Hyaluronan and Its Receptors as Regulatory Molecules of the Endothelial Interface

On the surface of endothelial cells (ECs) lies the glycocalyx, a barrier of polysaccharides that isolates the ECs from the blood. The role of the glycocalyx is dynamic and complex, thanks to not only its structure, but its vast number of components, one being hyaluronan (HA). HA is a critical component of the glycocalyx, having been found to have a wide variety of functions depending on its molecular weight, its modification, and receptor–ligand interactions. As HA and viscous blood are in constant contact, HA can transmit mechanosensory information directly to the cytoskeleton of the ECs. The degradation and synthesis of HA directly alters the permeability of the EC barrier; HA modulation not only alters the physical barrier but also can signal the initiation of other pathways. EC proliferation and angiogenesis are in part regulated by HA fragmentation, HA-dependent receptor binding, and downstream signals. The interaction between the CD44 receptor and HA is a driving force behind leukocyte recruitment, but each class of leukocyte still interacts with HA in unique ways during inflammation. HA regulates a diverse repertoire of EC functions.     

Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles

Mesenchymal stromal/stem cells (MSCs) have been widely tested against many diseases, with more than 1000 registered clinical trials worldwide. Despite many setbacks, MSCs have been approved for the treatment of graft-versus-host disease and Crohn disease. However, it is increasingly clear that MSCs exert their therapeutic functions in a paracrine manner through the secretion of small extracellular vesicles (sEVs) of 50–200 nm in diameter. Unlike living cells that can persist long-term, sEVs are non-living and non-replicative and have a transient presence in the body. Their small size also renders sEV preparations highly amenable to sterilization by filtration. Together, acellular MSC-sEV preparations are potentially safer and easier to translate into the clinic than cellular MSC products. Nevertheless, there are inherent challenges in the development of MSC-sEV drug products. MSC-sEVs are products of living cells, and living cells are sensitive to changes in the external microenvironment. Consequently, quality control metrics to measure key identity and potency features of MSC-sEV preparations have to be specified during development of MSC-sEV therapeutics. The authors have previously described quantifiable assays to define the identity of MSC-sEVs. Here the authors discuss requirements for prospective potency assays to predict the therapeutic effectiveness of the drug substance in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Although potency assays should ideally reflect the mechanism of action (MoA), this is challenging because the MoA for the reported efficacy of MSC-sEV preparations against multiple diseases of diverse underlying pathology is likely to be complex and different for each disease and difficult to fully elucidate. Nevertheless, robust potency assays could be developed by identifying the EV attribute most relevant to the intended biological activity in EV-mediated therapy and quantifying the EV attribute. Specifically, the authors highlight challenges and mitigation measures to enhance the manufacture of consistent and reproducibly potent sEV preparations, to identify and select the appropriate EV attribute for potency assays despite a complex “work-in-progress” MoA and to develop assays likely to be compliant with regulatory guidance for assay validation.     

Landscape simplification increases vineyard pest outbreaks and insecticide use

Diversifying agricultural landscapes may mitigate biodiversity declines and improve pest management. Yet landscapes are rarely managed to suppress pests, in part because researchers seldom measure key variables related to pest outbreaks and insecticides that drive management decisions. We used a 13‐year government database to analyse landscape effects on European grapevine moth (Lobesia botrana) outbreaks and insecticides across c. 400 Spanish vineyards. At harvest, we found pest outbreaks increased four‐fold in simplified, vineyard‐dominated landscapes compared to complex landscapes in which vineyards are surrounded by semi‐natural habitats. Similarly, insecticide applications doubled in vineyard‐dominated landscapes but declined in vineyards surrounded by shrubland. Importantly, pest population stochasticity would have masked these large effects if numbers of study sites and years were reduced to typical levels in landscape pest‐control studies. Our results suggest increasing landscape complexity may mitigate pest populations and insecticide applications. Habitat conservation represents an economically and environmentally sound approach for achieving sustainable grape production.     

