Pine Pitch Canker and Insects: Regional Risks, Environmental Regulation, and Practical Management Options

Producción CientíficaPine pitch canker (PPC), caused by the pathogenic fungus Fusarium circinatum (Nirenberg and O’ Donnell), is a serious threat to pine forests globally. The recent introduction of the pathogen to Southern Europe and its spread in Mediterranean region is alarming considering the immense ecological and economic importance of pines in the region. Pines in forests and nurseries can be infected, resulting in severe growth losses and mortality. The pathogen is known to spread in plants for planting and in seeds, and results from recent studies have indicated that F. circinatum may also spread through phoretic associations with certain insects. With this review, we aim to expand the current understanding of the risk of insect-mediated spread of PPC in different parts of Europe. Through the joint action of a multinational researcher team, we collate the existing information about the insect species spectrum in different biogeographic conditions and scrutinize the potential of these insects to transmit F. circinatum spores in forests and nurseries. We also discuss the impact of environmental factors and forest management in this context. We present evidence for the existence of a high diversity of insects with potential to weaken pines and disseminate PPC in Europe, including several common beetle species. In many parts of Europe, temperatures are projected to rise, which may promote the activity of several insect species, supporting multivoltinism and thus, further amplifying the risk of insect-mediated dissemination of PPC. Integrated pest management (IPM) solutions that comply with forest management practices need to be developed to reduce this risk. We recommend careful monitoring of insect populations as the basis for successful IPM. Improved understanding of environmental control of the interaction between insects, the pathogen, and host trees is needed in order to support development of bio-rational strategies to safeguard European pine trees and forests against F. circinatum in future.European Cooperation in Science and Technology (COST Action FP1406 PINESTRENGTH)Ministerio de Economía, Industria y Competitividad - Fondo Europeo de Desarrollo Regional (project AGL2015-69370-R)Portuguese Foundation for Science and Technology (contract IF/00471/2013/CP1203/CT0001)Russian Foundation for Basic Research (grant 17-04-01486)Saint Petersburg State Polytechnical University (project 2019-0420

Selection of elms tolerant to Dutch elm Disease in south-west Romania

Ophoiostoma novo- ulmi continues to be one of the most dangerous invasive fungi, destroying many autochthonous elm forests and cultures throughout the world. Searching for natural genotypes tolerant to Dutch Elm Disease (DED) is one of the main objectives of silviculturists all over the northern hemisphere in order to save the susceptible elms and to restore their ecosystem biodiversity. In this regard, the first trial was established between 1991 and 1994, in south-west Romania (Padurea Verde, Timis, oara), using three elm species (Ulmus minor, U. glabra, and U. laevis) with 38 provenances. A local strain of Ophiostoma novo-ulmi was used to artificially inoculate all elm variants and the DED evolution was observed. Furthermore, in 2018–2021 the trial was inventoried to understand the local genotype reaction to DED in the local environmental conditions after almost 30 years. The outcomes of the present study proved the continuous presence of the infections in the comparative culture and its proximity, but the identified pathogen had a new hybrid form (found for the first time in Romania) between O. novo-ulmi ssp. Americana x O. novo-ulmi ssp. novo-ulmi. Wych elm (U. glabra) was extremely sensitive to DED: only 12 trees (out of 69 found in 2018) survived in 2021, and only one tree could be selected according to the adopted health criteria (resistance and vigour). The field elm (U. minor) was sensitive to the pathogen, but there were still individuals that showed good health status and growth. In contrast, the European white elm (U. laevis) proved constant tolerance to DED: only 15% had been found dead or presented severe symptoms of dieback. Overall, the results of this study report the diverse reactions of the Romanian regional elm genotypes to DED over the last three decades, providing promising perspectives for improving the presence of elms in the forest ecosystems of the Carpathian basin

How to stop disproportionation of a hydrochloride salt of a very weakly basic compound in a non-clinical suspension formulation

