Molecular Recognition Profiles of Molecular Cocrystals

The manner in which molecules recognize each other holds critical importance to nearly every area of science. This significance stems from the key underpinning of molecular assembly to our most basic understanding of chemical processes. Whether these interactions relate to small-molecule catalytic transformations or complex physiological processes, the structural features responsible for molecular association play into the well-known adage that form follows function where material property arises from the collective structural features of the molecular components. Because the form of chemical systems is derived from a complex blend of covalent and non-bonded contacts, codifying each contributor has become essential for recognizing the functions and potential applications of materials. While considerable progress in this area has been realized by isolating and identifying molecular contacts and the structural details of their conditional exceptions, insight to the entire landscape of molecular associations remains an ongoing effort. This thesis explores the molecular recognition process from two uniquely different perspectives. The first is from cocrystalizing a variety of benzoic acids with the pharmaceutical agent sulfamethazine and the second area investigates how molecular shape controls quasiracemate formation. Sulfamethazine is an active pharmaceutical ingredient (API) with a strong ability to form hydrogen bonds due to its donor and acceptor groups. The chemical structure of this API allows it to exist in more than one tautomer. The cocrystallization of this molecule with a coformer has the ability to influence which tautomer is present in the crystal structure. This thesis provides data that defines the relationship of coformer acidity to tautomer formation in sulfamethazine. A total of eighteen cocrystals of sulfamethazine with benzoic acid derivatives were synthesized and the tautomeric form to coformer acidity was analyzed. The cocrystallization of APis is a classic example of molecular recognition between two or more compounds. Studies that seek to design these materials and others often focus on strong non-bonded contacts (e.g. hydrogen bonds) as a means to generate desired supramolecular architectures. Less well studied, but no less important to the overall molecular recognition process, are chemical features that produce less manageable motifs via ill-defined or weak contacts. Molecular shape is one such feature. This thesis exploits quasiracemates — i.e., near racemic materials — to probe the role molecular topology plays in the recognition process. A diverse set of diarylamide quasienantiomers that differ incrementally in substituent size and molecular framework has been prepared. Mixing of pairs of these quasienantiomers in the melt using video-assisted host stage microscopy provided a robust diagnostic tool for detecting new quasiracemic crystalline phases. Data retrieved using this virtual melting-point phase method not only draws considerable attention to the role of topological features to supramolecular assemblies, but also the structural boundaries of these co-crystalline systems. This investigation synthetically explores the broad structure space towards the identification of new isostructural building blocks and highlights important molecular relationships responsible for molecular recognition that may serve in the design of new functional materials

Molecular Recognition Profiles of Molecular Cocrystals

The manner in which molecules recognize each other holds critical importance to nearly every area of science. This significance stems from the key underpinning of molecular assembly to our most basic understanding of chemical processes. Whether these interactions relate to small-molecule catalytic transformations or complex physiological processes, the structural features responsible for molecular association play into the well-known adage that form follows function where material property arises from the collective structural features of the molecular components. Because the form of chemical systems is derived from a complex blend of covalent and non-bonded contacts, codifying each contributor has become essential for recognizing the functions and potential applications of materials. While considerable progress in this area has been realized by isolating and identifying molecular contacts and the structural details of their conditional exceptions, insight to the entire landscape of molecular associations remains an ongoing effort. This thesis explores the molecular recognition process from two uniquely different perspectives. The first is from cocrystalizing a variety of benzoic acids with the pharmaceutical agent sulfamethazine and the second area investigates how molecular shape controls quasiracemate formation. Sulfamethazine is an active pharmaceutical ingredient (API) with a strong ability to form hydrogen bonds due to its donor and acceptor groups. The chemical structure of this API allows it to exist in more than one tautomer. The cocrystallization of this molecule with a coformer has the ability to influence which tautomer is present in the crystal structure. This thesis provides data that defines the relationship of coformer acidity to tautomer formation in sulfamethazine. A total of eighteen cocrystals of sulfamethazine with benzoic acid derivatives were synthesized and the tautomeric form to coformer acidity was analyzed. The cocrystallization of APis is a classic example of molecular recognition between two or more compounds. Studies that seek to design these materials and others often focus on strong non-bonded contacts (e.g. hydrogen bonds) as a means to generate desired supramolecular architectures. Less well studied, but no less important to the overall molecular recognition process, are chemical features that produce less manageable motifs via ill-defined or weak contacts. Molecular shape is one such feature. This thesis exploits quasiracemates — i.e., near racemic materials — to probe the role molecular topology plays in the recognition process. A diverse set of diarylamide quasienantiomers that differ incrementally in substituent size and molecular framework has been prepared. Mixing of pairs of these quasienantiomers in the melt using video-assisted host stage microscopy provided a robust diagnostic tool for detecting new quasiracemic crystalline phases. Data retrieved using this virtual melting-point phase method not only draws considerable attention to the role of topological features to supramolecular assemblies, but also the structural boundaries of these co-crystalline systems. This investigation synthetically explores the broad structure space towards the identification of new isostructural building blocks and highlights important molecular relationships responsible for molecular recognition that may serve in the design of new functional materials

Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while <scp>CNS</scp> entry is required for locomotor and taste avoidance effects

