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Shouki Bazarbashi,1 Heba Mohamed El Zawahry,2 Tarek Owaidah,3 Mohammad A AlBader,4 Ashraf Warsi,5– 7 Mahmoud Marashi,8,9 Emad Dawoud,10 Hassan Jaafar,11 Sherif M Sholkamy,12 Fady Haddad,13 Alexander T Cohen14 1Section of Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia; 2Department of Medical Oncology, The National Cancer Institute, Cairo University, Cairo, Egypt; 3Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Alfaisal University, Riyadh, Saudi Arabia; 4Hematology Unit, Al Sabah Hospital, South Surra, Kuwait; 5Department of Adult Hematology, Princess Noorah Oncology Center, King Abdulaziz Medical City, Ministry of National Guard Health Affairs–Western Region, Jeddah, Saudi Arabia; 6College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs–Western Region, Jeddah, Saudi Arabia; 7King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs-Western Region, Jeddah, Saudi Arabia; 8Hematology Department, Dubai Hospital, Dubai, United Arab Emirates; 9Department of Hematology, Mediclinic City Hospital, Dubai, United Arab Emirates; 10Department of Oncology, Tawam Hospital, Al Ain, United Arab Emirates; 11Department of Oncology, Sheikh Khalifa Specialty Hospital, Ras Al-Khaimah, United Arab Emirates; 12Department of Vascular Surgery, Ain Shams University, Cairo, Egypt; 13Vascular and Endovascular Surgery, American University of Beirut Medical Center, Beirut, Lebanon; 14Department of Haematological Medicine, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, King’s College London, London, UKCorrespondence: Shouki Bazarbashi, Section of Medical Oncology, Oncology Center, King Faisal Specialist Hospital and Research Center, Alfaisal University, 1 Alzahrawi Street, Riyadh, 11211, Saudi Arabia, Tel +966 505443546, Email bazarbashi@gmail.com

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

Machine learning (ML) is gaining popularity as a tool for materials scientists to accelerate computation, automate data analysis, and predict materials properties. The representation of input material features is critical to the accuracy, interpretability, and generalizability of data-driven models for scientific research. In this Perspective, we discuss a few central challenges faced by ML practitioners in developing meaningful representations, including handling the complexity of real-world industry-relevant materials, combining theory and experimental data sources, and describing scientific phenomena across timescales and length scales. We present several promising directions for future research: devising representations of varied experimental conditions and observations, the need to find ways to integrate machine learning into laboratory practices, and making multi-scale informatics toolkits to bridge the gaps between atoms, materials, and devices.

Defending against future pandemics may require vaccine platforms that protect across a range of related pathogens. The presentation of multiple receptor-binding domains (RBDs) from evolutionarily-related viruses on a nanoparticle scaffold elicits a strong antibody response to conserved regions. Here we produce quartets of tandemly-linked RBDs from SARS-like betacoronaviruses coupled to the mi3 nanocage through a SpyTag/SpyCatcher spontaneous reaction. These Quartet Nanocages induce a high level of neutralizing antibodies against several different coronaviruses, including against viruses not represented on the vaccine. In animals primed with SARS-CoV-2 Spike, boost immunizations with Quartet Nanocages increased the strength and breadth of an otherwise narrow immune response. Quartet Nanocages are a strategy with potential to confer heterotypic protection against emergent zoonotic coronavirus pathogens and facilitate proactive pandemic protection.

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS.

