Homomesy via Toggleability Statistics

The rowmotion operator acting on the set of order ideals of a finite poset has been the focus of a significant amount of recent research. One of the major goals has been to exhibit homomesies: statistics that have the same average along every orbit of the action. We systematize a technique for proving that various statistics of interest are homomesic by writing these statistics as linear combinations of "toggleability statistics" (originally introduced by Striker) plus a constant. We show that this technique recaptures most of the known homomesies for the posets on which rowmotion has been most studied. We also show that the technique continues to work in modified contexts. For instance, this technique also yields homomesies for the piecewise-linear and birational extensions of rowmotion; furthermore, we introduce a $q$-analogue of rowmotion and show that the technique yields homomesies for "$q$-rowmotion" as well.Comment: 48 pages, 13 figures, 2 tables; forthcoming, Combinatorial Theor

Effective antiprotease-antibiotic treatment of experimental anthrax

BACKGROUND: Inhalation anthrax is characterized by a systemic spread of the challenge agent, Bacillus anthracis. It causes severe damage, including multiple hemorrhagic lesions, to host tissues and organs. It is widely believed that anthrax lethal toxin secreted by proliferating bacteria is a major cause of death, however, the pathology of intoxication in experimental animals is drastically different from that found during the infectious process. In order to close a gap between our understanding of anthrax molecular pathology and the most prominent clinical features of the infectious process we undertook bioinformatic and experimental analyses of potential proteolytic virulence factors of B. anthracis distinct from lethal toxin. METHODS: Secreted proteins (other than lethal and edema toxins) produced by B. anthracis were tested for tissue-damaging activity and toxicity in mice. Chemical protease inhibitors and rabbit immune sera raised against B. anthracis proteases were used to treat mice challenged with B. anthracis (Sterne) spores. RESULTS: B. anthracis strain delta Ames (pXO1(-), pXO2(-)) producing no lethal and edema toxins secrets a number of metalloprotease virulence factors upon cultivation under aerobic conditions, including those with hemorrhagic, caseinolytic and collagenolytic activities, belonging to M4 and M9 thermolysin and bacterial collagenase families, respectively. These factors are directly toxic to DBA/2 mice upon intratracheal administration at 0.5 mg/kg and higher doses. Chemical protease inhibitors (phosphoramidon and 1, 10-phenanthroline), as well as immune sera against M4 and M9 proteases of B. anthracis, were used to treat mice challenged with B. anthracis (Sterne) spores. These substances demonstrate a substantial protective efficacy in combination with ciprofloxacin therapy initiated as late as 48 h post spore challenge, compared to the antibiotic alone. CONCLUSION: Secreted proteolytic enzymes are important pathogenic factors of B. anthrasis, which can be considered as effective therapeutic targets in the development of anthrax treatment and prophylactic approaches complementing anti-lethal toxin therapy

Advancing Monitoring Infrastructure for Oregon’s Native Freshwater Turtles with Citizen Science Platforms

Monitoring is a core component of conservation plans as well as an opportunity for local stakeholders to contribute. Our objective was to advance monitoring infrastructure for the protection of native, threatened freshwater turtles in the Pacific Northwest through the creation of a citizen science application. This was done by researching previous designs of citizen science projects over the past ten years and improving the platform based on recommendations by practitioners. Current platforms can be improved by better crediting the work of citizen scientists, improving communication between scientists and users, building in flexibility for scientists, and accommodating for disabilities through ergonomic design. This set the framework to design and build a new multi-platform monitoring application. The final product is a mobile and web application that embodies these concepts and is ready for user-testing in the summer, providing scientists with critical data to help monitor multiple species of conservation concern, while engaging the public in this important task

Host Plant Associations of an Entomopathogenic Variety of the Fungus, Colletotrichum acutatum, Recovered from the Elongate Hemlock Scale, Fiorinia externa

A fungal epizootic has been detected in populations of the scale Fiorinia externa Ferris (Hemiptera: Diaspididae) in the eastern hemlock, Tsuga canadensis (L.) Carrière (Pinales: Pinaceae), of several northeastern states. Colletotrichum acutatum Simmonds var. fioriniae Marcelino and Gouli var. nov. inedit (Phyllachorales: Phyllachoraceae), a well-known plant pathogen, was the most commonly recovered fungus from these infected scales. This is the second report of a Colletotrichum sp. infecting scale insects. In Brazil C. gloeosporioides f. sp. ortheziidae recovered from Orthezia praelonga is under development as a biopesticide for citrus production. C. acutatum was detected growing endophytically in 28 species of plants within the epizootic areas. DNA sequences of the High Mobility Box at the MAT 1–2, mating type gene indicate that Colletotrichum sp. isolates recovered from scale insects and plants within epizootic areas were identical. Results from plant bioassays showed that this entomopathogenic Colletotrichum variety grew endophytically in all of the plants tested without causing external symptoms or signs of infection, with the exception of strawberry plants where mild symptoms of infection were observed. The implications of these findings with respect to the use of this fungus as a biological control agent are discussed

A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models

Progressive kidney diseases are often associated with scarring of the kidney’s filtration unit, a condition called focal segmental glomerulosclerosis (FSGS). This scarring is due to loss of podocytes, cells critical for glomerular filtration, and leads to proteinuria and kidney failure. Inherited forms of FSGS are caused by Rac1-activating mutations, and Rac1 induces TRPC5 ion channel activity and cytoskeletal remodeling in podocytes. Whether TRPC5 activity mediates FSGS onset and progression is unknown. We identified a small molecule, AC1903, that specifically blocks TRPC5 channel activity in glomeruli of proteinuric rats. Chronic administration of AC1903 suppressed severe proteinuria and prevented podocyte loss in a transgenic rat model of FSGS. AC1903 also provided therapeutic benefit in a rat model of hypertensive proteinuric kidney disease. These data indicate that TRPC5 activity drives disease and that TRPC5 inhibitors may be valuable for the treatment of progressive kidney diseases.National Institutes of Health (U.S.) (Grant DK095045)National Institutes of Health (U.S.) (Grant DK099465)National Institutes of Health (U.S.) (Grant DK103658)National Institutes of Health (U.S.) (Grant DK083511)National Institutes of Health (U.S.) (Grant DK093746

Computationally restoring the potency of a clinical antibody against Omicron.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs1-3 and revealed how quickly viral escape can curtail effective options4,5. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab4-6. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities

Homomesy via toggleability statistics

The rowmotion operator acting on the set of order ideals of a finite poset has been the focus of a significant amount of recent research. One of the major goals has been to exhibit homomesies: statistics that have the same average along every orbit of the action. We systematize a technique for proving that various statistics of interest are homomesic by writing these statistics as linear combinations of "toggleability statistics" (originally introduced by Striker) plus a constant. We show that this technique recaptures most of the known homomesies for the posets on which rowmotion has been most studied. We also show that the technique continues to work in modified contexts. For instance, this technique also yields homomesies for the piecewise-linear and birational extensions of rowmotion; furthermore, we introduce a $q$-analogue of rowmotion and show that the technique yields homomesies for "$q$-rowmotion" as well.Mathematics Subject Classifications: 06A07, 05E18, 05A30, 52B05Keywords: Homomesy, rowmotion, toggling, piecewise-linear & birational lift, $q$-analogu