ObjectivesOxytocin (OT) has a well‐established role in reproductive behaviours; however, it recently emerged as an important regulator of energy homeostasis. In addition to central nervous system (CNS), OT is found in the plasma and OT receptors (OT‐R) are found in peripheral tissues relevant to energy balance regulation. Here, we aim to determine whether peripheral OT‐R activation is sufficient to alter energy intake and expenditure.Methods and ResultsWe first show that systemic OT potently reduced food intake and food‐motivated behaviour for a high‐fat reward in male and female rats. As it is plausible that peripherally, intraperitoneally (IP) injected OT crosses the blood‐brain barrier (BBB) to produce some of the metabolic effects within the CNS, we screened, with a novel fluorescently labelled‐OT (fAF546‐OT, Roxy), for the presence of IP‐injected Roxy in CNS tissue relevant to feeding control and compared such with BBB‐impermeable fluorescent OT‐B$_{12}$ (fCy5‐OT‐B$_{12;}$ BRoxy). While Roxy did penetrate the CNS, BRoxy did not. To evaluate the behavioural and thermoregulatory impact of exclusive activation of peripheral OT‐R, we generated a novel BBB‐impermeable OT (OT‐B$_{12}$), with equipotent binding at OT‐R in vitro. In vivo, IP‐injected OT and OT‐B$_{12}$ were equipotent at food intake suppression in rats of both sexes, suggesting that peripheral OT acts on peripheral OT‐R to reduce feeding behaviour. Importantly, OT induced a potent conditioned taste avoidance, indistinguishable from that induced by LiCl, when applied peripherally. Remarkably, and in contrast to OT, OT‐B$_{12}$ did not induce any conditioned taste avoidance. Limiting the CNS entry of OT also resulted in a dose‐dependent reduction of emesis in male shrews. While both OT and OT‐B$_{12}$ proved to have similar effects on body temperature, only OT resulted in home‐cage locomotor depression.ConclusionsTogether our data indicate that limiting systemic OT CNS penetrance preserves the anorexic effects of the peptide and reduces the clinically undesired side effects of OT: emesis, taste avoidance and locomotor depression. Thus, therapeutic targeting of peripheral OT‐R may be a viable strategy to achieve appetite suppression with better patient outcomes

Cold atoms in space: community workshop summary and proposed road-map

We summarise the discussions at a virtual Community Workshop on Cold Atoms in Space concerning the status of cold atom technologies, the prospective scientific and societal opportunities offered by their deployment in space, and the developments needed before cold atoms could be operated in space. The cold atom technologies discussed include atomic clocks, quantum gravimeters and accelerometers, and atom interferometers. Prospective applications include metrology, geodesy and measurement of terrestrial mass change due to, e.g., climate change, and fundamental science experiments such as tests of the equivalence principle, searches for dark matter, measurements of gravitational waves and tests of quantum mechanics. We review the current status of cold atom technologies and outline the requirements for their space qualification, including the development paths and the corresponding technical milestones, and identifying possible pathfinder missions to pave the way for missions to exploit the full potential of cold atoms in space. Finally, we present a first draft of a possible road-map for achieving these goals, that we propose for discussion by the interested cold atom, Earth Observation, fundamental physics and other prospective scientific user communities, together with the European Space Agency (ESA) and national space and research funding agencies.publishedVersio

Cold atoms in space: community workshop summary and proposed road-map

We summarise the discussions at a virtual Community Workshop on Cold Atoms in Space concerning the status of cold atom technologies, the prospective scientific and societal opportunities offered by their deployment in space, and the developments needed before cold atoms could be operated in space. The cold atom technologies discussed include atomic clocks, quantum gravimeters and accelerometers, and atom interferometers. Prospective applications include metrology, geodesy and measurement of terrestrial mass change due to, e.g., climate change, and fundamental science experiments such as tests of the equivalence principle, searches for dark matter, measurements of gravitational waves and tests of quantum mechanics. We review the current status of cold atom technologies and outline the requirements for their space qualification, including the development paths and the corresponding technical milestones, and identifying possible pathfinder missions to pave the way for missions to exploit the full potential of cold atoms in space. Finally, we present a first draft of a possible road-map for achieving these goals, that we propose for discussion by the interested cold atom, Earth Observation, fundamental physics and other prospective scientific user communities, together with the European Space Agency (ESA) and national space and research funding agencies

Cold atoms in space: community workshop summary and proposed road-map

We summarise the discussions at a virtual Community Workshop on Cold Atoms in Space concerning the status of cold atom technologies, the prospective scientific and societal opportunities offered by their deployment in space, and the developments needed before cold atoms could be operated in space. The cold atom technologies discussed include atomic clocks, quantum gravimeters and accelerometers, and atom interferometers. Prospective applications include metrology, geodesy and measurement of terrestrial mass change due to, e.g., climate change, and fundamental science experiments such as tests of the equivalence principle, searches for dark matter, measurements of gravitational waves and tests of quantum mechanics. We review the current status of cold atom technologies and outline the requirements for their space qualification, including the development paths and the corresponding technical milestones, and identifying possible pathfinder missions to pave the way for missions to exploit the full potential of cold atoms in space. Finally, we present a first draft of a possible road-map for achieving these goals, that we propose for discussion by the interested cold atom, Earth Observation, fundamental physics and other prospective scientific user communities, together with the European Space Agency (ESA) and national space and research funding agencies

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead