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Tomato plants are susceptible to significant yield losses when infested by the northern root-knot nematode, Meloidogyne hapla. While there are many options for conventional chemical management, few of these options offer effective control for organic growers or those who seek to adopt more environmentally considerate strategies. In this study, we showed that a new, biologically based product (referred to as “MN21.2”) has potential for controlling populations of the northern root-knot nematode, Meloidogyne hapla, as a pest of susceptible tomato (cv. Rutgers) in a greenhouse trial. This is significant because if this product’s efficacy is supported under field conditions, it may provide organic tomato growers with a valuable tool for fighting the plant-parasitic nematode pest, M. hapla.

Nicola Farina,1,2,* Giovanni Benanti,1,2,* Giacomo De Luca,1,2 Anna Palmisano,2,3 Giovanni Peretto,4 Sara Tomassetti,5 Veronica Giorgione,6 Ornella Forma,7 Antonio Esposito,2,3 Silvio Danese,2,8 Lorenzo Dagna,1,2 Marco Matucci-Cerinic,1,9 Corrado Campochiaro1,2 1Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Milan, Italy; 2School of Medicine, Vita-Salute San Raffaele University, Milan, Italy; 3Unit of Clinical and Experimental Radiology, IRCCS San Raffaele Hospital, Milan, Italy; 4Unit of Cardiac Electrophysiology and Arrhythmology, IRCCS San Raffaele Hospital, Milan, Italy; 5Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy; 6Molecular and Clinical Sciences Research Institute, Fetal Medicine Unit, Department of Obstetrics and Gynaecology, St. George’s University Hospitals NHS Foundation Trust, London, UK; 7Vulnology Nursing Service, IRCCS San Raffaele Scientific Institute, Milan, Italy; 8Unit of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Milan, Italy; 9Department of Experimental and Clinical Medicine, University of Florence and Division of Rheumatology AOUC, Florence, Italy*These authors contributed equally to this workCorrespondence: Corrado Campochiaro, Unit of Immunology, Rheumatology, Allergy and Rare Diseases, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan, 20132, Italy, Tel +39 0226437060, Fax +39 0226433729, Email campochiaro.corrado@hsr.itAbstract: Systemic sclerosis (SSc) is a rare connective tissue disease characterised by immune dysfunction, vascular damage and fibrosis affecting the skin and multiple internal organs. The clinical spectrum of SSc is wide and its manifestations may lead to severe morbidity and mortality, in addition to a great impact on patients’ quality of life. Due to the multifaceted clinical manifestations of SSc, its management requires a combined expertise of different medical specialists to guarantee an adequate disease control and prevent organ complications. Multi-disciplinary teams (MDT), which are composed by physicians and other specialized health professionals, represent therefore a key element for the comprehensive management of SSc patients. Moreover, MTD can improve communication and patients’ empowerment while the presence of dedicated nurses can help patients to ask questions about their condition. The scope of this narrative review is to analyse the available evidences regarding the role of MDT in the management of SSc patients, and how this holistic approach may improve different disease domains and the overall prognosis. MDT regarding the cardiovascular and lung complication are the more represented in literature, given the great impact in prognosis. Nonetheless, MDT have been shown to be fundamental also in other disease domains as they can intercept early manifestations, thus stratifying patients based on the individual risks in order to personalize patients’ follow-up. MDTs may also minimize the treatment delay, enabling fast-track specialist referral. On the other hand, there are few trials specifically studying MDT in SSc and several authors have highlight the lack of standardization.Keywords: systemic sclerosis, scleroderma, multidisciplinary team, shared management

BACKGROUND: Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesitys impact on EV secretion from human AT remains limited. METHODS: We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography-mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry. RESULTS: EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation. CONCLUSIONS: We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders.

INTRODUCTION: Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD: We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS: Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p

Abstract Massive stars are a major source of chemical elements in the cosmos, ejecting freshly produced nuclei through winds and core-collapse supernova explosions into the interstellar medium. Among the material ejected, long-lived radioisotopes, such as 60Fe (iron) and 26Al (aluminum), offer unique signs of active nucleosynthesis in our galaxy. There is a long-standing discrepancy between the observed 60Fe/26Al ratio by γ-ray telescopes and predictions from supernova models. This discrepancy has been attributed to uncertainties in the nuclear reaction networks producing 60Fe, and one reaction in particular, the neutron-capture on 59Fe. Here we present experimental results that provide a strong constraint on this reaction. We use these results to show that the production of 60Fe in massive stars is higher than previously thought, further increasing the discrepancy between observed and predicted 60Fe/26Al ratios. The persisting discrepancy can therefore not be attributed to nuclear uncertainties, and points to issues in massive-star models.

