunotherapeutic for patients with recurrent and/or refractory ROR1 + NB., Competing Interests: This was presented in part at Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (2019). M.S.C. has served as a consultant for Jazz Pharmaceuticals, Omeros Pharmaceuticals, Servier Pharmaceuticals, Abbvie, and Novartis Pharmaceuticals; Speakers Bureau for Jazz Pharmaceuticals, Servier Pharmaceuticals, Amgen, Inc., Sanofi, and Sobi; Advisory Board for Astra Zeneca; and research funding from Celularity, Merck, Miltenyi Biotec, Servier, Omeros, Jazz, and Janssen. D.A.L. reports personal fees and other from Kiadis Pharma, CytoSen Therapeutics, Courier Therapeutics, and Caribou Biosciences outside the submitted work. In addition, D.A.L. has a patent broadly related to NK cell therapy of cancer with royalties paid to Kiadis Pharma. T.P.C. recently served as a one-time consultant to Blueprint, Incyte, Oncopeptides, DSMB chair for SpringWorks, and is a cofounder of Vironexis Biotherapeutics, Inc., (© 2024 The Authors.)

Background: Direct cardiac reprogramming is currently being investigated for the generation of cells with a true cardiomyocyte (CM) phenotype. Based on the original approach of cardiac transcription factor-induced reprogramming of fibroblasts into CM-like cells, various modifications of that strategy have been developed. However, they uniformly suffer from poor reprogramming efficacy and a lack of translational tools for target cell expansion and purification. Therefore, our group has developed a unique approach to generate proliferative cells with a pre-CM phenotype that can be expanded in vitro to yield substantial cell doses., Methods: Cardiac fibroblasts were reprogrammed toward CM fate using lentiviral transduction of cardiac transcriptions factors (GATA4, MEF2C, TBX5, and MYOCD). The resulting cellular phenotype was analyzed by RNA sequencing and immunocytology. Live target cells were purified based on intracellular CM marker expression using molecular beacon technology and fluorescence-activated cell sorting. CM commitment was assessed using 5-azacytidine-based differentiation assays and the therapeutic effect was evaluated in a mouse model of acute myocardial infarction using echocardiography and histology. The cellular secretome was analyzed using mass spectrometry., Results: We found that proliferative CM precursor-like cells were part of the phenotype spectrum arising during direct reprogramming of fibroblasts toward CMs. These induced CM precursors (iCMPs) expressed CPC- and CM-specific proteins and were selectable via hairpin-shaped oligonucleotide hybridization probes targeting Myh6/7-mRNA-expressing cells. After purification, iCMPs were capable of extensive expansion, with preserved phenotype when under ascorbic acid supplementation, and gave rise to CM-like cells with organized sarcomeres in differentiation assays. When transplanted into infarcted mouse hearts, iCMPs prevented CM loss, attenuated fibrotic scarring, and preserved ventricular function, which can in part be attributed to their substantial secretion of factors with documented beneficial effect on cardiac repair., Conclusions: Fibroblast reprogramming combined with molecular beacon-based cell selection yields an iCMP-like cell population with cardioprotective potential. Further studies are needed to elucidate mechanism-of-action and translational potential., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Aims: High epicardial adipose tissue (EAT) attenuation is a key characteristic of adipose tissue dysfunction and associated with coronary artery disease (CAD). As little is known about the modulation of EAT attenuation by metabolic disorders, we investigated the association between EAT attenuation and CAD risk factors, CAD presence and CAD severity in type 2 diabetes mellitus (T2DM) patients., Methods: We included 276 inpatients with T2DM and 305 control patients with normal glucose metabolism (NGM), who underwent cardiac computed tomography angiography (CCTA) and coronary artery calcium (CAC) scoring. EAT attenuation and volume were evaluated by contrast-enhanced CCTA image analysis. Furthermore, segment stenosis scores (SSSs) of the left main coronary artery (LMCA), left anterior descending artery (LAD), left circumflex artery (LCX), right coronary artery (RCA), diagonal/intermediate branch (D/I) and obtuse marginal branch (OM) were calculated to assess CAD severity., Results: T2DM patients showed higher significant CAC scores, coronary plaque prevalence, total SSSs and LMCA-SSSs, LAD-SSSs, LCX-SSSs, RCA-SSSs and D/I-SSSs compared with NGM controls. In contrast to NGM controls, EAT volume was significantly increased in T2DM patients, whereas EAT attenuation was similar. In T2DM patients, EAT attenuation was associated with discrete CAD risk factors, the presence of coronary and triple-vessel plaques, as well as LAD-SSSs, LCX-SSSs, RCA-SSSs