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Fibrinolysis, the plasmin-mediated degradation of the fibrin mesh that stabilizes blood clots, is an important physiological process, and understanding mechanisms underlying lysis is critical for improved stroke treatment. Experimentalists are now able to study lysis on the scale of single fibrin fibers, but mathematical models of lysis continue to focus mostly on fibrin network degradation. Experiments have shown that while some degradation occurs along the length of a fiber, ultimately the fiber is cleaved at a single location. We built a 2-dimensional stochastic model of a fibrin fiber cross-section that uses the Gillespie algorithm to study single fiber lysis initiated by plasmin. We simulated the model over a range of parameter values to learn about patterns and rates of single fiber lysis in various physiological conditions. We also used epifluorescent microscopy to measure the cleavage times of fibrin fibers with different apparent diameters. By comparing our model results to the laboratory experiments, we were able to: 1) suggest value ranges for unknown rate constants(namely that the degradation rate of fibrin by plasmin should be ≤ 10 s⁻¹and that if plasmin crawls, the rate of crawling should be between 10 s⁻¹and 60 s⁻¹); 2) estimate the fraction of fibrin within a fiber cross-section that must be degraded for the fiber to cleave in two; and 3) propose that that fraction is higher in thinner fibers and lower in thicker fibers. Collectively, this information provides more details about how fibrin fibers degrade, which can be leveraged in the future for a better understanding of why fibrinolysis is impaired in certain disease states, and could inform intervention strategies. 

ABSTRACT Assemblages in seasonal ecosystems undergo striking changes in species composition and diversity across the annual cycle. Despite a long‐standing recognition that seasonality structures biogeographic gradients in taxonomic diversity (e.g., species richness), our understanding of how seasonality structures other aspects of biodiversity (e.g., functional diversity) has lagged. Integrating seasonal species distributions with comprehensive data on key morphological traits for bird assemblages across North America, we find that seasonal turnover in functional diversity increases with the magnitude and predictability of seasonality. Furthermore, seasonal increases in bird species richness led to a denser packing of functional trait space, but functional expansion was important, especially in regions with higher seasonality. Our results suggest that the magnitude and predictability of seasonality and total productivity can explain the geography of changes in functional diversity with broader implications for understanding species redistribution, community assembly and ecosystem functioning. 

Abstract A tubular bone bead dating to ~ 12,940 BP was recovered from a hearth-centered activity area at the La Prele Mammoth site in Converse County, Wyoming, USA. This is the oldest known bead from the Western Hemisphere. To determine the taxonomic origin of the bead, we extracted collagen for zooarchaeology by mass spectrometry (ZooMS). We also used micro-CT scanning for morphological analysis to determine likely skeletal elements used for its production. We conclude that the bead was made from a metapodial or proximal phalanx of a hare (Lepus sp.). This find represents the first secure evidence for the use of hares during the Clovis period. While the use of hare bone for the manufacture of beads was a common practice in western North America during the Holocene, its origins can now be traced back to at least the terminal Pleistocene. 

The La Prele site (ca. 12,940 cal BP) is a deeply buried, single-component mammoth kill and campsite in Wyoming (USA). The site was discovered eroding from a creek bank 3 m deep within a 7-m tall terrace scarp, and prior investigations have primarily focused on excavations accessible from the creek bank, using heavy machinery to remove sterile overburden to access the deeply buried deposits. This approach has allowed excavations to occur safely outside of deep pits, but it has limited our ability to assess the total size and density of the site. To determine total site extent, we conducted systematic bucket auger testing of the La Prele site terrace, attempting 189 augers between 1.6 m and 6.2 m deep across the landform. We use a simulation and other mathematical procedures to infer artifact density from auger artifact counts and interpolate artifact densities across the site using GIS. We determine that La Prele is around 4500 m2 in area and likely contains a buried bison bonebed and two additional artifact concentrations comparable to or exceeding the size and density of previously excavated areas. We use these insights to infer Early Paleoindian group size, concluding that around 30 people occupied La Prele. 

