Computationally restoring the potency of a clinical antibody against Omicron.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs and revealed how quickly viral escape can curtail effective options. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination and is challenging to replace with existing approaches.

Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants.

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs, but also revealed how quickly viral escape can curtail effective options. With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including Evusheld and its constituent, cilgavimab. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination and is challenging to replace with existing approaches.

The Wilms Tumor Gene Contributes to Blood-Cerebrospinal Fluid Barrier Function in Zebrafish.

The Wilms tumor suppressor gene encodes a zinc finger transcription factor, which is highly conserved among vertebrates. It is a key regulator of urogenital development and homeostasis but also plays a role in other organs including the spleen and the heart. More recently additional functions for Wt1 in the mammalian central nervous system have been described.

The CH···HC interaction in biphenyl is a delocalized, molecular-wide and entirely non-classical interaction: Results from FALDI analysis.

In this study we aim to determine the origin of the electron density describing a CH···HC interaction in planar and twisted conformers of biphenyl. In order to achieve this, the fragment, atomic, localized, delocalized, intra- and inter-atomic (FALDI) decomposition scheme was utilized to decompose the density in the inter-nuclear region between the ortho-hydrogens in both conformers. Importantly, the structural integrity, hence also topological properties, were fully preserved as no 'artificial' partitioning of molecules was implemented.

Molecular Orbitals Support Energy-Stabilizing "Bonding" Nature of Bader's Bond Paths.

Our MO-based findings proved a bonding nature of each density bridge (DB, or a bond path with an associated critical point, CP) on a Bader molecular graph. A DB pinpoints universal physical and net energy-lowering processes that might, but do not have to, lead to a chemical bond formation. Physical processes leading to electron density (ED) concentration in internuclear regions of three distinctively different homopolar H,H atom-pairs as well as classical C-C and C-H covalent bonds were found to be .

Wilms Tumor 1b Expression Defines a Pro-regenerative Macrophage Subtype and Is Required for Organ Regeneration in the Zebrafish.

Organ regeneration is preceded by the recruitment of innate immune cells, which play an active role during repair and regrowth. Here, we studied macrophage subtypes during organ regeneration in the zebrafish, an animal model with a high regenerative capacity. We identified a macrophage subpopulation expressing Wilms tumor 1b (wt1b), which accumulates within regenerating tissues.

Kidney regeneration in fish.

Age-related diseases, such as kidney diseases, are becoming more prevalent in aging societies. Currently, patients with reduced kidney function require dialysis or organ transplants. Those who suffer from kidney disease would benefit from regenerative therapies.

Fluorescence-Activated Cell Sorting (FACS) Protocol for Podocyte Isolation in Adult Zebrafish.

Zebrafish is becoming a very important model for studying human diseases. The conserved structure of the nephrons in the kidney allows the user to answer questions relating to study human kidney disorders. Wt1a-expressing podocytes are the most important cells within the glomeruli of adult zebrafish.

Function and Regulation of the Wilms' Tumor Suppressor 1 (WT1) Gene in Fish.

The Wilms' tumor suppressor gene Wt1 is highly conserved among vertebrates. In contrast to mammals, most fish species possess two wt1 paralogs that have been named wt1a and wt1b. Concerning wt1 in fish, most work so far has been done using zebrafish, focusing on the embryonic kidney, the pronephros.

A Conceptual Architecture for National Biosurveillance: Moving Beyond Situational Awareness to Enable Digital Detection of Emerging Threats.

Despite numerous calls for improvement, the US biosurveillance enterprise remains a patchwork of uncoordinated systems that fail to take advantage of the rapid progress in information processing, communication, and analytics made in the past decade. By synthesizing components from the extensive biosurveillance literature, we propose a conceptual framework for a national biosurveillance architecture and provide suggestions for implementation. The framework differs from the current federal biosurveillance development pathway in that it is not focused on systems useful for "situational awareness" but is instead focused on the long-term goal of having true warning capabilities.

