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Ventenata (Ventenata dubia) is an invasive grass species that infested rangelands in the inland Northwest, causing significant economic damage through declines in forage production. Despite its nutritional similarity to other forages such as cheatgrass in terms of CP content and NDF digestibility, its palatability for livestock is poor. The objective of this study was to investigate the role of texture and surface-bound microbes in determining palatability of ventenata-infested hay. Thirty-five weaned Charolais calves were separated into 5 treatments according to a taste-preference study that lasted for 7 d. Each animal had access to 2 feed bunks: one with a reference diet (mixed grass hay) and one with a treatment diet. The 5 treatments were the control, which was mixed grass hay used as the reference diet (CTRL); ventenata-infested hay (VENT); autoclaved mixed grass hay; autoclaved ventenata-infested hay; and pelleted ventenata-infested hay (PELT). Preference between mixed-grass hay and ventenata-infested hay was calculated such that 0% preference implies a total preference against the treatment diet, 50% preference implies an equal preference between mixed grass hay and ventenata-infested hay, and 100% preference implies a total preference for the treatment diet. Body weight gain was measured at the start and end of the experiment. Daily, intake of the reference diet and treatment diet were measured and percent preference was calculated. Among the 5 treatments, there was no difference in BW gain during the 7 d on treatment. The CTRL treatment showed no difference from 50% preference, indicating that our feed preference test worked. Calves on the VENT treatment had a preference of 19%, highlighting the poor palatability of ventenata-infested hay. Although autoclaving ventenata-infested hay made no difference to palatability, the PELT treatment increased preference to 50%, completely erasing the negative palatability of the ventenata-infested hay. Together, these results show the poor palatability of ventenata-infested hay may be due to texture of the hay and that ventenata's palatability can be improved through feed processing. [ABSTRACT FROM AUTHOR]

Following logic of the mate-availability hypothesis, females are expected to show asynchronous reproduction in those species where operational sex ratios are female-biased and under circumstances where an individual female is sexually receptive only for short durations. We show that females of the intertidal amphipod Corophium volutator are receptive to mating only for a few days following their moult and are unable to hasten onset of moulting in the presence of a male. Despitemeeting the conditions of the mate-availability hypothesis, reproduction was synchronous for female C. volutator across spatial and temporal scales relevant to mate-searching abilities of males. As such, some females are not expected to mate between moults, which coincide with their ability to mate. However, females do moult frequently (relative to males) which should increase their likelihood of mating over their lifetimes. It is unlikely that seasonal constraints, predation, or competition can account for the high degree of synchrony among breeding female amphipods. We suggest that dispersal of females or theiroffspring may constrain activity of females, as they moulted almost entirely during spring tides (although not always during the same setof spring tides). Female reproductive synchrony also has implications for reproductive behaviour of males, in particular, the possibilityof harem-defence polygyny. [ABSTRACT FROM AUTHOR]

Systemic autoinflammatory diseases (SAID) are a growing family of disorders of the innate immune system. Over the years, there have been changes in the definition, classification and nomenclature of SAID as new syndromes and pathophysiologic mechanisms continue to be described. Recognizing the clinical manifestations of SAID is important for their early diagnosis and management. The field continues to advance with potential new therapies underway., Competing Interests: Disclosure There was no financial support, grants or benefits from commercial sources utilized for the elaboration of this article. S. Nazzar Romero with Aurinia pharmaceuticals. D. McCurdy has no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pediatric antiphospholipid syndrome (APS) is characterized by autoantibodies directed against protein complexes on cellular membranes and leads to a prothrombotic, proinflammatory state. A child with APS may present with venous, arterial, or small vessel thrombosis. Other manifestations of APS include nonthrombotic manifestations, such as hematologic and neurologic symptoms. APS may be a primary condition or related to other autoimmune diseases. If APS-related thrombosis is unrecognized, the child may suffer recurrent thrombotic events after the withdrawal of anticoagulation. Thus, it is important to consider APS as a cause of thrombosis in children. Appropriate testing confirms the diagnosis and directs further care., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Mesenchymal stem cells have recently been recoined as medicinal signaling cells (MSC) for their ability to promote tissue homeostasis through immune modulation, angiogenesis and tropism. During the last 20 years, there has been a plethora of publications using MSC in adults and to lesser extent neonates on a variety of illnesses. In parts of the world, autologous and allogeneic MSCs have been purified and used to treat a range of autoimmune conditions, including graft versus host disease, Crohn's disease, multiple sclerosis, refractory systemic lupus erythematosus and systemic sclerosis. Generally, these reports are not part of stringent clinical trials but are of note for good outcomes with minimal side effects. This review is to summarize the current state of the art in MSC therapy, with a brief discussion of cell preparation and safety, insights into mechanisms of action, and a review of published reports of MSC treatment of autoimmune diseases, toward the potential application of MSC in treatment of children with severe autoimmune diseases using multicenter clinical trials and treatment algorithms., 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 © 2022 Jones and McCurdy.)