For half a century, the possibility of organic molecules in sulfuric acid droplets in the clouds above Venus has been largely discounted. Here, we report the first results from an experimental exploration of this possibility, of primary interest to astronomers but also uncovering reactions that are remarkable to organic chemistry. This work provides a detailed mechanism of how small organic molecules might be generated in the sulfuric acid (H2SO4) aerosol droplets that form the clouds above Venus, starting from formaldehyde (HCHO), a simple one carbon species produced photochemically in the gas phase. Laboratory 13C and 1H nuclear magnetic resonance studies detail processes by which dissolved HCHO reacts with dissolved carbon monoxide (CO) to produce a two-carbon organic species, glycolic acid (HOCH2COOH). They show that glycolic acid is surprisingly stable, for days or longer, depending on temperature, in concentrated H2SO4. However, glycolic acid slowly reacts further to give higher molecular weight organic materials, including colored and fluorescent species. These may contribute to the UV and visible light astronomy of Venus, and are guiding the design of an autofluorescence nephelometer scheduled to fly on a Rocket Lab mission to Venus in 2025. 

Advancement toward dye-sensitized photoelectrochemical cells to produce solar fuels by solar-driven water splitting requires a photosensitizer that is firmly attached to the semiconducting photoelectrodes. Covalent binding enhances the efficiency of electron injection from the photoexcited dye into the metal oxide. Optimization of charge transfer, efficient electron injection, and minimal electron-hole recombination are mandatory for achieving high efficiencies. Here, a BODIPY-based dye exploiting an innovative surface-anchoring mode via boron is compared with a similar dye bound by a traditional carboxylic acid anchoring group. Through terahertz and transient absorption spectroscopic studies, along with GFN-xTB calculations, we find that, when compared to the traditional carboxylic acid anchoring group, electron injection of boron-bound BODIPY is faster into both TiO2 and SnO2. Although the surface coverage is low compared with carboxylic acids, the binding stability is improved over a wide range of pH. Subsequent photoelectrochemical studies using a sacrificial electron donor showed this combined dye and anchoring group maintained photocurrent with good stability over long-time irradiation. This recently discovered binding mode of BODIPY shows excellent electron injection and good stability over time, making it promising for future investigations. 

Theory often predicts that host populations should evolve greater resistance when parasites become abundant. Furthermore, that evolutionary response could ameliorate declines in host populations during epidemics. Here, we argue for an update: when all host genotypes become sufficiently infected, higher parasite abundance can select for lower resistance because its cost exceeds its benefit. We illustrate such a “resistance is futile” outcome with mathematical and empirical approaches. First, we analyzed an eco-evolutionary model of parasites, hosts, and hosts’ resources. We determined eco-evolutionary outcomes for prevalence, host density, and resistance (mathematically, “transmission rate”) along ecological and trait gradients that alter parasite abundance. With high enough parasite abundance, hosts evolve lower resistance, amplifying infection prevalence and decreasing host density. In support of these results, a higher supply of nutrients drove larger epidemics of survival-reducing fungal parasites in a mesocosm experiment. In two-genotype treatments, zooplankton hosts evolved less resistance under high-nutrient conditions than under low-nutrient conditions. Less resistance, in turn, was associated with higher infection prevalence and lower host density. Finally, in an analysis of naturally occurring epidemics, we found a broad, bimodal distribution of epidemic sizes consistent with the resistance is futile prediction of the eco-evolutionary model. Together, the model and experiment, supplemented by the field pattern, support predictions that drivers of high parasite abundance can lead to the evolution of lower resistance. Hence, under certain conditions, the most fit strategy for individual hosts exacerbates prevalence and depresses host populations. 

This is section "h" of the Arctic chapter (chapter 5) in the BAMS State of the Climate 2022 report. 

Abstract Purpose: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) ‘primes’ PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them, and devise approaches to stratify SHHi-responsive tumors non-invasively based on clinically-quantifiable parameters. Experimental design: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intra-tumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key ‘nodes’ responsible for EMT induction. Results: multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Non-responding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. Conclusion: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.