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Plague pandemics and outbreaks have killed millions of people during the history of humankind. The disease, caused by the bacteria Yersinia pestis, is currently treated effectively with antibiotics. However, in the case of multidrug-resistant (MDR) bacteria, alternative treatments are required. Bacteriophage (phage) therapy has shown efficient antibacterial activity in various experimental animal models and in human patients infected with different MDR pathogens. Here, we evaluated the efficiency of фA1122 and PST phage therapy, alone or in combination with second-line antibiotics, using a well-established mouse model of pneumonic plague. Phage treatment significantly delayed mortality and limited bacterial proliferation in the lungs. However, the treatment did not prevent bacteremia, suggesting that phage efficiency may decrease in the circulation. Indeed, in vitro phage proliferation assays indicated that blood exerts inhibitory effects on lytic activity, which may be the major cause of treatment inefficiency. Combining phage therapy and second-line ceftriaxone treatment, which are individually insufficient, provided protection that led to the survival of all infected animals—a synergistic protective effect that represents a proof of concept for efficient combinatorial therapy in an emergency event of a plague outbreak involving MDR Y. pestis strains.

A novel COVID-19 vaccine (BriLife®) has been developed by the Israel Institute for Biological Research (IIBR) to prevent the spread of the SARS-CoV-2 virus throughout the population in Israel. One of the components in the vaccine formulation is tris(hydroxymethyl)aminomethane (tromethamine, TRIS), a buffering agent. TRIS is a commonly used excipient in various approved parenteral medicinal products, including the mRNA COVID-19 vaccines produced by Pfizer/BioNtech and Moderna. TRIS is a hydrophilic basic compound that does not contain any chromophores/fluorophores and hence cannot be retained and detected by reverse-phase liquid chromatography (RPLC)-ultraviolet (UV)/fluorescence methods. Among the few extant methods for TRIS determination, all exhibit a lack of selectivity and/or sensitivity and require laborious sample treatment. In this study, LC–mass spectrometry (MS) with its inherent selectivity and sensitivity in the multiple reaction monitoring (MRM) mode was utilized, for the first time, as an alternative method for TRIS quantitation. Extensive validation of the developed method demonstrated suitable specificity, linearity, precision, accuracy and robustness over the investigated concentration range (1.2–4.8 mg/mL). Specifically, the R2 of the standard curve was >0.999, the recovery was >92%, and the coefficient of variance (%CV) was <12% and <6% for repeatability and intermediate precision, respectively. Moreover, the method was validated in accordance with strict Good Manufacturing Practice (GMP) guidelines. The developed method provides valuable tools that pharmaceutical companies can use for TRIS quantitation in vaccines and other pharmaceutical products.

A novel COVID-19 vaccine (BriLife[sup.®]) has been developed by the Israel Institute for Biological Research (IIBR) to prevent the spread of the SARS-CoV-2 virus throughout the population in Israel. One of the components in the vaccine formulation is tris(hydroxymethyl)aminomethane (tromethamine, TRIS), a buffering agent. TRIS is a commonly used excipient in various approved parenteral medicinal products, including the mRNA COVID-19 vaccines produced by Pfizer/BioNtech and Moderna. TRIS is a hydrophilic basic compound that does not contain any chromophores/fluorophores and hence cannot be retained and detected by reverse-phase liquid chromatography (RPLC)-ultraviolet (UV)/fluorescence methods. Among the few extant methods for TRIS determination, all exhibit a lack of selectivity and/or sensitivity and require laborious sample treatment. In this study, LC–mass spectrometry (MS) with its inherent selectivity and sensitivity in the multiple reaction monitoring (MRM) mode was utilized, for the first time, as an alternative method for TRIS quantitation. Extensive validation of the developed method demonstrated suitable specificity, linearity, precision, accuracy and robustness over the investigated concentration range (1.2–4.8 mg/mL). Specifically, the R[sup.2] of the standard curve was >0.999, the recovery was >92%, and the coefficient of variance (%CV) was <12% and <6% for repeatability and intermediate precision, respectively. Moreover, the method was validated in accordance with strict Good Manufacturing Practice (GMP) guidelines. The developed method provides valuable tools that pharmaceutical companies can use for TRIS quantitation in vaccines and other pharmaceutical products.