We investigate a variety of short warning time, terminal mitigation scenarios via fragmentation for a hypothetical impact of asteroid 2023 NT1, a Near-Earth Object (NEO) that was discovered on July 15, 2023, two days after its closest approach to Earth on July 13. The asteroid passed by Earth within ~0.25 lunar distances with a closest approach distance of ~10$^{5}$ km and speed of 11.27 km/s. Its size remains largely uncertain, with an estimated diameter range of 26 - 58 m and probable diameter estimate (weighted by the NEO size frequency distribution) of 34 m (JPL Sentry, September 12, 2023). The asteroid approached Earth from the direction of the Sun, as did both the Chelyabinsk asteroid in 2013 and comet NEOWISE in 2021. As a result, 2023 NT1 remained undetected until after its closest approach. If it had been on a collision course, it would have had an impact energy of ~1.5 Mt (assuming a spherical asteroid with the probable diameter estimate of 34 m, 2.6 g/cm$^{3}$ uniform density, and impact speed of 15.59 km/s). 2023 NT1 represents a threat that could have caused significant local damage (~3x Chelyabinsk airburst energy). We utilize the PI ("Pulverize It") method for planetary defense to model potential mitigation scenarios of an object like 2023 NT1 through simulations of hypervelocity asteroid disruption and atmospheric ground effects for the case of a terminal defense mode. Simulations suggest that PI is an effective multimodal approach for planetary defense that can operate in extremely short interdiction modes (with intercepts as short as hours prior to impact), in addition to long interdiction time scales with months to years of warning. Our simulations support the proposition that threats like 2023 NT1 can be effectively mitigated with intercepts of one day (or less) prior to impact, yielding minimal to no ground damage, using modest resources and existing technologies.

The 1918-1919 flu pandemic resulted in an estimated 50 to 100 million deaths worldwide, making it the deadliest pandemic in modern history. It was caused by a new influenza virus that likely spilled over from birds and reassorted with a human influenza virus. Since the human population was immunologically naïve to this virus, transmission and lethality was much higher than for seasonal influenza outbreaks. Numerous pandemic influenza viruses emerged within the next century, with none causing the same amount of carnage. There is likely to be future influenza pandemics, with wild migratory birds being carriers of a wide swath of different influenza A viruses. Zoonotic transmission of Avian influenza has taken place with limited human to human transmission. There is evidence showing that the barrier of human transmissibility by some of these avian viruses is not very high, and therefore emergence into humans is possible, with most if not all of the population immunologically naïve. The humoral immune response to influenza is defined by the imprinting of the antibody response to immunodominant epitopes. Such responses can impair immunity, providing less adequate protection against seasonal and pandemic infections, as well as poorer immunity induced by seasonal vaccines. There are instances where imprinting can be advantageous and even offer protection against pandemic or avian viruses, particularly when conserved epitopes to the HA stalk are exploited. Manipulating the antibody response to recognizing conserved stalk epitopes on influenza HA is therefore a strategy being used for universal influenza vaccines. In the second Chapter of this thesis, a mosaic nanoparticle immunization strategy for inducing breadth of antibody responses against HA will be described. This strategy involves the co-display of HAs from up to eight different strains on a particle platform. Although the breadth of antibody responses elicited by immunization of these particles was limited, this

The 1918-1919 flu pandemic resulted in an estimated 50 to 100 million deaths worldwide, making it the deadliest pandemic in modern history. It was caused by a new influenza virus that likely spilled over from birds and reassorted with a human influenza virus. Since the human population was immunologically naïve to this virus, transmission and lethality was much higher than for seasonal influenza outbreaks. Numerous pandemic influenza viruses emerged within the next century, with none causing the same amount of carnage. There is likely to be future influenza pandemics, with wild migratory birds being carriers of a wide swath of different influenza A viruses. Zoonotic transmission of Avian influenza has taken place with limited human to human transmission. There is evidence showing that the barrier of human transmissibility by some of these avian viruses is not very high, and therefore emergence into humans is possible, with most if not all of the population immunologically naïve. The humoral immune response to influenza is defined by the imprinting of the antibody response to immunodominant epitopes. Such responses can impair immunity, providing less adequate protection against seasonal and pandemic infections, as well as poorer immunity induced by seasonal vaccines. There are instances where imprinting can be advantageous and even offer protection against pandemic or avian viruses, particularly when conserved epitopes to the HA stalk are exploited. Manipulating the antibody response to recognizing conserved stalk epitopes on influenza HA is therefore a strategy being used for universal influenza vaccines. In the second Chapter of this thesis, a mosaic nanoparticle immunization strategy for inducing breadth of antibody responses against HA will be described. This strategy involves the co-display of HAs from up to eight different strains on a particle platform. Although the breadth of antibody responses elicited by immunization of these particles was limited, this