Our objectives were to stabilize a non-clinical suspension for use in toxicological studies and to develop methods to investigate the stability of the formulation in terms of salt disproportionation. The compound under research was a hydrochloride salt of a practically insoluble discovery compound ODM-203. The first of the three formulation approaches was a suspension prepared and stored at room temperature. The second formulation was stabilized by pH adjustment. In the third approach cooling was used to prevent salt disproportionation. 5 mg/mL aqueous suspension consisting of 20 mg/mL PVP/VA and 5 mg/mL Tween 80 was prepared for each of the approaches. The polymer was used as precipitation inhibitor to provide prolonged supersaturation while Tween 80 was used to enhance dissolution and homogeneity of the suspension. The consequences of salt disproportionation were studied by a small-scale in vitro dissolution method and by an in vivo pharmacokinetic study in rats. Our results show that disproportionation was successfully suppressed by applying cooling of the suspension in an ice bath at 2-8 degrees C. This procedure enabled us to proceed to the toxicological studies in rats. The in vivo study results obtained for the practically insoluble compound showed adequate exposures with acceptable variation at each dose level.Peer reviewe

Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Barriers to Care in Juvenile Localized and Systemic Scleroderma: An Exploratory Survey Study of Caregivers’ Perspectives

BACKGROUND: Juvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child\u27s scleroderma. METHODS: In this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child\u27s condition and factors affecting diagnosis and treatment. RESULTS: The response rate was 61% (73/120), with 38 parents of LS patients and 31 parents of SSc patients. Most patients were female (80%) and over half were non-Hispanic white (55%). Most families had at least one person with a college education or higher (87%), traveled ≤ 2 h to see their rheumatologist (83%), and had private insurance (75%). Almost half had an annual household income ≥ $100,000 (46$100,000, and Hispanic ethnicity were associated with specific barriers to care. Lower socioeconomic status was associated with longer travel times to see the rheumatologist/specialist. Diagnosis and systemic treatment initiation occurred at greater than one year from initial presentation for approximately 28% and 36% of patients, respectively. Families of LS patients were commonly given erroneous information about the disease, including on the need and importance of treating active disease with systemic immunosuppressants in patients with deep tissue or rapidly progressive disease. CONCLUSION: Caregivers of children with LS or SSc reported numerous common barriers to the diagnosis, treatment, and ongoing care of juvenile scleroderma. The major problem highlighted was the lack of knowledge of scleroderma within the general medical community. Given that most of the caregiver respondents to the survey had relatively high socioeconomic status, additional studies are needed to reach a broader audience, including caregivers with limited English proficiency, geographical limitations, and financial constraints, to determine if the identified problems are generalizable. Identifying key care barriers will help direct efforts to address needs, reduce disparities in care, and improve patient outcomes

Hyperlipidemia and Atherosclerotic Lesion Development in Ldlr-Deficient Mice on a Long-Term High-Fat Diet

BACKGROUND: Mice deficient in the LDL receptor (Ldlr(-/-) mice) have been widely used as a model to mimic human atherosclerosis. However, the time-course of atherosclerotic lesion development and distribution of lesions at specific time-points are yet to be established. The current study sought to determine the progression and distribution of lesions in Ldlr(-/-) mice. METHODOLOGY/PRINCIPAL FINDINGS: Ldlr-deficient mice fed regular chow or a high-fat (HF) diet for 0.5 to 12 months were analyzed for atherosclerotic lesions with en face and cross-sectional imaging. Mice displayed significant individual differences in lesion development when fed a chow diet, whereas those on a HF diet developed lesions in a time-dependent and site-selective manner. Specifically, mice subjected to the HF diet showed slight atherosclerotic lesions distributed exclusively in the aortic roots or innominate artery before 3 months. Lesions extended to the thoracic aorta at 6 months and abdominal aorta at 9 months. Cross-sectional analysis revealed the presence of advanced lesions in the aortic sinus after 3 months in the group on the HF diet and in the innominate artery at 6 to 9 months. The HF diet additionally resulted in increased total cholesterol, LDL, glucose, and HBA1c levels, along with the complication of obesity. CONCLUSIONS/SIGNIFICANCE: Ldlr-deficient mice on the HF diet tend to develop site-selective and size-specific atherosclerotic lesions over time. The current study should provide information on diet induction or drug intervention times and facilitate estimation of the appropriate locations of atherosclerotic lesions in Ldlr(-/-) mice