The need for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) next-generation vaccines has been highlighted by the rise of variants of concern (VoCs) and the long-term threat of emerging coronaviruses. Here, we design and characterize four categories of engineered nanoparticle immunogens that recapitulate the structural and antigenic properties of the prefusion SARS-CoV-2 spike (S), S1, and receptor-binding domain (RBD). These immunogens induce robust S binding, ACE2 inhibition, and authentic and pseudovirus neutralizing antibodies against SARS-CoV-2. A spike-ferritin nanoparticle (SpFN) vaccine elicits neutralizing titers (ID 50 > 10,000) following a single immunization, whereas RBD-ferritin nanoparticle (RFN) immunogens elicit similar responses after two immunizations and also show durable and potent neutralization against circulating VoCs. Passive transfer of immunoglobulin G (IgG) purified from SpFN- or RFN-immunized mice protects K18-hACE2 transgenic mice from a lethal SARS-CoV-2 challenge. Furthermore, S-domain nanoparticle immunization elicits ACE2-blocking activity and ID 50 neutralizing antibody titers >2,000 against SARS-CoV-1, highlighting the broad response elicited by these immunogens., Competing Interests: Declaration of interests M.G.J. and K.M. are named as inventors on international patent application WO/2021/178971 A1 entitled “Vaccines against SARS-CoV-2 and other coronaviruses.” M.G.J. is named as an inventor on international patent application WO/2018/081318 and U.S. patent 10,960,070 entitled “Prefusion coronavirus spike proteins and their use.” Z.B. is named as an inventor on U.S. patent 10,434,167 entitled “Non-toxic adjuvant formulation comprising a monophosphoryl lipid A (MPLA)-containing liposome composition and a saponin.” Z.B. and G.R.M. are named as inventors on U.S. patent application 16/607,917 entitled “Compositions and methods for vaccine delivery.” M.S.D. is a consultant for Inbios, Vir Biotechnology, Fortress Biotech, and Carnival Corporation and on the scientific advisory boards of Moderna and Immunome. The Diamond laboratory has received funding support from sponsored research agreements from Moderna, Vir Biotechnology, Kaleido, and Emergent BioSolutions. S.R., P.M.M., and M.T.E. are employees of AstraZeneca and currently hold AstraZeneca stock or stock options. Z.B. is currently employed at Pfizer., (Copyright © 2021. Published by Elsevier Inc.)

Objective: Specific risk alleles for childhood-onset systemic lupus erythematosus SLE (cSLE) vs adult-onset SLE (aSLE) patients have not been identified. The aims of this study were to determine if there is an association (1) between non-HLA-related genetic risk score (GRS) and age of SLE diagnosis, and (2) between HLA-related GRS and age of SLE diagnosis., Methods: Genomic DNA was obtained from 2001 multiethnic patients and genotyped using the Immunochip. Following quality control, genetic risk counting (GRCS), weighted (GRWS), standardized counting (GRSCS), and standardized weighted (GRSWS) scores were calculated based on independent single-nucleotide polymorphisms from validated SLE loci. Scores were analyzed in a regression model and adjusted by sex and ancestral population., Results: The analyzed cohort consisted of 1540 patients: 1351 females and 189 males (675 cSLE and 865 aSLE). There were significant negative associations between all non-HLA GRS and age of SLE diagnosis: P = 0.011 and r 2 = 0.175 for GRWS; P = 0.008 and r 2 = 0.178 for GRSCS; P = 0.002 and r 2 = 0.176 for GRSWS (higher GRS correlated with lower age of diagnosis.) All HLA GRS showed significant positive associations with age of diagnosis: P = 0.049 and r 2 = 0.176 for GRCS; P = 0.022 and r 2 = 0.176 for GRWS; P = 0.022 and r 2 = 0.176 for GRSCS; P = 0.011 and r 2 = 0.177 for GRSWS (higher GRS correlated with higher age of diagnosis)., Conclusion: Our data suggest that there is a linear relationship between genetic risk and age of SLE diagnosis and that HLA and non-HLA GRS are associated with age of diagnosis in opposite directions., (Copyright © 2021 by the Journal of Rheumatology.)

