The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication

Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (MPro, 3CLPro, NSP5). Its therapeutic application reduces but does not abolish the progression of COVID-19 in humans. Here we report a strong synergy of Nirmatrelvir with inhibitors of the ER chaperone GRP78 (HSPA5, BiP). Combining Nirmatrelvir with the GRP78-antagonizing drug candidate HA15 strongly inhibits the replication of SARS-CoV-2, to a far greater extent than either drug alone, as observed by diminished cytopathic effect, levels of detectable virus RNA, TCID50 titers, and reduced accumulation of the non-structural proteins, as well as Spike and N proteins. The original SARS-CoV-2 strain as well as an Omicron variant were similarly susceptible towards the drug combination. Other GRP78 inhibitors or siRNAs targeting GRP78 also fortified the antiviral effect of Nirmatrelvir. In a hamster model of COVID-19, the combination of Nirmatrelvir with HA15 alleviated pneumonia-induced pulmonary atelectasis more effectively than the single drugs. In conclusion, inhibition of the virus Main protease and cellular GRP78 cooperatively diminishes virus replication and may improve COVID-19 therapy

H5N1 clade 2.3.4.4b dynamics in experimentally infected calves and cows

In March 2024, highly pathogenic avian influenza virus (HPAIV) clade 2.3.4.4b H5N1 infections in dairy cows were first reported from Texas, USA1. Rapid dissemination to more than 190 farms in 13 states followed2. Here, we provide results of two independent clade 2.3.4.4b experimental infection studies evaluating (i) oronasal susceptibility and transmission in calves to a US H5N1 bovine isolate genotype B3.13 (H5N1 B3.13) and (ii) susceptibility of lactating cows following direct mammary gland inoculation of either H5N1 B3.13 or a current EU H5N1 wild bird isolate genotype euDG (H5N1 euDG). Inoculation of the calves resulted in moderate nasal replication and shedding with no severe clinical signs or transmission to sentinel calves. In dairy cows, infection resulted in no nasal shedding, but severe acute mammary gland infection with necrotizing mastitis and high fever was observed for both H5N1 isolates. Milk production was rapidly and drastically reduced and the physical condition of the cows was severely compromised. Virus titers in milk rapidly peaked at 108 TCID50/mL, but systemic infection did not ensue. Notably, adaptive mutation PB2 E627K emerged after intramammary replication of H5N1 euDG. Our data suggest that in addition to H5N1 B3.13, other HPAIV H5N1 strains have the potential to replicate in the udder of cows and that milk and milking procedures, rather than respiratory spread, are likely the primary routes of H5N1 transmission between cattle

Outcome of H5N1 clade 2.3.4.4b virus infection in calves and lactating cows: [Preprint]

In March 2024, highly pathogenic avian influenza virus (HPAIV) clade 2.3.4.4b H5N1 infections in dairy cows were first reported from Texas, USA. Rapid dissemination to more than 190 farms in 13 states followed. Here, we provide results of two independent clade 2.3.4.4b experimental infection studies evaluating (i) oronasal susceptibility and transmission in calves to a US H5N1 bovine isolate genotype B3.13 (H5N1 B3.13) and (ii) susceptibility of lactating cows following direct mammary gland inoculation of either H5N1 B3.13 or a current EU H5N1 wild bird isolate genotype euDG (H5N1 euDG). Inoculation of the calves resulted in moderate nasal replication and shedding with no severe clinical signs or transmission to sentinel calves. In dairy cows, infection resulted in no nasal shedding, but severe acute mammary gland infection with necrotizing mastitis and high fever was observed for both H5N1 genotypes/strains. Milk production was rapidly and drastically reduced and the physical condition of the cows was severely compromised. Virus titers in milk rapidly peaked at 108 TCID50/mL, but systemic infection did not ensue. Notably, adaptive mutation PB2 E627K emerged after intramammary replication of H5N1 euDG. Our data suggest that in addition to H5N1 B3.13, other HPAIV H5N1 strains have the potential to replicate in the udder of cows and that milk and milking procedures, rather than respiratory spread, are likely the primary routes of H5N1 transmission between cattle

A Robust, Scalable Framework for Conducting Climate Change Susceptibility Analyses

PURPOSE: Resource managers must consider climate change during their planning processes as future landscapes have the potential to vary greatly from current conditions. Military training and testing lands are extremely important and must be assessed for potential impacts of climate change. Climate change susceptibility analyses are commonly limited in their scope, thereby requiring multiple independent analyses within the same region. Without a standardized, comprehensive analysis method, the ability to prioritize areas susceptible to climate change within a region of interest is hindered. This deficit limits the applicability of results as well, further illustrating the need to develop a standardized method that incorporates multiple factors into a scalable framework to provide a more complete climate change susceptibility analysis. This framework must allow individual users the option of weighting environmental variables differently based on conservation concerns in managed areas. In this technical note, the authors present a method that allows multiple stakeholders — each with their own management requirements and concerns for assessing susceptibility — to use a common framework to assess climate change susceptibility. This framework enables improved analytical results of climate change to be incorporated into long-term regional conservation planning. The framework should prove to be a valuable tool for resource managers faced with integrating the potential impacts of climate change into their natural resource plans. INTRODUCTION: Potential impacts of climate change are receiving a great deal of attention as resource managers attempt to plan for predicted changes (e.g., Spittlehouse and Stewart 2003, Millar et al. 2007, Rustad et al. 2012). While substantial changes may take decades to appear, more rapid changes to both plant and animal ranges have already been extensively documented (e.g.

Fish fauna of the trans-Andean Tumbes river basin in northern Peru

To update the knowledge of the ichthyofauna of the Tumbes River basin, we provide a list of species. We report 47 species of fishes, grouped into 23 families and 11 orders. Characiformes was the most diverse order with 12 species (25.5% of the total richness), followed by Carangiformes with eight species (17%). In our study, two species are newly reported from this river basin: Pseudophallus starksii (Jordan &amp; Culver, 1895) and Evorthodus minutus Meek &amp; Hildebrand 1928. According to salinity tolerance, the ichthyofauna is composed of 20 primary, 14 secondary, and 13 peripheral species. Despite having the highest diversity of fish on the Peruvian Pacific slope, the Tumbes river basin is one of the most polluted coastal drainages. This study compiles information on the ichthyofauna of the entire basin, increases the known diversity of freshwater fish from trans-Andean drainages in Peru, and can be used in the management and conservation of the Tumbes River.</jats:p

Fish fauna of the trans-Andean Tumbes river basin in northern Peru

To update the knowledge of the ichthyofauna of the Tumbes River basin, we provide a list of species. We report 47 species of fishes, grouped into 23 families and 11 orders. Characiformes was the most diverse order with 12 species (25.5% of the total richness), followed by Carangiformes with eight species (17%). In our study, two species are newly reported from this river basin: Pseudophallus starksii (Jordan & Culver, 1895) and Evorthodus minutus Meek & Hildebrand 1928. According to salinity tolerance, the ichthyofauna is composed of 20 primary, 14 secondary, and 13 peripheral species. Despite having the highest diversity of fish on the Peruvian Pacific slope, the Tumbes river basin is one of the most polluted coastal drainages. This study compiles information on the ichthyofauna of the entire basin, increases the known diversity of freshwater fish from trans-Andean drainages in Peru, and can be used in the management and conservation of the Tumbes River