and total SSSs. In addition, EAT attenuation was only associated with the total SSS of calcified plaques, but not with noncalcified plaques., Conclusion: In T2DM patients, high EAT attenuation is associated with the presence and severity of CAD in general and with coronary stenosis caused by calcified plaques in particular., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Monitoring peri-operative body temperature in children is currently mainly achieved through invasive devices. The Temple Touch Pro Temperature Monitoring System estimates core temperature noninvasively based on heat flux thermometry., Objective: To investigate the agreement of this noninvasive sensor against standard oesophageal core temperature., Design: A prospective observational study., Setting: University hospital recruiting between April and July 2021., Patients: One hundred children (32 girls) aged 6 years or younger scheduled for noncardiac surgery, resulting in 6766 data pairs. Exclusion criteria were contraindication for the insertion of an oesophageal temperature probe, and procedures in which one of the measurement methods would interfere with the surgical field., Main Outcome Measures: Primary outcome was the agreement analysis by a Bland-Altman comparison with multiple measurements. Posthoc, we performed another agreement analysis after exclusion of a statistically determined equilibration time. Secondary outcomes were the temperature differences over time and subgroup analysis of hypothermic, normothermic and hyperthermic temperature ranges, age, sex and sensor's side by type III analysis of variance. Further, we correlated the sonographically determined depth of the artery with trueness., Results: The mean difference was -0.07°C (95% CI -0.15 to +0.05) with limits of agreement of -1.00 and +0.85°C. After adjusting for an equilibration time of 13 min, the mean difference improved to -0.04°C (95% CI -0.08 to +0.01) with limits of agreement of -0.68 and +0.60°C. Concordance correlation coefficient was 0.83 (95% CI 0.82 to 0.84). Differences between the skin sensor and oesophageal reference increased over time by -0.05°C per hour. Subgroup analysis showed no clinically relevant differences. Depth of artery negatively correlated with trueness by 0.03°C per millimetre., Conclusions: Although the Temple Touch Pro sensor showed acceptable accuracy after allowing for an equilibration time, it still needs further investigation for routine use in children. This particularly affects accuracy in hypothermic ranges, imprecise positioning and applicability in children with immature or vulnerable skin., Trial Registration: German Clinical Trials Register, identifier: DRKS00024703., (Copyright © 2023 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: Maintenance of normothermia is an important quality metric in pediatric anesthesia. While inadvertent hypothermia is effectively prevented by forced-air warming, this therapeutic approach can lead to iatrogenic hyperthermia in young children., Aims: To estimate the influence of external warming by forced air on the development of intraoperative hyperthermia in anesthetized children aged 6 years or younger., Methods: We pooled data from two previous clinical studies. Primary outcome was the course of core temperature over time analyzed by a quadratic regression model. Secondary outcomes were the incidence of hyperthermia (body core temperature >38°C), the probability of hyperthermia over the duration of warming in relation to age and surface-area-to-weight ratio, respectively, analyzed by multiple logistic regression models. The influence of baseline temperature on hyperthermia was estimated using a Cox proportional hazards model., Results: Two hundred children (55 female) with a median age of 2.1 [1 st -3 rd quartile 1-4.2] years were analyzed. Mean temperature increased by 0.43°C after 1 h, 0.64°C after 2 h, and reached a peak of 0.66°C at 147 min. Overall, 33 children were hyperthermic at at least one measurement point. The odds ratios of hyperthermia were 1.14 (95%-CI: 1.07-1.22) or 1.13 (95%-CI: 1.06-1.21) for every 10 min of warming therapy in a model with age or surface-area-to weight ratio (ceteris paribus), respectively. Odds ratio was 1.33 (95%-CI: 1.07-1.71) for a decrease of 1 year in age and 1.63 (95%-CI: 0.93-2.83) for an increase of 0.01 in the surface-to-weight-area ratio (ceteris paribus). An increase of 0.1°C in baseline temperature increased the hazard of becoming hyperthermic by a factor of 1.33 (95%-CI: 1.23-1.43)., Conclusions: In children, external warming by forced-air needs to be closely monitored and adjusted in a timely manner to avoid iatrogenic hyperthermia especially during long procedures, in young age, higher surface-area-to-weight ratio, and higher baseline temperature., (© 2022 The Authors. Pediatric Anesthesia published by John Wiley & Sons Ltd.)

Canine prostate cancer is classified into adenocarcinoma, transitional cell carcinoma with prostatic involvement, and mixed forms. Early metastatic spread leads to poor prognosis and limited treatment options. Masitinib is approved for the treatment of canine mast cell tumours and inhibits tyrosine kinase c-Kit, tyrosine-protein kinase Lyn (Lyn), and platelet-derived growth factor receptors alpha and beta (PDGFR-α, PDGFR-β), which are known to be expressed in canine prostate cancer. The aim of this study was to evaluate masitinib in an in vitro model consisting of cell lines from primary prostate adenocarcinoma, the associated lymph node metastasis of the same patient, and transitional cell carcinoma. To assess the suitability of the model system, the targets of masitinib were investigated by immunocytochemistry in the cell lines and by immunohistochemistry in the respective formalin-fixed, paraffin-embedded (FFPE) original neoplastic tissue. After exposure to masitinib, cell viability, cell count, apoptosis induction, and protein expression of c-Kit, Lyn, PDGFR-α, and PDGFR-β were assessed. To hedge the efficacy, two application protocols of masitinib (single application or 12-h double-dose regimen) were compared. Immunocytochemical and immunohistochemical analysis revealed increased Lyn, PDGFR-α, and PDGFR-β expression in cell lines and FFPE original neoplastic tissue compared to healthy prostate tissue. Masitinib exposure increased apoptosis, while the cell counts and cell viability decreased in a dose- and application interval-dependent manner, with increased impact in the 12-h double-dose regimen. These in vitro effects of masitinib in canine prostate cancer and associated metastasis support further in vivo research and modifications of the clinical treatment protocol in future studies., (© 2022 The Authors. Veterinary and Comparative Oncology published by John Wiley & Sons Ltd.)

Objective: As a follow-up to a previous study on the incidence, history and clinical findings of tibial neuropathy (TN), the present work aimed at describing the treatment and prognosis of this disease., Materials and Methods: Of 88 German Holstein dairy cows with unilateral (UTN, n = 71) or bilateral (BTN, n = 17) TN, 68 (56 UTN, 12 BTN) with a complete data set were analyzed. They were retrospectively assigned to one of four groups: no treatment - spontaneous healing within 48 h (Spontaneous, 5 UTN), no bandage (0Cast, 8 UTN, 3 BTN) or treatment with anti-inflammatory drugs and support bandage (StV, 3 UTN) or fiberglass cast (Cast, 40 UTN, 9 BTN). Treated cows were re-examined five times (14, 21, 28, 42 and 56 days after the first presentation). The plasma activity of creatine kinase was measured at the last re-examination in 29 cows similar to measurement at day 0., Results: The observed overall success rate of treatment of cows with UTN was considerably higher compared with untreated cows (Cast 98 % and StV 100 % vs. 0Cast 62 %). By comparison, the observed difference between treated and untreated cows with BTN was not so clear (78 % vs. 67 %). Recovering cows exhibited a calculated longer median survival time than cows that did not recover (545 d vs. 100 d). Plasma creatine kinase activities were increased initially and returned within the reference interval (434 U/l and 152 U/L) following treatment., Conclusions: Cows with ETN have an excellent prognosis provided that treatment with anti-inflammatory drugs and stabilizing bandage is administered. In cows with BTN, the prognosis depended on the type and degree of the primary injury. Loss of skin sensitivity indicated a poor prognosis. From an economic standpoint, treatment of TN is indicated provided that the prognosis is good. In cows that had healed clinically, the average survival time extended into the following lactation., Clinical Relevance: This study highlights the advantages of a support bandage for the treatment of cows with TN. Compared with other peripheral neuropathies, muscle damage appears to be of particular importance in TN., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

An important approach in tumor therapy is combining substances with different action mechanisms aiming to enhance the antineoplastic effect, decrease the therapeutic dosage, and avoid resistance mechanisms. Moreover, evaluating compounds already approved for the treatment of non-neoplastic diseases is promising for new antineoplastic therapies. Sodium dichloroacetate (DCA) reactivates oxidative phosphorylation in the cancer cell mitochondria, reducing apoptosis resistance in cancer cells. Furthermore, metformin inhibits the proliferation of tumor cells and CD133+ cancer -stem-like cells. In the present study, we evaluated the independent and synergistic effect of metformin and DCA on the metabolic activity, cell proliferation, and apoptosis of a canine prostate adenocarcinoma (Adcarc1258) and a transitional cell carcinoma cell line (TCC1506) in comparison to a primary canine fibroblast culture. Determining metformin uptake in tumor cells was performed by quantitative HPLC. Depending on the dosage, metformin as a single agent inhibited the metabolic activity and cell proliferation of the tumor cells, showing only minor effects on the fibroblasts. Furthermore, 1 mM metformin increased apoptosis over 96 h in the tumor cell lines but not in fibroblasts. Additionally, metformin uptake into the tumor cells in vitro was measurable by quantitative HPLC. Synergistic effects for the combination therapy were observed in both neoplastic cell lines as well as in the fibroblasts. Based on these results, metformin might be a promising therapeutic agent for canine urogenital tumors. Further studies on kinetics, toxicology, bioavailability, and application of metformin in dogs are necessary., Competing Interests: The authors declare that they have no competing interests.