Plague pandemics and outbreaks have killed millions of people during the history of humankind. The disease, caused by Yersinia pestis bacteria, can currently be treated efficiently with antibiotics. However, in the case of multidrug-resistant (MDR) bacteria, alternative treatments are required. Bacteriophage (phage) therapy has shown efficient antibacterial activity in various experimental animal models and in human patients infected with different MDR pathogens. Herein, we evaluated the efficiency of фA1122 and PST phage therapy, alone or in combination with second-line antibiotics, using a well-established mouse model of pneumonic plague. Phage treatment significantly delayed mortality and limited bacterial proliferation in the lungs. However, the treatment did not prevent bacteremia, suggesting that phage efficiency may decrease in circulation. Indeed, in vitro phage proliferation assays indicated that blood has inhibitory effects on lytic activity, which may be the major cause of treatment inefficiency. Combining phage therapy and second-line ceftriaxone treatment, which are individually insufficient, provided protection that led to survival of all infected animals, presenting a synergistic protective effect that represents a proof of concept for efficient combinatorial therapy in an emergency event of a plague outbreak involving MDR Y. pestis strains. Competing Interest Statement The authors have declared no competing interest.

The order Pezizales (Ascomycota) consists of cup and truffle fungi growing in a wide range of habitats and geographical zones worldwide, exhibiting diverse nutritional behaviors. In Israel, morphological studies have designated most Pezizales as saprotrophs. We re-screened Pezizales mushrooms collected in northern Israel between 2020–2022 using molecular tools based on DNA sequences of partial large subunit rRNA (28S), internal transcribed spacer (ITS), and partial heat shock protein (Hsp90) regions, along with macro images of each freshly collected samples. Trophic mode was determined through available literature and δ13C and δ15N stable isotope analysis along with a quadratic discriminator analysis (QDA) model to predict trophic modes: 112 collections were positively identified with identification of 23 genera; 23 taxa were resolved to the species level, 11 to approximate species, and 15 to the genus level. Helvella was the most species-rich genus; 25 species and species approximations were newly reported for Israel. Further molecular phylogenetic studies are needed to resolve species identity of the Israeli Pezizales. Most Pezizales collections were determined by trophic mode studies to be ectomycorrhizal, with a few saprotrophs. The QDA model yielded several samples with undefined nutritional behavior or a different trophic mode than previously inferred, suggesting that more in-depth study is needed to understand their trophic ecology. This study improves knowledge regarding species diversity, ecology, and evolution of Israeli Pezizales.

The order Pezizales (Ascomycota) consists of cup and truffle fungi growing in a wide range of habitats and geographical zones worldwide, exhibiting diverse nutritional behaviors. In Israel, morphological studies have designated most Pezizales as saprotrophs. We re-screened Pezizales mushrooms collected in northern Israel between 2020-2022 using molecular tools based on DNA sequences of partial large subunit rRNA (28S), internal transcribed spacer (ITS), and partial heat shock protein ( ) regions, along with macro images of each freshly collected samples. Trophic mode was determined through available literature and δ C and δ N stable isotope analysis along with a quadratic discriminator analysis (QDA) model to predict trophic modes: 112 collections were positively identified with identification of 23 genera; 23 taxa were resolved to the species level, 11 to approximate species, and 15 to the genus level. was the most species-rich genus; 25 species and species approximations were newly reported for Israel. Further molecular phylogenetic studies are needed to resolve species identity of the Israeli Pezizales. Most Pezizales collections were determined by trophic mode studies to be ectomycorrhizal, with a few saprotrophs. The QDA model yielded several samples with undefined nutritional behavior or a different trophic mode than previously inferred, suggesting that more in-depth study is needed to understand their trophic ecology. This study improves knowledge regarding species diversity, ecology, and evolution of Israeli Pezizales.

The order Pezizales (Ascomycota) consists of cup and truffle fungi growing in a wide range of habitats and geographical zones worldwide, exhibiting diverse nutritional behaviors. In Israel, morphological studies have designated most Pezizales as saprotrophs. We re-screened Pezizales mushrooms collected in northern Israel between 2020–2022 using molecular tools based on DNA sequences of partial large subunit rRNA (28S), internal transcribed spacer (ITS), and partial heat shock protein (Hsp90) regions, along with macro images of each freshly collected samples. Trophic mode was determined through available literature and δ[sup.13]C and δ[sup.15]N stable isotope analysis along with a quadratic discriminator analysis (QDA) model to predict trophic modes: 112 collections were positively identified with identification of 23 genera; 23 taxa were resolved to the species level, 11 to approximate species, and 15 to the genus level. Helvella was the most species-rich genus; 25 species and species approximations were newly reported for Israel. Further molecular phylogenetic studies are needed to resolve species identity of the Israeli Pezizales. Most Pezizales collections were determined by trophic mode studies to be ectomycorrhizal, with a few saprotrophs. The QDA model yielded several samples with undefined nutritional behavior or a different trophic mode than previously inferred, suggesting that more in-depth study is needed to understand their trophic ecology. This study improves knowledge regarding species diversity, ecology, and evolution of Israeli Pezizales.