Microtubule-associated protein, MAP1B, encodes functionally distinct polypeptides.

Microtubule-associated protein, MAP1B, is crucial for neuronal morphogenesis and disruptions in MAP1B function are correlated with neurodevelopmental disorders. MAP1B encodes a single polypeptide that is processed into discrete proteins, a heavy chain (HC) and a light chain (LC); however, it is unclear if these two chains operate individually or as a complex within the cell. In vivo studies have characterized the contribution of MAP1B HC and LC to microtubule and actin-based processes, but their molecular mechanisms of action are unknown. Using in vitro reconstitution with purified proteins, we dissect the biophysical properties of the HC and LC and uncover distinct binding behaviors and functional roles for these MAPs. Our biochemical assays indicate that MAP1B HC and LC do not form a constitutive complex, supporting the hypothesis that these proteins operate independently within cells. Both HC and LC inhibit the microtubule motors, kinesin-3, kinesin-4, and dynein, and differentially affect the severing activity of spastin. Notably, MAP1B LC binds to actin filaments in vitro and can simultaneously bind and crosslink actin filaments and microtubules, a function not observed for MAP1B HC. Phosphorylation of MAP1B HC by DYRK1a negatively regulates its actin-binding activity without significantly affecting its microtubule-binding capacity, suggesting a dynamic contribution of MAP1B HC in cytoskeletal organization. Overall, our study provides new insights into the distinct functional properties of MAP1B HC and LC, underscoring their roles in coordinating cytoskeletal networks during neuronal development.

Next-generation precision medicine for suicidality prevention.

Suicidality remains a clear and present danger in society in general, and for mental health patients in particular. Lack of widespread use of objective and/or quantitative information has hampered treatment and prevention efforts. Suicidality is a spectrum of severity from vague thoughts that life is not worth living, to ideation, plans, attempts, and completion. Blood biomarkers that track suicidality risk provide a window into the biology of suicidality, as well as could help with assessment and treatment. Previous studies by us were positive. Here we describe new studies we conducted transdiagnostically in psychiatric patients, starting with the whole genome, to expand the identification, prioritization, validation and testing of blood gene expression biomarkers for suicidality, using a multiple independent cohorts design. We found new as well as previously known biomarkers that were predictive of high suicidality states, and of future psychiatric hospitalizations related to them, using cross-sectional and longitudinal approaches. The overall top increased in expression biomarker was SLC6A4, the serotonin transporter. The top decreased biomarker was TINF2, a gene whose mutations result in very short telomeres. The top biological pathways were related to apoptosis. The top upstream regulator was prednisolone. Taken together, our data supports the possibility that biologically, suicidality is an extreme stress-driven form of active aging/death. Consistent with that, the top subtypes of suicidality identified by us just based on clinical measures had high stress and high anxiety. Top therapeutic matches overall were lithium, clozapine and ketamine, with lithium stronger in females and clozapine stronger in males. Drug repurposing bioinformatic analyses identified the potential of renin-angiotensin system modulators and of cyclooxygenase inhibitors. Additionally, we show how patient reports for doctors would look based on blood biomarkers testing, personalized by gender. We also integrated with the blood biomarker testing social determinants and psychological measures (CFI-S, suicidal ideation), showing synergy. Lastly, we compared that to machine learning approaches, to optimize predictive ability and identify key features. We propose that our findings and comprehensive approach can have transformative clinical utility.

Influence of deployment method and maintenance on efficacy of sticky card traps for Halyomorpha halys (Hemiptera: Pentatomidae).

Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) is an invasive pest which feeds on numerous economically significant crops. Many integrated pest management strategies for this species rely on effective season-long monitoring for H. halys populations, including attract-and-kill and threshold-based insecticide sprays. Previous studies have shown that a black pyramid trap effectively captures all mobile life stages of H. halys, however, these bulky, ground-deployed traps can be impractical in active orchard rows. Clear sticky cards have been used as a more practical tool for monitoring when paired with the H. halys aggregation pheromone and synergist. Here, the efficacy of deploying single- or double-sided sticky cards hanging in trees or deployed on wooden stakes was compared to standard black pyramid traps over 2 years. The efficacy of single-sided sticky cards deployed on wooden stakes was also evaluated after occlusion of 25%, 50%, or 75% of the surface area by 2D inert materials and 3D organic matter. Single-sided sticky cards were also exposed to simulated sunlight and rainfall for 0, 4, 8, and 12 wk before deployment on wooden stakes. Captures of H. halys adults using sticky cards deployed on wooden stakes were comparable to pyramid traps. Occlusion of cards by 25% or more of any material type led to a decrease in H. halys captures, however, weathering did not influence capture. These data show that clear sticky cards deployed on wooden stakes are effective for season-long monitoring of H. halys in apple orchards, and card replacement should be driven by maintenance of cleanliness.

Potential value of animal microphysiological systems.

Microphysiological systems (MPS) are designed to recapitulate aspects of tissue/organ physiology in vivo, thereby providing potential value in safety and efficacy assessments of FDA-regulated products and regulatory decision-making. While there have been significant advances in the development, use, and proposals of qualification criteria for human organ MPS, there remains a gap in the development using animal tissues. Animal MPS may be of value in many areas including the study of zoonotic diseases, assessment of the safety and efficacy of animal therapeutics, and possibly reduction of the use of animals in regulatory submissions for animal therapeutics. In addition, the development of MPS from various animal species enables comparison to animal in vivo data. This comparison, while not always critical for all contexts of use, could help gain confidence in the use and application of human MPS data for regulatory decision-making and for the potential identification of species-specific effects. The use of animal MPS is consistent with the replacement, reduction, and refinement (3Rs) principles of animal use by identifying toxic compounds before conducting in vivo studies and identifying the appropriate species for testing.

Microphysiological systems (MPS) mimic aspects of organs in humans or animals. These systems may provide information useful for FDA-regulated products. While there have been significant advances in the development of MPS made from human cells, there remains a gap in the development of MPS using animal cells. FDA believes animal MPS may be of value in many areas including the study of diseases transmitted from animals to humans, assessment of the safety and efficacy of animal drugs, and reduction of the use of animals in regulatory submissions. The development of animal MPS enables comparison to data from studies conducted in animals. This comparison provides confidence in the use of human MPS data for regulatory decision-making. The use of animal MPS is consistent with the 3Rs principles of animal use by allowing identification of toxic compounds before conducting animal studies and by helping select the appropriate species for further testing.

MicroRNA-7 regulates endocrine progenitor delamination and endocrine cell mass in developing pancreatic islets.

ß-cell replenishment in patients with diabetes through cadaveric islet transplantation has been successful; however, it requires long-term immunosuppression and suitable islet donors are scarce. Stepwise in vitro differentiation of pluripotent stem cells into ß-cells represents a viable alternative, but limitations in our current understanding of in vivo islet endocrine differentiation constrains its clinical use. Here, we show that microRNA-7 (miR-7) is highly expressed in embryonic pancreatic endocrine progenitors. Genetic deletion of the miR-7 gene family in endocrine progenitors leads to reduced islet endocrine cell mass, due to endocrine progenitors failing to delaminate from the epithelial plexus. This is associated with a reduction in neurogenin-3 levels and increased expression of Sry-box transcription factor 9. Further, we observe that a significant number of endocrine progenitors lacking miR-7 differentiate into ductal cells. Our study suggests that increasing miR-7 expression could improve efficiency of in vitro differentiation and augment stem cell-derived ß-cell terminal maturity.

Evaluation of insecticide residues against spotted lanternfly (Hemiptera: Fulgoridae).

