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"Goodwin, Matthew"
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Bad education : why our universities are broken and how we can fix them
Our universities are broken. Consumed by funding and admissions crises, governed by corruption and self-interest, they have become frontiers of cultural, social and political division. Established as ivory towers and sanctuaries of higher learning, they are now broken institutions that are failing a generation of young people. This book shows us why, and what we must do to fix them.
BOOK
Lactate metabolism: historical context, prior misinterpretations, and current understanding
Lactate (La−) has long been at the center of controversy in research, clinical, and athletic settings. Since its discovery in 1780, La− has often been erroneously viewed as simply a hypoxic waste product with multiple deleterious effects. Not until the 1980s, with the introduction of the cell-to-cell lactate shuttle did a paradigm shift in our understanding of the role of La− in metabolism begin. The evidence for La− as a major player in the coordination of whole-body metabolism has since grown rapidly. La− is a readily combusted fuel that is shuttled throughout the body, and it is a potent signal for angiogenesis irrespective of oxygen tension. Despite this, many fundamental discoveries about La− are still working their way into mainstream research, clinical care, and practice. The purpose of this review is to synthesize current understanding of La− metabolism via an appraisal of its robust experimental history, particularly in exercise physiology. That La− production increases during dysoxia is beyond debate, but this condition is the exception rather than the rule. Fluctuations in blood [La−] in health and disease are not typically due to low oxygen tension, a principle first demonstrated with exercise and now understood to varying degrees across disciplines. From its role in coordinating whole-body metabolism as a fuel to its role as a signaling molecule in tumors, the study of La− metabolism continues to expand and holds potential for multiple clinical applications. This review highlights La−’s central role in metabolism and amplifies our understanding of past research.
Journal Article
Lactate is always the end product of glycolysis
Through much of the history of metabolism, lactate (La(-)) has been considered merely a dead-end waste product during periods of dysoxia. Congruently, the end product of glycolysis has been viewed dichotomously: pyruvate in the presence of adequate oxygenation, La(-) in the absence of adequate oxygenation. In contrast, given the near-equilibrium nature of the lactate dehydrogenase (LDH) reaction and that LDH has a much higher activity than the putative regulatory enzymes of the glycolytic and oxidative pathways, we contend that La(-) is always the end product of glycolysis. Cellular La(-) accumulation, as opposed to flux, is dependent on (1) the rate of glycolysis, (2) oxidative enzyme activity, (3) cellular O2 level, and (4) the net rate of La(-) transport into (influx) or out of (efflux) the cell. For intracellular metabolism, we reintroduce the Cytosol-to-Mitochondria Lactate Shuttle. Our proposition, analogous to the phosphocreatine shuttle, purports that pyruvate, NAD(+), NADH, and La(-) are held uniformly near equilibrium throughout the cell cytosol due to the high activity of LDH. La(-) is always the end product of glycolysis and represents the primary diffusing species capable of spatially linking glycolysis to oxidative phosphorylation.
Journal Article
Applying Machine Learning to Facilitate Autism Diagnostics: Pitfalls and Promises
Machine learning has immense potential to enhance diagnostic and intervention research in the behavioral sciences, and may be especially useful in investigations involving the highly prevalent and heterogeneous syndrome of autism spectrum disorder. However, use of machine learning in the absence of clinical domain expertise can be tenuous and lead to misinformed conclusions. To illustrate this concern, the current paper critically evaluates and attempts to reproduce results from two studies (Wall et al. in Transl Psychiatry 2(4):e100,
2012a
; PloS One 7(8),
2012b
) that claim to drastically reduce time to diagnose autism using machine learning. Our failure to generate comparable findings to those reported by Wall and colleagues using larger and more balanced data underscores several conceptual and methodological problems associated with these studies. We conclude with proposed best-practices when using machine learning in autism research, and highlight some especially promising areas for collaborative work at the intersection of computational and behavioral science.