The 1918-1919 flu pandemic resulted in an estimated 50 to 100 million deaths worldwide, making it the deadliest pandemic in modern history. It was caused by a new influenza virus that likely spilled over from birds and reassorted with a human influenza virus. Since the human population was immunologically naïve to this virus, transmission and lethality was much higher than for seasonal influenza outbreaks. Numerous pandemic influenza viruses emerged within the next century, with none causing the same amount of carnage. There is likely to be future influenza pandemics, with wild migratory birds being carriers of a wide swath of different influenza A viruses. Zoonotic transmission of Avian influenza has taken place with limited human to human transmission. There is evidence showing that the barrier of human transmissibility by some of these avian viruses is not very high, and therefore emergence into humans is possible, with most if not all of the population immunologically naïve. The humoral immune response to influenza is defined by the imprinting of the antibody response to immunodominant epitopes. Such responses can impair immunity, providing less adequate protection against seasonal and pandemic infections, as well as poorer immunity induced by seasonal vaccines. There are instances where imprinting can be advantageous and even offer protection against pandemic or avian viruses, particularly when conserved epitopes to the HA stalk are exploited. Manipulating the antibody response to recognizing conserved stalk epitopes on influenza HA is therefore a strategy being used for universal influenza vaccines. In the second Chapter of this thesis, a mosaic nanoparticle immunization strategy for inducing breadth of antibody responses against HA will be described. This strategy involves the co-display of HAs from up to eight different strains on a particle platform. Although the breadth of antibody responses elicited by immunization of these particles was limited, this

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

We discuss a hypothetical existential threat from a 10 km diameter bolide discovered 6 months prior to impact with one case being a comet and the other being an asteroid. We show that an extension of our work on bolide fragmentation using an array of penetrators but modified with small nuclear explosive devices (NED) in the penetrators, combined with soon-to-be-realized heavy lift launch assets with positive $C_3$ such as NASA SLS or SpaceX Starship (with in-orbit refueling) is sufficient to mitigate this existential threat. A threat of this magnitude hitting the Earth at a closing speed of 40 km/s for the comet and 20 km/s for the asteroid would have an impact energy of roughly 65 Teratons TNT, or about ten thousand times larger than the current combined nuclear arsenal of the entire world. This is similar in energy to the KT extinction event that killed the dinosaurs some 66 million years ago. Such an event, if not mitigated, would be an existential threat to humanity. We show that mitigation is conceivable using existing technology, even with the short time scale of 6 months warning, but that the efficient coupling of the NED energy is critical., Comment: 17 pages, 8 figures

Relativistic spacecraft, like those proposed by the NASA Starlight program and the Breakthrough Starshot Initiative, will have to survive radiation production that is unique when compared to that experienced by conventional spacecraft. In a relativistic interstellar spacecraft’s reference frame, the interstellar medium (ISM) will look like a nearly monoenergetic beam of charged particles which impinges upon the leading edge of the spacecraft. Upon impact, ISM protons and electrons will travel characteristic lengths through the spacecraft shield and come to a stop via electronic and nuclear stopping mechanisms. As a result, bremsstrahlung photons will be produced within the spacecraft shield. In this work, we discuss the interstellar environment and its implications for radiation damage on relativistic spacecraft. We also explore expected radiation doses in terms of onboard device radiation tolerance.

Relativistic spacecraft, like those proposed by the NASA Starlight program and the Breakthrough Starshot Initiative, will have to survive radiation production that is unique when compared to that experienced by conventional spacecraft. In a relativistic interstellar spacecraft’s reference frame, the interstellar medium (ISM) will look like a nearly monoenergetic beam of charged particles which impinges upon the leading edge of the spacecraft. Upon impact, ISM protons and electrons will travel characteristic lengths through the spacecraft shield and come to a stop via electronic and nuclear stopping mechanisms. As a result, bremsstrahlung photons will be produced within the spacecraft shield. In this work, we discuss the interstellar environment and its implications for radiation damage on relativistic spacecraft. We also explore expected radiation doses in terms of onboard device radiation tolerance.

Protection from SARS-related coronaviruses with spillover potential and SARS-CoV-2 variants could prevent and/or end pandemics. We show that mice immunized with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicit cross-reactive anti-sarbecovirus antibodies against conserved class 1/4 and class 3 RBD epitopes. Monoclonal antibodies (mAbs) identified from initial screening of <10,000 single B-cells secreting IgGs binding two or more sarbecovirus RBDs showed cross-reactive binding and neutralization of SARS-CoV-2 variants and animal sarbecoviruses. Single-particle cryo-EM structures of antibody–spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes and revealed neutralization mechanisms, potentials for intra-spike trimer crosslinking by single IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticles to identify therapeutic pan-sarbecovirus and pan-variant mAbs and to elicit them by vaccination.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against conserved/relatively-occluded, rather than variable/immunodominant/exposed, epitopes. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicron and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

Prime-boost regimens for COVID-19 vaccines elicit poor antibody responses against Omicron-based variants and employ frequent boosters to maintain antibody levels. We present a natural infection-mimicking technology that combines features of mRNA- and protein nanoparticle-based vaccines through encoding self-assembling enveloped virus-like particles (eVLPs). eVLP assembly is achieved by inserting an ESCRT- and ALIX-binding region (EABR) into the SARS-CoV-2 spike cytoplasmic tail, which recruits ESCRT proteins to induce eVLP budding from cells. Purified spike-EABR eVLPs presented densely-arrayed spikes and elicited potent antibody responses in mice. Two immunizations with mRNA-LNP encoding spike-EABR elicited potent CD8+ T-cell responses and superior neutralizing antibody responses against original and variant SARS-CoV-2 compared to conventional spike-encoding mRNA-LNP and purified spike-EABR eVLPs, improving neutralizing titers >10-fold against Omicron-based variants for three months post-boost. Thus, EABR technology enhances potency and breadth of vaccine-induced responses through antigen presentation on cell surfaces and eVLPs, enabling longer-lasting protection against SARS-CoV-2 and other viruses.

The International Consortium for Health Outcomes Measurement assembled an international working group of venous thromboembolism experts and patient representatives to develop a standardised minimum set of outcomes and outcome measurements for integration into clinical practice and potentially research to support clinical decision making and benchmarking of quality of care. 15 core outcomes important to patients and health-care professionals were selected and categorised into four domains: patient-reported outcomes, long term consequences of the disease, disease-specific complications, and treatment-related complications. The outcomes and outcome measures were designed to apply to all patients with venous thromboembolism aged 16 years or older. A measurement tool package was selected for inclusion in the core standard set, with a minimum number of items to be measured at predefined timepoints, which capture all core outcomes. Additional measures can be introduced to the user by a cascade opt-in system that allows for further assessment if required. This set of outcomes and measurement tools will facilitate the implementation of the use of patient-centred outcomes in daily practice.

We discuss a hypothetical existential threat from a 10 km diameter bolide discovered 6 months prior to impact with one case being a comet and the other being an asteroid. We show that an extension of our work on bolide fragmentation using an array of penetrators but modified with small nuclear explosive devices (NED) in the penetrators, combined with soon-to-be-realized heavy lift launch assets with positive $C_3$ such as NASA SLS or SpaceX Starship (with in-orbit refueling) is sufficient to mitigate this existential threat. A threat of this magnitude hitting the Earth at a closing speed of 40 km/s for the comet and 20 km/s for the asteroid would have an impact energy of roughly 65 Teratons TNT, or about ten thousand times larger than the current combined nuclear arsenal of the entire world. This is similar in energy to the KT extinction event that killed the dinosaurs some 66 million years ago. Such an event, if not mitigated, would be an existential threat to humanity. We show that mitigation is conceivable using existing technology, even with the short time scale of 6 months warning, but that the efficient coupling of the NED energy is critical., Comment: 17 pages, 8 figures

