Faculty reviews最新文献

Skeletal muscle mass is a very plastic characteristic of skeletal muscle and is regulated by signaling pathways that control the balance between anabolic and catabolic processes. The serine/threonine kinase mechanistic/mammalian target of rapamycin (mTOR) has been shown to be critically important in the regulation of skeletal muscle mass through its regulation of protein synthesis and degradation pathways. In this commentary, recent advances in the understanding of the role of mTORC1 in the regulation of muscle mass under conditions that induce hypertrophy and atrophy will be highlighted.

Systems consolidation has mostly been treated as a neural construct defined by the time-dependent change in memory representation from the hippocampus (HPC) to other structures, primarily the neocortex. Here, we identify and evaluate the explicit and implicit premises that underlie traditional or standard models and theories of systems consolidation based on evidence from research on humans and other animals. We use the principle that changes in neural representation over time and experience are accompanied by corresponding changes in psychological representations, and vice versa, to argue that each of the premises underlying traditional or standard models and theories of systems consolidation is found wanting. One solution is to modify or abandon the premises or theories and models. This is reflected in moderated models of systems consolidation that emphasize the early role of the HPC in training neocortical memories until they stabilize. The fault, however, may lie in the very concept of systems consolidation and its defining feature. We propose that the concept be replaced by one of memory systems reorganization, which does not carry the theoretical baggage of systems consolidation and is flexible enough to capture the dynamic nature of memory from inception to very long-term retention and retrieval at a psychological and neural level. The term "memory system reorganization" implies that memory traces are not fixed, even after they are presumably consolidated. Memories can continue to change as a result of experience and interactions among memory systems across the lifetime. As will become clear, hippocampal training of neocortical memories is only one type of such interaction, and not always the most important one, even at inception. We end by suggesting some principles of memory reorganization that can help guide research on dynamic memory processes that capture corresponding changes in memory at the psychological and neural levels.

The primary plant cell wall is a hydrated meshwork of polysaccharides that is strong enough to withstand large mechanical stresses imposed by turgor while remaining pliant in ways that permit growth. To understand how its macromolecular architecture produces its complex mechanical properties, Zhang et al.¹ computationally assembled a realistic network of cellulose microfibrils, hemicellulose, and pectin. The simulated wall responded to computationally applied stress like the real wall on which it was based. The model showed the location and chemical identity of stress-bearing components. It showed that cellulose microfibril interactions and movements dominated the wall's mechanical behavior, while hemicellulose and pectin had surprisingly minor effects.

Cells need to couple intracellular actin flows with the substrate to generate forward movement. This has traditionally been studied in the context of specific transmembrane receptors, particularly integrin adhesion receptors, which link extracellular adhesive molecules to the actin cytoskeleton. However, leukocytes and other cells can also migrate using integrin-independent strategies both in vivo and in vitro, though the cellular and environmental requirements for this mode are not fully understood. In seminal recent work, Reversat et al.¹ develop a range of innovative 2D and 3D engineered microdevices and probe the biophysical mechanisms underlying T lymphocytes and dendritic cells in conditions of limited substrate adhesion. They identify a physical principle of mechano-coupling between retrograde actin flow and irregular extracellular confinement, which allows the cell to generate mechanical resistance and move in the absence of receptor-mediated adhesion. Through the combined use of experiments and theoretical modeling, this work resolves a long-standing question in cell biology and establishes mechanical interaction with an irregular-shaped 3D environment which may be relevant to cell migration in a range of tissue contexts.

A major advance in the study of Huntington's disease (HD) has been the development of human disease models employing induced pluripotent stem cells (iPSCs) derived from patients with HD. Because iPSCs provide an unlimited source of cells and can be obtained from large numbers of HD patients, they are a uniquely valuable tool for investigating disease mechanisms and for discovering potential disease-modifying therapeutics. Here, we summarize some of the important findings in HD pathophysiology that have emerged from studies of patient-derived iPSC lines. Because they retain the genome and actual disease mutations of the patient, they provide a cell source to investigate genetic contributions to the disease. iPSCs provide advantages over other disease models. While iPSC-based technology erases some epigenetic marks, newly developed transdifferentiation methods now let us investigate epigenetic factors that control expression of mutant huntingtin (mHTT). Human HD iPSC lines allow us to investigate how endogenous levels of mHTT affect cell health, in contrast to other models that often rely on overexpressing the protein. iPSCs can be differentiated into neurons and other disease-related cells such as astrocytes from different brain regions to study brain regional differences in the disease process, as well as the cell-cell dependencies involved in HD-associated neurodegeneration. They also serve as a tissue source to investigate factors that impact CAG repeat instability, which is involved in regional differences in neurodegeneration in the HD brain. Human iPSC models can serve as a powerful model system to identify genetic modifiers that may impact disease onset, progression, and symptomatology, providing novel molecular targets for drug discovery.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant state for a spectrum of lymphoplasmacytic malignancies. The risk of progression of MGUS to a symptomatic therapy requiring plasma cell dyscrasia is about 1% per year. Studies carried out over the previous 10 years have improved risk stratification of MGUS based on serologic and genomic evaluations, which has led to better management of patients. In this review, we address the epidemiology, diagnosis, and pathogenesis of MGUS and discuss risk-adapted best practice approaches to monitor patients.

Allergic diseases in general, and chronic allergic inflammation in particular, are on the rise in the United States and other developed countries. The idea of chronic allergic disease as a chronic type 2 immune response has been around for several decades. However, data suggest that other mechanisms may be important in chronic disease. Therefore, we believe it is time for a paradigm shift in understanding the mechanistic causes of disease symptoms in these diseases. In this review, we have avoided the classic canonical pathways and focused on the emerging idea that oxidative stress, changes in immuno-metabolism, mitochondrial dysfunction, and epigenetic changes (particularly microRNA profile) may be working concurrently or synergistically to potentiate allergic disease symptoms. Furthermore, we have addressed how the epidemic of obesity exacerbates allergic disease via the dysregulation of the aforementioned factors.

Soil compaction, in which soil grains are pressed together leaving less pore space for air and water, is a persistent problem in mechanized agriculture. Most plant roots fail to penetrate soil if it is too dense. One might assume that they are physically unable to penetrate the compact soil. However, new research demonstrates a more complex mechanism that requires the build-up of the volatile plant hormone ethylene in the rhizosphere¹. Ethylene itself can arrest growth and, in compact soil, it is present in higher concentrations near roots due to its reduced ability to diffuse. Roots that lack the ethylene response pathway grow better through compact soil, demonstrating that it is physically possible to do so. The work suggests new levers for crop improvement in increasingly degraded soils.

Plasma membrane rupture (PMR), the final event in lytic cell death that is in part responsible for the release of pro-inflammatory signals, was believed to be a passive event that followed osmotic swelling. Kayagaki et al. ¹ have discovered that PMR is, in fact, mediated by ninjurin-1 (NINJ1), adding a novel regulatory step that is conserved across different types of lytic cell death, such as pyroptosis, necroptosis, and apoptosis. PMR is dependent on NINJ1 oligomerization, which is mediated by its highly conserved putative N-terminal α-helix. In vivo data suggest that the NINJ1-dependent secretome that is released upon PMR is likely to modulate antimicrobial host defense, suggesting this additional regulatory step also has physiological relevance.

The protein structure prediction problem is solved, at last, thanks in large part to the use of artificial intelligence. The structures predicted by AlphaFold and RoseTTAFold are becoming the requisite starting point for many protein scientists. New frontiers, such as the conformational sampling of intrinsically disordered proteins, are emerging.