The objectives of this study were to determine the effects of the weaning transition and supplemental rumen-protected butyrate on subacute ruminal acidosis, feed intake, and growth parameters. Holstein bull calves (n = 36; age = 10.7 ± 4.1 d; ± standard deviation) were assigned to 1 of 4 treatment groups: 2 preweaning groups, animals fed milk replacer only (PRE-M) and those fed milk replacer, calf starter, and hay (PRE-S); and 2 postweaning groups, animals fed milk replacer, calf starter, and hay without supplemental rumen-protected butyrate (POST-S) or with supplemental rumen-protected butyrate at a rate of 1% wt/wt during the 2-wk weaning transition (POST-B). Milk replacer was provided at 1,200 g/d; starter, water, and hay were provided ad libitum. Weaning took place over 14 d by reducing milk replacer provision to 900 g/d in wk 7, 600 g/d in wk 8, and 0 g/d in wk 9. Rumen pH was measured continuously for 7 d during wk 6 for PRE-S and PRE-M and during wk 9 for POST-S and POST-B. After rumen pH was measured for 7 d, calves were euthanized, and rumen fluid was sampled and analyzed for volatile fatty acid (VFA) profile. Individual feed intake was recorded daily, whereas, weekly, body weights were recorded, and blood samples were collected. Compared with PRE-M, PRE-S calves tended to have a greater total VFA concentration (35.60 ± 11.4 vs. 11.90 ± 11.8 mM) but mean rumen pH was unaffected (6.25 ± 0.22 vs. 6.17 ± 0.21, respectively). Between PRE-S (wk 6) and POST-S (wk 9), calf starter intake increased (250 ± 219 vs. 2,239 ± 219 g/d), total VFA concentrations increased (35.6 ± 11.4 vs. 154.4 ± 11.8 mM), but mean rumen pH was unaffected (6.25 ± 0.22 vs. 6.40 ± 0.22, respectively). Compared with POST-S, POST-B calves had greater starter intake in wk 7, 8, and 9, but POST-B tended to have lower total VFA concentration (131.0 ± 11.8 vs. 154.4 ± 11.8 mM) and lower mean ruminal pH (5.83 ± 0.21 vs. 6.40 ± 0.22). In conclusion, the weaning transition does not appear to affect rumen pH and VFA profile, but supplementing rumen-protected butyrate during the weaning transition increased starter intake and average daily gain. Further, these data suggest that the ability of the rumen to manage rumen pH changes fundamentally postweaning. Why weaned calves with lower rumen pH can achieve higher calf starter intakes is unclear; these data suggest the effect of rumen pH on feed intake differs between calves and cows., (Copyright © 2019 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Transgenic mice expressing the Notch-4 intracellular domain (designated Int3) in the mammary gland have two phenotypes exhibited with 100% penetrance: arrest of mammary alveolar/lobular development and mammary tumorigenesis. Notch-4 signaling is mediated primarily through the interaction of Int3 with the transcription repressor/activator Rbpj. Interestingly, WAP-Int3/Rbpj knockout mice have normal mammary gland development but still developed mammary tumors with a slightly longer latency than the WAP-Int3 mice. Thus, Notch-induced mammary tumor development is Rbpj-independent. Here, we show that Int3 activates NF-κB in HC11 cells in absence of Rbpj through an association with the IKK signalosome. Int3 induced the canonical NF-κB activity and P50 phosphorylation in HC11 cells without altering the NF-κB2 pathway. The minimal domain within the Int3 protein required to activate NF-κB consists of the CDC10/Ankyrin (ANK) repeats domain. Treatment of WAP-Int3 tumor bearing mice with an IKK inhibitor resulted in tumor regression. In a soft agar assay, treatment of HC11-Int3 cells with P50-siRNA caused a significant decrease in colony formation. In addition, Wap-Int3/P50 knockout mice did not develop mammary tumors. This data indicates that the activation of NF-κB canonical signaling by Notch-4/Int3 is ANK repeats dependent, Rbpj-independent, and is mediated by IKK activation and P50 phosphorylation causing mammary tumorigenesis.

Objective: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA)., Methods: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons., Results: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil., Conclusion: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding., (© 2016, American College of Rheumatology.)