A new guideline for mitigating indoor airborne transmission of COVID-19 prescribes a limit on the time spent in a shared space with an infected individual (Bazant & Bush, Proceedings of the National Academy of Sciences of the United States of America, vol. 118, issue 17, 2021, e2018995118). Here, we rephrase this safety guideline in terms of occupancy time and mean exhaled carbon dioxide (CO2) concentration in an indoor space, thereby enabling the use of CO2 monitors in the risk assessment of airborne transmission of respiratory diseases. While CO2 concentration is related to airborne pathogen concentration (Rudnick & Milton, Indoor Air, vol. 13, issue 3, 2003, pp. 237–245), the guideline developed here accounts for the different physical processes affecting their evolution, such as enhanced pathogen production from vocal activity and pathogen removal via face-mask use, filtration, sedimentation and deactivation. Critically, transmission risk depends on the total infectious dose, so necessarily depends on both the pathogen concentration and exposure time. The transmission risk is also modulated by the fractions of susceptible, infected and immune people within a population, which evolve as the pandemic runs its course. A mathematical model is developed that enables a prediction of airborne transmission risk from real-time CO2 measurements. Illustrative examples of implementing our guideline are presented using data from CO2 monitoring in university classrooms and office spaces.

Background As mortality from pulmonary embolism (PE) decreases, the personal and societal costs among survivors are receiving increasing attention. Detailing this burden would support an efficient public health resource allocation. We aimed to provide estimates for the economic and disease burden of PE also accounting for long-term health care use and both direct and indirect costs beyond the acute phase. Methods and Results This is a cost-of-illness analysis with a bottom-up approach based on data from the PREFER in VTE registry (Prevention of Thromboembolic Events-European Registry in Venous Thromboembolism). We calculated direct (clinical events and anticoagulation) and indirect costs (loss of productivity) of an acute PE event and its 12-month follow-up in 2020 Euros. We estimated a disability weight for the 12-month post-PE status and corresponding disability adjusted life years presumably owing to PE. Disease-specific costs in the first year of follow-up after an incident PE case ranged between 9135 Euros and 10 620 Euros. The proportion of indirect costs was 42% to 49% of total costs. Costs were lowest in patients with ongoing cancer, mainly because productivity loss was less evident in this already burdened population. The calculated disability weight for survivors who were cancer free 12 months post-PE was 0.017, and the estimated disability adjusted life years per incident case were 1.17. Conclusions The economic burden imposed by PE to society and affected patients is considerable, and productivity loss is its main driver. The disease burden from PE is remarkable and translates to the loss of roughly 1.2 years of healthy life per incident PE case.

Terrestrial accelerator facilities can generate ion beams which enable the testing of the resistance of materials and thin film coatings to be used in the space environment. In this work, a [Formula: see text]/Al bi-layer coating has been irradiated with a [Formula: see text] beam at three different energies. The same flux and dose have been used in order to investigate the damage dependence on the energy. The energies were selected to be in the range 4-100 keV, in order to consider those associated to the quiet solar wind and to the particles present in the near-Earth space environment. The optical, morphological and structural modifications have been investigated by using various techniques. Surprisingly, the most damaged sample is the one irradiated at the intermediate energy, which, on the other hand, corresponds to the case in which the interface between the two layers is more stressed. Results demonstrate that ion energies for irradiation tests must be carefully selected to properly qualify space components.

