Project description:This is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein-protein interactions and to nucleic acids and to protein-nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena.
Project description:Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors. Structures of antigen receptors in the innate immune system then explained their inherent specificity for particular microbial antigens including lipids, carbohydrates, nucleic acids, small molecules, and specific proteins. These two sides of the immune system act immediately (innate) to particular microbial antigens or evolve (adaptive) to attain high specificity and affinity to a much wider range of antigens. We also include examples of other key receptors in the immune system (cytokine receptors) that regulate immunity and inflammation. Furthermore, these antigen receptors use a limited set of protein folds to accomplish their various immunological roles. The other main players are the antigens themselves. We focus on surface glycoproteins in enveloped viruses including SARS-CoV-2 that enable entry and egress into host cells and are targets for the antibody response. This review covers what we have learned over the past half century about the structural basis of the immune response to microbial pathogens and how that information can be utilized to design vaccines and therapeutics.
Project description:Vision is the most powerful sense guiding our interaction with the environment. Its process starts with the retinal image as input and results in visually guided behaviors as output. This paper summarizes insights I gained over >40 years dealing with clinical ophthalmology, visual science, and vision rehabilitation, disciplines that all involve vision, but from different points of view. The retinal image contains 2-dimensional forms that have no inherent meaning. The brain matches this input to stored concepts, to create a Mental Model that is filled with 3-dimensional objects that are meaningful and linked to other senses. Ultimately this leads to the output of goal-directed visually guided behavior. The processes involved are too complex to be covered by a single practitioner. Optimal vision rehabilitation requires teamwork that includes contributions from various professions. It also requires an understanding, as well as possible, of the cerebral processes involved. The visual sciences study mostly the input-driven process from retinal image to visual percepts. Their studies deal mostly with groups and group averages and only occasionally with individual disease conditions. Clinical ophthalmology deals mostly with individuals, rather than group averages. The motto of the American Academy of Ophthalmology reminds us that the end point of patient care goes beyond "preserving sight." It also includes "empowering lives" by creating the conditions for goal-directed interaction with the environment through visually directed behavior. Traditionally, the study of vision has mainly involved the conscious part of vision, handled mostly in the ventral stream. However, the subconscious part of vision, handled mostly in the dorsal stream must also be considered. This is further stimulated by the demands of computer vision, image processing, and artificial intelligence. Vision rehabilitation traditionally deals with the input side through better illumination and various magnification devices. This is the domain of low vision aids. Increasingly, however, it must also address the output side, and the involvement of other senses (braille, long cane, and talking books). This requires better understanding of the goal-directed higher visual processes. The supplemental material covers the development of numerical scales to quantify not only visual acuity but also visual abilities, and the use of different tests. The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Project description:March 2013 represented the 50th anniversary of the first license granted for a fibrinogen concentrate. In this review, we look at the history of bleeding management that led to the development of fibrinogen concentrate, discuss its current use, and consider future developments for this product.
Project description:BackgroundAlthough the relationship between maternal bonding and risk of offspring depression has been demonstrated, it is unclear whether this risk exists for subsequent generations. This study examines the association between maternal reports of her own mother's parenting and later risk of depression in offspring at age 18.MethodThis study is based on data from the Avon Longitudinal Study of Parents and Children. Mothers enrolled in the study, completed the Parental Bonding Instrument to provide an assessment of how they were parented by their own mothers up to the age of 16. Offspring depression was assessed at age of 18 using the Clinical Interview Schedule-Revised. The sample comprised 10,405 respondents who had completed the Parental Bonding Instrument during the antenatal period. Results were adjusted for grandmother's history of depression, maternal depression, and a range of socioeconomic variables.ResultsA one standard deviation increase in mothers' perceived lack of care in their own childhood was associated with a 16% increase in the odds of offspring depression at age 18 (odds ratios = 1.16, 95% confidence intervals = [1.04, 1.30]). This effect remained following adjustment for potential confounders (odds ratios = 1.14, 95% confidence intervals = [1.02, 1.27]). There was no evidence for an association between overprotection and offspring depression.ConclusionsThis study is consistent with the hypothesis that sensitive caregiving is important to future risk of depression across generations. Preventative interventions could be aimed at promoting positive parenting practices, which may help to reduce the risk of depression in subsequent generations.
Project description:Over 50 years ago, the discovery of poly(ADP-ribose) (PAR) set a new field of science in motion-the field of poly(ADP-ribosyl) transferases (PARPs) and ADP-ribosylation. The field is still flourishing today. The diversity of biological processes now known to require PARPs and ADP-ribosylation was practically unimaginable even two decades ago. From an initial focus on DNA damage detection and repair in response to genotoxic stresses, the field has expanded to include the regulation of chromatin structure, gene expression, and RNA processing in a wide range of biological systems, including reproduction, development, aging, stem cells, inflammation, metabolism, and cancer. This special focus issue of Molecular Cell includes a collection of three Reviews, three Perspectives, and a SnapShot, which together summarize the current state of the field and suggest where it may be headed.