Alzheimer's disease (AD) is a progressive age-related neurodegenerative disease. At the time of clinical manifestation of dementia, significant irreversible brain damage is already present, rendering the diagnosis of AD at early stages of the disease an urgent prerequisite for therapeutic treatment to halt, or at least slow, disease progression. In this review, we discuss various neuroimaging measures that are proving to have potential value as biomarkers of AD pathology for the detection and prediction of AD before the onset of dementia. Recent studies that have identified AD-like structural and functional brain changes in elderly people who are cognitively within the normal range or who have mild cognitive impairment (MCI) are discussed. A dynamic sequence model of changes that occur in neuroimaging markers during the different disease stages is presented and the predictive value of multimodal neuroimaging for AD dementia is considered.
Cells respond to the accumulation of unfolded proteins by activating signal transduction cascades that improve protein folding. One example of such a cascade is the unfolded protein response (UPR), which senses protein folding stress in the endoplasmic reticulum (ER) and leads to improvement in the protein folding and processing capacity of the organelle. A central paradox of the UPR, and indeed of all such stress pathways, is that the response is designed to facilitate both adaptation to stress and apoptosis, depending upon the nature and severity of the stressor. Understanding how the UPR can allow for adaptation, instead of apoptosis, is of tremendous physiological importance. Recent advances have improved our understanding of ER stress and the vertebrate UPR, which suggest possible mechanisms by which cells adapt to chronic stress.
We challenge the view that our species, Homo sapiens, evolved within a single population and/or region of Africa. The chronology and physical diversity of Pleistocene human fossils suggest that morphologically varied populations pertaining to the H. sapiens clade lived throughout Africa. Similarly, the African archaeological record demonstrates the polycentric origin and persistence of regionally distinct Pleistocene material culture in a variety of paleoecological settings. Genetic studies also indicate that present-day population structure within Africa extends to deep times, paralleling a paleoenvironmental record of shifting and fractured habitable zones. We argue that these fields support an emerging view of a highly structured African prehistory that should be considered in human evolutionary inferences, prompting new interpretations, questions, and interdisciplinary research directions.
G-Protein-coupled receptors (GPCRs) were classically described as monomers. We now appreciate that they also function as homo- and hetero-oligomers, for which structural information is lacking. Here, we use available 3D structures and biochemical considerations to present and evaluate experimentally testable structural models for GPCR oligomers and associated G proteins.
Organismal adaptation to extreme temperatures yields enzymes with distinct configurational stabilities, including thermophilic and psychrophilic enzymes, which are adapted to high and low temperatures, respectively. These enzymes are widely assumed to also have unique rate–temperature dependencies. Thermophilic enzymes, for example, are considered optimal at high temperatures and effectively inactive at low temperatures due to excess rigidity. Surveying published data, we find that thermophilic, mesophilic, and psychrophilic enzymes exhibit indistinguishable rate–temperature dependencies. Furthermore, given the nonenzymatic rate–temperature dependency, all enzymes, regardless of their operation temperatures, become >10-fold less powerful catalysts per 25°C temperature increase. Among other factors, this loss of rate acceleration may be ascribed to thermally induced vibrations compromising the active-site catalytic configuration, suggesting that many enzymes are in fact insufficiently rigid.
The current definition of major depressive disorder (MDD) emerged from efforts to create reliable diagnostic criteria for clinical and research use. However, despite decades of research, the neurobiology of MDD is largely unknown, and treatments are no more effective today than they were 50–70 years ago. Here, we propose that the current conception of depression is misguiding basic and clinical research. Redefinition is necessary and could include a focus on a more narrowly defined set of core symptoms. However, we conclude that depression is better defined as the tendency to enter into, and inability to disengage from, a negative mood state rather than the mood state per se . We also discuss the implications of this revised definition for future clinical and basic research.
Every animal occupies a unique cognitive world based on its sensory capacities, and attentional and learning biases. Behaviour results from the interaction of this cognitive world with the environment. As humans alter environments, cognitive processes ranging from perceptual processes to learned behaviour govern animals’ reactions. By harnessing animals’ perceptual biases and applying insights from cognitive theory, we can purposefully alter cues to reduce maladaptive responses and shape behaviour. Despite the fundamental connection between cognition and behaviour, the breadth of cognitive theory is underutilised in conservation practice. Bridging these disciplines could augment existing conservation efforts targeting animal behaviour. We outline relevant principles of perception and learning, and develop a step-by-step process for applying aspects of cognition towards specific conservation issues.
Early-life stress lastingly affects adult cognition and increases vulnerability to psychopathology, but the underlying mechanisms remain elusive. In this Opinion article, we propose that early nutritional input together with stress hormones and sensory stimuli from the mother during the perinatal period act synergistically to program the adult brain, possibly via epigenetic mechanisms. We hypothesize that stress during gestation or lactation affects the intake of macro- and micronutrients, including dietary methyl donors, and/or impairs the dam's metabolism, thereby altering nutrient composition and intake by the offspring. In turn, this may persistently modulate gene expression via epigenetic programming, thus altering hippocampal structure and cognition. Understanding how the combination of stress, nutrition, and epigenetics shapes the adult brain is essential for effective therapies.
LINE-1 (L1) elements are retrotransposons that insert extra copies of themselves throughout the genome using a ‘copy and paste’ mechanism. L1s comprise nearly ∼20% of the human genome and are able to influence chromosome integrity and gene expression upon reinsertion. Recent studies show that L1 elements are active and ‘jumping’ during neuronal differentiation. New somatic L1 insertions could generate ‘genomic plasticity’ in neurons by causing variation in genomic DNA sequences and by altering the transcriptome of individual cells. Thus, L1-induced variation could affect neuronal plasticity and behavior. We discuss potential consequences of L1-induced neuronal diversity and propose that a mechanism for generating diversity in the brain could broaden the spectrum of behavioral phenotypes that can originate from any single genome.
Carbonic anhydrase isoform IX (CA IX) is highly overexpressed in many types of cancer. Its expression, which is regulated by the HIF-1 transcription factor, is strongly induced by hypoxia and correlates with a poor response to classical chemo- and radiotherapies. CA IX contributes to acidification of the tumor environment by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons, thereby leading to acquisition of metastasic phenotypes and chemoresistance to weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific inhibitors, such as the sulfonamide indisulam, reverts these processes, establishing a clear-cut role for CA IX in tumorigenesis. Thus, selective CA IX inhibitors could prove useful for elucidating the role of CA IX in hypoxic cancers, for controlling the pH imbalance in tumor cells and for developing diagnostic or therapeutic applications for tumor management. Indeed, fluorescent inhibitors and membrane-impermeant sulfonamides have recently been used as proof-of-concept tools, demonstrating that CA IX is an interesting target for anticancer drug development.