Site-selective α-amino acylation of proteins with N-terminal Gly-HisTags using 6-azido-6-deoxy-glucono-1,5-lactone (6AGDL) is reported. To demonstrate the usefulness of this reaction, we multimerise the SARS-CoV-2 receptor-binding domain (RBD) protein antigen onto virus-like particles (VLPs) via strain-promoted alkyne-azide cycloaddition (SPAAC). The resulting COVID-19 vaccine candidate induces single-shot seroconversion, and virus-neutralizing antibodies in mice.

Our ability to explore the cosmos by direct contact has been limited to a small number of lunar and interplanetary missions. However, the NASA Starlight program points a path forward to send small, relativistic spacecraft far outside our solar system via standoff directed-energy propulsion. These miniaturized spacecraft are capable of robotic exploration but can also transport seeds and organisms, marking a profound change in our ability to both characterize and expand the reach of known life. Here we explore the biological and technological challenges of interstellar space biology, focusing on radiation-tolerant microorganisms capable of cryptobiosis. Additionally, we discuss planetary protection concerns and other ethical considerations of sending life to the stars., Comment: 17 pages, 3 figures

As part of the NASA Starlight collaboration, we look at the implications of impacts with the interstellar medium (ISM) on a directed energy-driven relativistic spacecraft. The spacecraft experiences a stream of MeV/nucleon impacts along the forward edge primarily from hydrogen and helium nuclei. The accumulation of implanted slowly diffusing gas atoms in solids drives damage through the meso-scale processes of bubble formation, blistering, and exfoliation. This results in macroscopic changes to material properties and, in the cases of blistering and exfoliation, material erosion via blister rupture and delamination. Relativistic hydrogen and helium at constant velocity will stop in the material at a similar depth, as predicted by Bethe–Bloch stopping and subsequent simulations of the implantation distribution, leading to a mixed hydrogen and helium system similar to that observed within fusion plasma-facing components. However, the difference in depth of near-surface gas atoms with respect to the direction of exposure means that previously developed empirical models of blistering cannot be used to predict bubble formation or blistering onset. In this work, we present a model of the local gas concentration threshold for material blistering from exposure to the ISM at relativistic speeds. Expected effects on the spacecraft and mitigation strategies are also discussed. The same considerations apply to the Breakthrough Starshot mission.

Terrestrial accelerator facilities can generate ion beams which enable the testing of the resistance of materials and thin film coatings to be used in the space environment. In this work, a [Formula: see text]/Al bi-layer coating has been irradiated with a [Formula: see text] beam at three different energies. The same flux and dose have been used in order to investigate the damage dependence on the energy. The energies were selected to be in the range 4-100 keV, in order to consider those associated to the quiet solar wind and to the particles present in the near-Earth space environment. The optical, morphological and structural modifications have been investigated by using various techniques. Surprisingly, the most damaged sample is the one irradiated at the intermediate energy, which, on the other hand, corresponds to the case in which the interface between the two layers is more stressed. Results demonstrate that ion energies for irradiation tests must be carefully selected to properly qualify space components.

Our ability to explore the cosmos by direct contact has been limited to a small number of lunar and interplanetary missions. However, the NASA Starlight program points a path forward to send small, relativistic spacecraft far outside our solar system via standoff directed-energy propulsion. These miniaturized spacecraft are capable of robotic exploration but can also transport seeds and organisms, marking a profound change in our ability to both characterize and expand the reach of known life. Here we explore the biological and technological challenges of interstellar space biology, focusing on radiation-tolerant microorganisms capable of cryptobiosis. Additionally, we discuss planetary protection concerns and other ethical considerations of sending life to the stars., Comment: 17 pages, 3 figures