Molecular specification of germ layers in vertebrate embryos.

In order to generate the tissues and organs of a multicellular organism, different cell types have to be generated during embryonic development. The first step in this process of cellular diversification is the formation of the three germ layers: ectoderm, endoderm and mesoderm. The ectoderm gives rise to the nervous system, epidermis and various neural crest-derived tissues, the endoderm goes on to form the gastrointestinal, respiratory and urinary systems as well as many endocrine glands, and the mesoderm will form the notochord, axial skeleton, cartilage, connective tissue, trunk muscles, kidneys and blood.

Coco regulates dorsoventral specification of germ layers via inhibition of TGFβ signalling.

One of the earliest steps in embryonic development is the specification of the germ layers, the subdivision of the blastula embryo into endoderm, mesoderm and ectoderm. Maternally expressed members of the Transforming Growth Factor β (TGFβ) family influence all three germ layers; the ligands are required to induce endoderm and mesoderm, whereas inhibitors are required for formation of the ectoderm. Here, we demonstrate a vital role for maternal Coco, a secreted antagonist of TGFβ signalling, in this process.

Neuronatin promotes neural lineage in ESCs via Ca(2+) signaling.

Neural induction is the first step in the formation of the vertebrate central nervous system. The emerging consensus of the mechanisms underlying neural induction is the combined influences from inhibiting bone morphogenetic protein (BMP) signaling and activating fibroblast growth factor (FGF)/Erk signaling, which act extrinsically via either autocrine or paracrine fashions. However, do intrinsic forces (cues) exist and do they play decisive roles in neural induction? These questions remain to be answered.

A simulation model of intraherd transmission of foot and mouth disease with reference to disease spread before and after clinical diagnosis.

Intraherd transmission of foot and mouth disease virus (FMDV) was examined using a simulation model for a hypothetical 1,000-cow dairy, assuming clinical diagnosis was made when at least 1% (10 cows) or 5% (50 cows) had clinical signs of FMD, I index case cow, and transition state distributions for the latent, subclinically infectious, and clinically infectious periods of FMD calculated from published data. Estimates assumed for the number of animal-to-animal contacts (k) adequate for transmission ranged from 0.6 to 9.

Benefit-cost analysis of vaccination and preemptive slaughter as a means of eradicating foot-and-mouth disease.

Objective: To assess relative costs and benefits of vaccination and preemptive herd slaughter to control transmission of foot-and-mouth disease (FMD) virus (FMDV).

Sample Population: 2,238 herds and 5 sale yards located in Fresno, Kings, and Tulare counties of California.

Procedure: Direct costs associated with indemnity, slaughter, cleaning and disinfecting livestock premises, and vaccination were compared for various eradication strategies.

Results of epidemic simulation modeling to evaluate strategies to control an outbreak of foot-and-mouth disease.

Objective: To assess estimated effectiveness of control and eradication procedures for foot-and-mouth disease (FMD) in a region of California.

Sample Population: 2,238 herds and 5 sale yards in Fresno, Kings, andTulare counties of California.

Procedure: A spatial stochastic model was used to simulate hypothetical epidemics of FMD for specified control scenarios that included a baseline eradication strategy mandated by USDA and supplemental control strategies of slaughter or vaccination of all animals within a specified distance of infected herds, slaughter of only high-risk animals identified by use of a model simulation, and expansion of infected and surveillance zones.

Description of an epidemic simulation model for use in evaluating strategies to control an outbreak of foot-and-mouth disease.

Objective: To develop a spatial epidemic model to simulate intraherd and interherd transmission of foot-and-mouth disease (FMD) virus.

Sample Population: 2,238 herds, representing beef, dairy, swine, goats, and sheep, and 5 sale yards located in Fresno, Kings, and Tulare counties of California.

Procedure: Using Monte-Carlo simulations, a spatial stochastic epidemic simulation model was developed to identify new herds that would acquire FMD following random selection of an index herd and to assess progression of an epidemic after implementation of mandatory control strategies.