Lycorma delicatula White (Hemiptera: Fulgoridae), spotted lanternfly, is a univoltine, phloem-feeding, polyphagous and invasive insect in the United States. Although a primary host for this species is Ailanthus altissima (Mill.) Swingle, tree of heaven, L. delicatula also feeds on many other plant species, including cultivated grapevines. As this species continues to spread, it is important to develop effective management tools. Here, we evaluated the residual efficacy of 4 insecticides commonly used in tree fruit management programs: dinotefuran, bifenthrin, carbaryl, and thiamethoxam. First, all mobile life stages (early instars, late instars, and adults) of L. delicatula were exposed for 1 h to dry insecticide residues (18 h old) applied to glass or A. altissima bark surfaces. While some mortality was detected immediately following the 1 h exposure period, 100% mortality occurred within 24 h for all materials and life stages exposed on both glass and bark surfaces. To evaluate longer residual activity of these materials, groups of adult L. delicatula were introduced into cages containing A. altissima trees treated with the same individual insecticides and exposed 6 h to residues that were 18 h or 7 days old. Paired, untreated A. altissima served as controls. In these bioassays, 48 h mortality for 18 h old residue reached 95% for thiamethoxam and 100% for bifenthrin and dinotefuran. Seven-day-old bifenthrin and dinotefuran residues again yielded 100% mortality, while thiamethoxam resulted in 58% mortality, and carbaryl yielded only 13.3% and was not significantly different from the control. These results clearly document the efficacy of specific insecticide applications as management tools against L. delicatula.

Effects of nonnutritive sugar inclusion in laboratory diets and attracticidal spheres on survivorship and mobility of 2 Dipteran species, Rhagoletis pomonella (Diptera: Tephritidae) and Drosophila suzukii (Diptera: Drosophilidae).

Native apple maggot fly, Rhagoletis pomonella, and invasive spotted-wing drosophila, Drosophila suzukii, are key pests of apple and small fruit, respectively, in the United States. Both species are typically managed with standard insecticide applications. However, interest in alternative strategies that result in insecticide reductions has led to evaluations of nonnutritive sugars as toxicants for Drosophila species and development of attracticidal spheres for both species. Here, we evaluated the survivorship of R. pomonella and D. suzukii when provided with standard diets that substituted saccharin, sucralose, aspartame, erythritol, dextrose, or mannitol for the sucrose component and compared them with standard diets and water-only controls for up to 15 days. Presence of erythritol and mannitol significantly decreased survivorship of R. pomonella and erythritol significantly decreased the survivorship of D. suzukii. However, mobility trials following a 2 h exposure to aqueous solutions of each sugar treatment resulted in no strong impact on either species. Survivorship after 30 min exposure to erythritol or mannitol alone, or in combination with varying concentrations of sucrose (serving as a phagostimulant) at 30 min and 24 h were evaluated for both species. Only D. suzukii survivorship was affected with decreased survivorship on erythritol:sucrose solutions of 20:0% and 15:5% for 24 h. Based on all results, erythritol appeared most promising, and was integrated into attracticidal spheres as a toxicant but even at the highest concentration, survivorship remained unaffected for either species, thus making this nonnutritive sugar impractical and ineffective as a toxicant substitute in attracticidal spheres.

Landscape-scale spatiotemporal dynamics of Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) populations: implications for spatially-based pest management.

BACKGROUND: Brown marmorated stink bug (BMSB), Halyomorpha halys (Stål), is an invasive and severe pest of specialty and row crops. A 2-year field study conducted in four Mid-Atlantic states in the USA characterized the spatial and temporal dynamics of BMSB populations and its association with landscape elements in commercial agriculture settings. In each state, two 1 km2 sites included typical landscape elements (i.e., tree fruit orchards, annual field and vegetable crops, woodlands, and human-made structures). Twenty-seven georeferenced pheromone traps were deployed per site and the number of BMSB adults and nymphs captured was counted throughout the growing season. RESULTS: Findings from spatial analysis by distance indices, along with time-series maps of BMSB distribution, showed that BMSB exhibited significant spatial aggregation, and that its distribution was spatially consistent between years. Analyses with geographic information systems (GIS) revealed that BMSB 'hot spots' occurred in different landscape elements throughout each season. Most patches (i.e., clusters of significantly higher trap captures) were found near woodlands early in the season, near tree fruit orchards in summer, and on the border of annual field crops in autumn. Buffer analysis with GIS indicated that more BMSB adults were captured closer to woodlands compared with other landscape elements. CONCLUSION: Understanding the spatial and temporal movement and distribution of BMSB is critical to predicting their potential impact and ultimately devising strategies to mitigate this risk to vulnerable crops. The results of this study can be used to design streamlined, spatially-based areawide management of BMSB in heterogeneous and complex agricultural landscapes. © 2023 Society of Chemical Industry. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.