INTRODUCTION: Edoxaban had a positive risk-benefit ratio for the treatment of venous thromboembolism (VTE) compared to conventional therapy with warfarin. The objective of this analysis of the ongoing ETNA-VTE Europe study was to assess the real-world benefits and risks of edoxaban during the first 3 months of treatment, the highest risk period for further VTE events. METHODS: ETNA-VTE Europe is a prospective, non-interventional, post-authorization study, conducted in eight European countries. Participants had initial or recurrent acute VTE (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) that occurred ≤2 weeks prior to enrolment and received edoxaban therapy. RESULTS: The analysis set included 2672 patients (PE ± DVT, n = 1117; DVT only, n = 1555); mean age 62.9 ± 16.0 years, bodyweight 81.9 ± 17.4 kg, estimated glomerular filtration rate 95.4 ± 42.8 mL/min; 46.4% were female. Overall, 66.4% of patients (PE ± DVT, 68.5%; DVT-only, 64.8%) received heparin lead-in treatment for at least 5 days. Most patients (87.7%) received edoxaban at a dose of 60 mg once daily. Event rates at 3 months were: recurrent VTE 0.34% (n = 9), major bleeding 0.97% (n = 26), all-cause mortality 0.79% (n = 21). Rates were numerically higher in the PE ± DVT group compared with the DVT-only group (recurrent VTE, 0.45% (n = 5) versus 0.26% (n = 4); major bleeding, 1.34% (n = 15) versus 0.71% (n = 11); and all-cause mortality 1.16% (n = 13) versus 0.51% (n = 8)). CONCLUSIONS: The results support the safety and effectiveness of edoxaban in a general VTE population during the most critical time period, the first 3 months. The outcomes of this study extend the principal efficacy and safety data on edoxaban into the routine clinical practice setting.

INTRODUCTION: Edoxaban has proven its efficacy and safety in the ENGAGE AF-TIMI 48 and HOKUSAI-VTE clinical trials. Clinical practice patients, however, may differ from those enolled in clinical trials. We aimed to compare patients from the HOKUSAI-VTE clinical trial with those treated in clinical practice. MATERIALS AND METHODS: ETNA-VTE-Europe is a prospective, non-interventional post-authorisation safety study conducted in eight European countries. RESULTS: A total of 2,879 patients presenting with acute symptomatic venous thromboembolism (VTE) were enrolled at 339 sites. Of the 2,680 patients with complete data, 23.6% reported prior VTE and 2.8% had a history of bleeding. Patients in ETNA-VTE were older (65vs.57 years), more likely to be female (46.5vs.39.8%) and had a higher prevalence of chronic venous insufficiency (11.1vs.1.6%) than those in the European cohort of the HOKUSAI-VTE trial (n=1,512). Bodyweight and creatinine clearance were substantially lower in clinical practice. Edoxaban dosing was adherent to label in 90% of patients, with higher (60 mg) and lower than recommended doses (30 mg) used in 6.6% and 3.3% of the patients, respectively. Heparin lead-in was used in 84.7% of the patients overall, and was more frequently used in patients with PE than patients with DVT only (91.3% vs. 80.1%; p<0.0001). CONCLUSIONS: These data reinforce the largely appropriate use of edoxaban in routine clinical practice, where the study population differs from those in prior randomised controlled trials. CLINICALTRIALS. GOV IDENTIFIER: NCT02943993.

Broadly neutralizing monoclonal antibodies protect against infection with HIV-1 in animal models, suggesting that a vaccine that elicits these antibodies would be protective in humans. However, it has not yet been possible to induce adequate serological responses by vaccination. Here, to activate B cells that express precursors of broadly neutralizing antibodies within polyclonal repertoires, we developed an immunogen, RC1, that facilitates the recognition of the variable loop 3 (V3)-glycan patch on the envelope protein of HIV-1. RC1 conceals non-conserved immunodominant regions by the addition of glycans and/or multimerization on virus-like particles. Immunization of mice, rabbits and rhesus macaques with RC1 elicited serological responses that targeted the V3-glycan patch. Antibody cloning and cryo-electron microscopy structures of antibody-envelope complexes confirmed that immunization with RC1 expands clones of B cells that carry the anti-V3-glycan patch antibodies, which resemble precursors of human broadly neutralizing antibodies. Thus, RC1 may be a suitable priming immunogen for sequential vaccination strategies in the context of polyclonal repertoires.