Mps1 promotes poleward chromosome movements in meiotic prometaphase

In prophase of meiosis I, homologous chromosomes pair and become connected by cross-overs. Chiasmata, the connections formed by cross-overs, enable the chromosome pair, called a bivalent, to attach as a single unit to the spindle. When the meiotic spindle forms in prometaphase, most bivalents are associated with one spindle pole and then go through a series of oscillations on the spindle, attaching to and detaching from microtubules until the partners of the bivalent become bioriented—attached to microtubules from opposite sides of the spindle. The conserved kinase, Mps1, is essential for the bivalents to be pulled by microtubules across the spindle in prometaphase. Here we show that MPS1 is needed for efficient triggering of the migration of microtubule-attached kinetochores toward the poles and promotes microtubule depolymerization. Our data support the model Mps1 acts at the kinetochore to coordinate the successful attachment of a microtubule and the triggering of microtubule depolymerization to then move the chromosome.     

Caring for US Children: Barriers to Effective Treatment in Children with the Disease of Obesity

In 2020, impediments to pediatric obesity (PO) treatment remain pervasive, even though these barriers are clearly documented in medical literature. Providers must invest considerable resources to overcome these barriers to care. Notable barriers include gaps in medical education, misperceptions of the disease, weight bias and stigma, exclusion of coverage in health plans, and thus an unsustainable financial framework. Hence, this review offers an updated social‐ecological framework of accessibility to care, wherein each barrier to care or variable is interdependent on the other and each is critical to creating forward momentum. The sum of all these variables is instrumental to overall smooth function, configured as a wheel. To treat PO effectively, all variables must be adequately addressed by stakeholders throughout the health care system in order to holistically comprehend and appreciate undertakings to advance the burgeoning field of PO medicine.     

Interrupted incubation: How dabbling ducks respond when flushed from the nest

Nesting birds must provide a thermal environment sufficient for egg development while also meeting self‐maintenance needs. Many birds, particularly those with uniparental incubation, achieve this balance through periodic incubation recesses, during which foraging and other self‐maintenance activities can occur. However, incubating birds may experience disturbances such as predator or human activity which interrupt natural incubation patterns by compelling them to leave the nest. We characterized incubating mallard Anas platyrhynchos and gadwall Mareca strepera hens’ responses when flushed by predators and investigators in Suisun Marsh, California, USA. Diurnal incubation recesses initiated by investigators approaching nests were 63% longer than natural diurnal incubation recesses initiated by the hen (geometric mean: 226.77 min versus 142.04 min). Nocturnal incubation recesses, many of which were likely the result of predators flushing hens, were of similar duration regardless of whether the nest was partially depredated during the event (115.33 [101.01;131.68] minutes) or not (119.62 [111.96;127.82] minutes), yet were 16% shorter than natural diurnal incubation recesses. Hens moved further from the nest during natural diurnal recesses or investigator‐initiated recesses than during nocturnal recesses, and the proportion of hen locations recorded in wetland versus upland habitat during recesses varied with recess type (model‐predicted means: natural diurnal recess 0.77; investigator‐initiated recess 0.82; nocturnal recess 0.31). Hens were more likely to take a natural recess following an investigator‐initiated recess earlier that same day than following a natural recess earlier that same day, and natural recesses that followed an investigator‐initiated recess were longer than natural recesses that followed an earlier natural recess, suggesting that hens may not fulfill all of their physiological needs during investigator‐initiated recesses. We found no evidence that the duration of investigator‐initiated recesses was influenced by repeated visits to the nest, whether by predators or by investigators, and trapping and handling the hen did not affect investigator‐initiated recess duration unless the hen was also fitted with a backpack‐harness style GPS–GSM transmitter at the time of capture. Hens that were captured and fitted with GPS–GSM transmitters took recesses that were 26% longer than recesses during which a hen was captured but a GPS–GSM transmitter was not attached. Incubation interruptions had measurable but limited and specific effects on hen behavior.