Abstract Objective Locomotion is an automated voluntary movement sustained by coordinated neural synchronization across a distributed brain network. The cerebral cortex is central for adapting the locomotion pattern to the environment and alterations of cortical network dynamics can lead to gait impairments. Gait problems are a common symptom with a still unclear pathophysiology and represent an unmet therapeutical need in Parkinson's disease. Little is known about the cortical network dynamics of locomotor control in these patients. Methods We studied the cortical basis of parkinsonian gait by combining metabolic brain imaging with high‐density EEG recordings and kinematic measurements performed at rest and during unperturbed overground walking. Results We found significant changes in functional connectivity between frontal, sensorimotor, and visuomotor cortical areas during walking as compared to resting. Specifically, hypokinetic gait was associated with poor information flow from the supplementary motor area (SMA) to precuneus and from calcarine to lingual gyrus, as well as high information flow from calcarine to cuneus. Interpretation Our findings support a role for visuomotor integration processes in PD‐related hypokinetic gait and suggest that reinforcing visual information may act as a compensatory strategy to allow SMA‐mediated feedforward locomotor control in PD.

Abstract Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER‐HCM (NCT03470545) study used a dose‐titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure‐response modeling and simulations of virtual patients, this in silico study evaluated alternative dose‐titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only. Mavacamten exposure‐response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed‐effects models. Simulations of five echocardiography‐guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure‐response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit–risk profile across CYP2C19 phenotypes had steps for down‐titration at weeks 4 and 8 (for VLVOTg

Abstract Mavacamten is a selective, allosteric, reversible cardiac myosin inhibitor that has been developed for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PopPK) model was developed to characterize mavacamten pharmacokinetics (PK) and the variation in mavacamten exposure associated with intrinsic and extrinsic factors. Data from 12 clinical studies (phases 1, 2, and 3) were used. Evaluable participants were those who had at least one mavacamten concentration measurement with associated sampling time and dosing information. The base model included key covariates: body weight, cytochrome P450 isozyme 2C19 (CYP2C19) phenotype with respect to PK, and formulation. The final model was generated using stepwise covariate testing and refinement processes. Simulations were performed to evaluate PK: apparent clearance (CL/F); apparent central and peripheral volumes of distribution; and steady‐state average, trough, and maximum concentrations. Overall, 9244 measurable PK observations from 497 participants were included. A two‐compartment model structure was selected. After stepwise covariate model building and refinement, additional covariates included were: specified mavacamten dose, omeprazole or esomeprazole administration, health/disease status, estimated glomerular filtration rate, fed status, and sex. The final PopPK model accurately characterized mavacamten concentrations. At any given dose, CYP2C19 phenotype was the most influential covariate on exposure parameters (e.g., median CL/F was reduced by 72% in CYP2C19:poor metabolizers compared with the reference participant [CYP2C19:normal metabolizer]). CL/F was also approximately 16% higher in women than in men but lower in participants receiving concomitant omeprazole or esomeprazole (by 33% and 42%, respectively) than in participants not receiving such concomitant therapy.

Abstract Background Bronchoalveolar lavage (BAL) is a common procedure for evaluation of the equine lower airways. Time to resolution of post‐BAL inflammation has not been clearly defined. Hypothesis Residual inflammation, evident by changes in immune cell populations and inflammatory cytokines, will resolve by 72 hours after BAL. Animals Six adult, healthy, institution‐owned horses. Methods Randomized, complete cross‐over design. Each horse underwent 3 paired BALs, including a baseline and then 48, 72, and 96 hours later, with a 7‐day washout between paired BALs. Each sample underwent cytological evaluation and cytokine concentrations were determined by a commercially available multiplex bead immunoassay. Statistical analysis was performed by multilevel mixed‐effects Poisson regression analysis. Data are reported as marginal means and 95% confidence interval (CI). Results Neutrophil, eosinophil and mast cell percentages were not significantly different at any time points. Macrophage percentages were higher at 72 hours (45.0 [95% CI, 41.6‐48.4]%) and 96 hours (45.3 [95% CI, 42.9‐47.7]%) vs baseline (37.4 [95% CI, 33.5‐41.4]%; P

Abstract We consider models of accidental dark matter, namely models in which the dark matter is a composite state that is stable thanks to an accidental symmetry of the theory. The fundamental constituents are vectorlike fermions, taken to be fragments of representations of the grand unifying gauge group SU(5), as well as a scalar singlet. All the new fields are charged under a new confining gauge group, which we take to be SU(N), leading to models with complex dark matter. We analyse the models in the context of SU(5) grand unification with a non-standard approach recently proposed in the literature. The advantage of including the scalar mainly resides in the fact that it allows several undesired accidental symmetries to be broken, leading to a larger set of viable models with respect to previous literature, in which only fermions (or only scalars) were considered. Moreover these models present distinct novelties, namely dark states with non-zero baryon and lepton number and the existence of composite hybrid states of fermions and scalars. We identify phenomena that are specific to the inclusion of the scalar and discuss possibilities to test this setup.