Faculty reviews最新文献

Constitutive vesicle trafficking is the default pathway used by all cells for movement of intracellular cargoes between subcellular compartments and in and out of the cell. Classically, constitutive trafficking was thought to be continuous and unregulated, in contrast to regulated secretion, wherein vesicles are stored intracellularly until undergoing synchronous membrane fusion following a Ca²⁺ signal. However, as shown in the literature reviewed here, many continuous trafficking steps can be up- or down-regulated by Ca²⁺, including several steps associated with human pathologies. Notably, we describe a series of Ca²⁺ pumps, channels, Ca²⁺-binding effector proteins, and their trafficking machinery targets that together regulate the flux of cargo in response to genetic alterations as well as baseline and agonist-dependent Ca²⁺ signals. Here, we review the most recent advances, organized by organellar location, that establish the importance of these components in trafficking steps. Ultimately, we conclude that Ca²⁺ regulates an expanding series of distinct mechanistic steps. Furthermore, the involvement of Ca²⁺ in trafficking is complex. For example, in some cases, the same Ca²⁺ effectors regulate surprisingly distinct trafficking steps, or even the same trafficking step with opposing influences, through binding to different target proteins.

Cognitive behavioral therapy for insomnia (CBT-I) has been shown to be efficacious and now is considered the first-line treatment for insomnia for both uncomplicated insomnia and insomnia that occurs comorbidly with other chronic disorders (comorbid insomnia). The purposes of this review are to provide a comprehensive summary of the efficacy data (for example, efficacy overall and by clinical and demographic considerations and by CBT-I formulation) and to discuss the future of CBT-I (for example, what next steps should be taken in terms of research, dissemination, implementation, and practice).

The origin of cellular complexity characterizing eukaryotic cells remains a central unresolved issue in the study of diversification of cellular life on Earth. The isolation by Imachi et al.¹ of a member of the Asgard archaea² - a contemporary relative of organisms thought to have given rise to eukaryotic cells about 2 billion years ago - now promises new insight. The complete genome sequence of the isolated Lokiarchaeum strain confirms that the eukaryotic signature proteins (ESPs) previously identified in the Lokiarchaeota³ and other Asgard archaea² are indeed encoded by these archaeal genomes and do not represent contamination from eukaryotes. These ESPs encode homologs of eukaryotic actins, small GTPases and the ESCRT complex proteins and are required for the functioning of complex eukaryotic cells. The new, slowly growing, anaerobic laboratory strain allows a first direct look at these organisms and provides key insights into the morphology and metabolism of an Asgard archaeal organism. The work has provided valuable information for other laboratories that aim to isolate and characterize related organisms from other environments.

Infectious diseases emerge via many routes and may need to overcome stepwise bottlenecks to burgeon into epidemics and pandemics. About 60% of human infections have animal origins, whereas 40% either co-evolved with humans or emerged from non-zoonotic environmental sources. Although the dynamic interaction between wildlife, domestic animals, and humans is important for the surveillance of zoonotic potential, exotic origins tend to be overemphasized since many zoonoses come from anthropophilic wild species (for example, rats and bats). We examine the equivocal evidence of whether the appearance of novel infections is accelerating and relate technological developments to the risk of novel disease outbreaks. Then we briefly compare selected epidemics, ancient and modern, from the Plague of Athens to COVID-19.

Hair is a deeply rooted component of identity and culture. Recent articles in this series have focused on scientific evidence relating to hair growth and new insights into the pathogenesis and mechanism of hair loss. This article reviews emerging evidence that has advanced our understanding of hair growth in both of these areas to provide a context for outlining current and emerging therapies. These include finasteride, minoxidil, topical prostaglandins, natural supplements, microneedling, low-level laser light, platelet-rich plasma, fractional lasers, cellular therapy, Wnt activators and SFRP1 antagonism.

For more than three decades, RNA has been known to be a relevant and attractive macromolecule to target but figuring out which RNA should be targeted and how remains challenging. Recent years have seen the confluence of approaches for screening, drug optimization, and target validation that have led to the approval of a few RNA-targeting therapeutics for clinical applications. This focused perspective aims to highlight - but not exhaustively review - key factors accounting for these successes while pointing at crucial aspects worth considering for further breakthroughs.

Synapses are specialized cellular junctions essential for communication between neurons. Synapse loss occurs in many neurodegenerative diseases. Harnessing our molecular knowledge of the development and maintenance of synapses, Suzuki et al. present the first comprehensive attempt to use a synthetic protein to bridge the pre- and postsynaptic membranes¹. They show that this powerful approach can stimulate the formation of pre- and postsynaptic specializations in vitro, rescue synaptic deficits of mutant mice in vivo, and ameliorate synapse loss and behavioral abnormalities in both Alzheimer's disease and spinal cord injury mouse models.

The publication of papers containing data obtained with suboptimal rigor in the experimental design and choice of key reagents, such as antibodies, can result in a lack of reproducibility and generate controversy that can both needlessly divert resources and, in some cases, damage public perception of the scientific enterprise. This exemplary paper by Buonarati et al. (2018)¹ shows how a previously published, potentially important paper on calcium channel regulation falls short of the necessary mark, and aims to resolve the resulting controversy.

Membrane growth requires lipid supply, which is usually accomplished by lipid synthesis or vesicular trafficking. In the case of autophagosomes, these principles do not apply. Ghanbarpour et al. postulate that autophagosome expansion relies on non-vesicular lipid delivery from the ER, whereby the activity of a lipid transfer protein (LTP) is directly coupled to scramblase activities in the donor and acceptor bilayers¹. This new concept opens the possibility that lipid traffic is controlled by scramblases that provide not only specific docking sites for LTPs, thereby directing lipid flow, but also support their activity by overcoming barriers for lipid extraction and deposition.