Journal Article
The Roles of Host and Viral Antibody Fc Receptors in Herpes Simplex Virus (HSV) and Human Cytomegalovirus (HCMV) Infections and Immunity
Herpesvirus infections are a leading cause of neurodevelopmental delay in newborns and end-organ disease in immunocompromised patients. One leading strategy to reduce the disease burden of herpesvirus infections such as herpes simplex virus (HSV) and human cytomegalovirus (HCMV) is to prevent primary acquisition by vaccination, yet vaccine development remains hampered by limited understanding of immune correlates of protection against infection. Traditionally, vaccine development has aimed to increase antibody titers with neutralizing function, which involves the direct binding of antibodies to viral particles. However, recent research has explored the numerous other responses that can be mediated by engagement of the antibody constant region (Fc) with Fc receptors (FcR) present on immune cells or with complement molecules. These functions include antiviral responses such as antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Uniquely, herpesviruses encode FcR that can act as distractor receptors for host antiviral IgG, thus enabling viral evasion of host defenses. This review focuses on the relative roles of neutralizing and non-neutralizing functions antibodies that target herpesvirus antigens for HSV and HCMV, as well as the roles of Fc-FcR interactions for both host defenses and viral escape.
Journal Article
New British Fascism
The British National Party (BNP) is the most successful far right party in British political history. Based on unprecedented access to the party and its members, this book examines the rise of the BNP and explains what drives some citizens to support far right politics. It is essential reading for all those with an interest in British politics, extremism, voting, race relations and community cohesion. The book helps us understand:
how wider trends in society have created a favourable climate for the far right;
how the far right has presented a 'modernised' ideology and image;
how the movement is organized, and has evolved over time;
who votes for the far right and why;
why people join, become and remain actively involved in far right parties.
eBook
Temporal point process modeling of aggressive behavior onset in psychiatric inpatient youths with autism
Aggressive behavior, including aggression towards others and self-injury, occurs in up to 80% of children and adolescents with autism, making it a leading cause of behavioral health referrals and a major driver of healthcare costs. Predicting when autistic youth will exhibit aggression can be challenging due to their communication difficulties. Many are minimally verbal or have poor emotional insight. Recent advances in Machine Learning and wearable biosensing demonstrate the ability to predict aggression within a limited future window (typically one to three minutes) in autistic individuals. However, existing works do not estimate aggression onset probability or the expected number of aggression onsets over longer periods, nor do they provide interpretable insights into onset dynamics. To address these limitations, we apply Temporal Point Processes(TPPs), particularly self-exciting Hawkes processes, to model the timing of aggressive behavior onsets in psychiatric inpatient autistic youth. We benchmark several TPP models by evaluating their goodness-of-fit and predictive metrics. Our results demonstrate that self-exciting TPPs more accurately capture the irregular and clustered nature of aggression onsets, especially compared to traditional Poisson models. These incipient findings suggest that TPPs can provide interpretable, probabilistic forecasts of aggression onset along a time continuum, supporting future clinical decision-making and preemptive intervention.
Journal Article
Construction and in vivo assembly of a catalytically proficient and hyperthermostable de novo enzyme
Although catalytic mechanisms in natural enzymes are well understood, achieving the diverse palette of reaction chemistries in re-engineered native proteins has proved challenging. Wholesale modification of natural enzymes is potentially compromised by their intrinsic complexity, which often obscures the underlying principles governing biocatalytic efficiency. The maquette approach can circumvent this complexity by combining a robust de novo designed chassis with a design process that avoids atomistic mimicry of natural proteins. Here, we apply this method to the construction of a highly efficient, promiscuous, and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H
2
O
2
. The maquette exhibits kinetics that match and even surpass those of certain natural peroxidases, retains its activity at elevated temperature and in the presence of organic solvents, and provides a simple platform for interrogating catalytic intermediates common to natural heme-containing enzymes.
Catalytic mechanisms of enzymes are well understood, but achieving diverse reaction chemistries in re-engineered proteins can be difficult. Here the authors show a highly efficient and thermostable artificial enzyme that catalyzes a diverse array of substrate oxidations coupled to the reduction of H
2
O
2
.
Journal Article