Cripto-1, a member of the epidermal growth factor-Cripto-1/FRL-1/Cryptic family, is critical for early embryonic development. Together with its ligand Nodal, Cripto-1 has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Several studies have clearly shown that Cripto-1 is involved in regulating branching morphogenesis and epithelial-mesenchymal transition of the mammary gland both in vitro and in vivo and together with the cofactor GRP78 is critical for the maintenance of mammary stem cells ex vivo. Our previous studies showed that mammary-specific overexpression of human Cripto-1 exhibited dramatic morphological alterations in nulliparous mice mammary glands. The present study shows a novel mechanism for Cripto-1 regulation of mammary gland development through direct effects on progesterone receptor expression and pathways regulated by progesterone in the mammary gland. We demonstrate a strict temporal regulation of mouse Cripto-1 (mCripto-1) expression that occurs during mammary gland development and a stage-specific function of mCripto-1 signaling during mammary gland development. Our data suggest that Cripto-1, like the progesterone receptor, is not required for the initial ductal growth but is essential for subsequent side branching and alveologenesis during the initial stages of pregnancy. Dissection of the mechanism by which this occurs indicates that mCripto-1 activates receptor activator NF-κB/receptor activator NF-κB ligand, and NF-κB signaling pathways., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH-2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)-associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection., Methods: International pediatric rheumatologists and hemato-oncologists were asked to retrospectively collect clinical information from patients with systemic JIA-associated MAS and confusable conditions. The ability of the guidelines to differentiate MAS from the control diseases was evaluated by calculating the sensitivity and specificity of each set of guidelines and the kappa statistics for concordance with the physician's diagnosis. Owing to the fact that not all patients were assessed for hemophagocytosis on bone marrow aspirates and given the lack of data on natural killer cell activity and soluble CD25 levels, the HLH-2004 guidelines were adapted to enable the diagnosis of MAS when 3 of 5 of the remaining items (3/5-adapted) or 4 of 5 of the remaining items (4/5-adapted) were present., Results: The study sample included 362 patients with systemic JIA and MAS, 404 patients with active systemic JIA without MAS, and 345 patients with systemic infection. The best capacity to differentiate MAS from systemic JIA without MAS was found when the preliminary MAS guidelines were applied. The 3/5-adapted HLH-2004 guidelines performed better than the 4/5-adapted guidelines in distinguishing MAS from active systemic JIA without MAS. The 3/5-adapted HLH-2004 guidelines and the preliminary MAS guidelines with the addition of ferritin levels ≥500 ng/ml discriminated best between MAS and systemic infections., Conclusion: The preliminary MAS guidelines showed the strongest ability to identify MAS in systemic JIA. The addition of hyperferritinemia enhanced their capacity to differentiate MAS from systemic infections. The HLH-2004 guidelines are likely not appropriate for identification of MAS in children with systemic JIA., (Copyright © 2014 by the American College of Rheumatology.)

Mesenchymal stem cells (MSCs) are being tested in a wide range of human diseases; however, loss of potency and inconsistent quality severely limit their use. To overcome these issues, we have utilized a developmental precursor called the hemangioblast as an intermediate cell type in the derivation of a highly potent and replenishable population of MSCs from human embryonic stem cells (hESCs). This method circumvents the need for labor-intensive hand-picking, scraping, and sorting that other hESC-MSC derivation methods require. Moreover, unlike previous reports on hESC-MSCs, we have systematically evaluated their immunomodulatory properties and in vivo potency. As expected, they dynamically secrete a range of bioactive factors, display enzymatic activity, and suppress T-cell proliferation that is induced by either allogeneic cells or mitogenic stimuli. However, they also display unique immunophenotypic properties, as well as a smaller size and >30,000-fold proliferative capacity than bone marrow-derived MSCs. In addition, this is the first report which demonstrates that hESC-MSCs can inhibit CD83 up-regulation and IL-12p70 secretion from dendritic cells and enhance regulatory T-cell populations induced by interleukin 2 (IL-2). This is also the first report which shows that hESC-MSCs have therapeutic efficacy in two different autoimmune disorder models, including a marked increase in survival of lupus-prone mice and a reduction of symptoms in an autoimmune model of uveitis. Our data suggest that this novel and therapeutically active population of MSCs could overcome many of the obstacles that plague the use of MSCs in regenerative medicine and serve as a scalable alternative to current MSC sources.

Adults recovered from Anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)