A vaccine protecting against different Streptococcus suis serotypes is highly needed in porcine practice to improve animal welfare and reduce the use of antibiotics. We hypothesized that immunogens prominently recognized by convalescence sera but significantly less so by sera of susceptible piglets are putative protective antigens. Accordingly, we investigated immunogenicity and protective efficacy of a multicomponent vaccine including six main conserved immunogens, namely SSU0934, SSU1869, SSU0757, SSU1950, SSU1664 and SSU0187. Flow cytometry confirmed surface expression of all six immunogens in S. suis serotypes 2, 9 and 14. Although prime-booster vaccination after weaning resulted in significantly higher specific IgG levels against all six immunogens compared to the placebo-treated group, no significant differences between bacterial survival in blood from either vaccinated or control animals were recorded for serotype 2, 9 and 14 strains. Furthermore, vaccinated piglets were not protected against morbidity elicited through intranasal challenge with S. suis serotype 14. As ~50% of animals in both groups did not develop disease, we investigated putative other correlates of protection. Induction of reactive oxygen species (ROS) in blood granulocytes was not associated with vaccination but correlated with protection as all piglets with >5% ROS survived the challenge. Based on these findings we discuss that the main immunogens of S. suis might actually not be a priori good candidates for protective antigens. On the contrary, expression of immunogens that evoke antibodies that do not mediate killing of this pathogen might constitute an evolutionary advantage conserved in many different S. suis strains., (© 2021. The Author(s).)

Streptococcus suis ( S. suis ) is an important opportunistic pathogen, which can cause septicemia and meningitis in pigs and humans. Previous in vivo observations in S. suis -infected pigs revealed lesions at the choroid plexus (CP). In vitro experiments with primary porcine CP epithelial cells (PCPEC) and human CP epithelial papilloma (HIBCPP) cells demonstrated that S. suis can invade and traverse the CP epithelium, and that the CP contributes to the inflammatory response via cytokine expression. Here, next generation sequencing (RNA-seq) was used to compare global transcriptome profiles of PCPEC and HIBCPP cells challenged with S. suis serotype (ST) 2 infected in vitro , and of pigs infected in vivo . Identified differentially expressed genes (DEGs) were, amongst others, involved in inflammatory responses and hypoxia. The RNA-seq data were validated via quantitative PCR of selected DEGs. Employing Gene Set Enrichment Analysis (GSEA), 18, 28, and 21 enriched hallmark gene sets (GSs) were identified for infected HIBCPP cells, PCPEC, and in the CP of pigs suffering from S. suis ST2 meningitis, respectively, of which eight GSs overlapped between the three different sample sets. The majority of these GSs are involved in cellular signaling and pathways, immune response, and development, including inflammatory response and hypoxia. In contrast, suppressed GSs observed during in vitro and in vivo S. suis ST2 infections included those, which were involved in cellular proliferation and metabolic processes. This study suggests that similar cellular processes occur in infected human and porcine CP epithelial cells, especially in terms of inflammatory response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lauer, Scholtysik, Beineke, Baums, Klose, Valentin-Weigand, Ishikawa, Schroten, Klein-Hitpass and Schwerk.)

Rodentibacter (R.) heylii is frequently detected in laboratory rodents. Repeats in toxin (RTX) toxins are considered important virulence factors of this major murine pathogen. We evaluated the virulence of a R.heylii strain negative for all known RTX toxin genes and Muribacter (M.) muris, a commensal in mice, in experimental infections of C57BL/6 and BALB/c mice. Experimental intranasal infection with 10 8  CFU of the pnxI-, pnxII- and pnxIII- R. heylii strain resulted in 75% and 100% mortality in C57BL/6 and BALB/c mice, respectively. In early losses, multiple internal organs were infected and purulent bronchopneumonia was the main pathology. Intranasal application of M. muris did not result in mortality or severe weight loss. Immunoproteomics led to the identification of a surface-associated and specific immunogen, which was designated as R. heylii immunogen A (RhiA) and which was exclusively recognised by sera obtained from mice infected with this R. heylii pathotype. RhiA is a 262.6 kDa large protein containing long imperfect tandem repeats and C-terminal RTX consensus sequences. Immunohistochemical analysis confirmed that this R.heylii pathotype expresses RhiA in the lower respiratory tract. In summary, this study describes a specific immunogen in a virulent R. heylii, strain which is an excellent antigen for pathotype-specific serological screenings and which might carry out RTX-related functions., Competing Interests: Declaration of competing interest GVG Diagnostics is a diagnostic service provider. Felix Fingas is an employee at GVG Diagnostics., (Copyright © 2020 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)