In eukaryotic cells, various membrane-bound organelles compartmentalize diverse cellular activities in a spatially and temporally controlled manner. Numerous membraneless organelles assembled via ...liquid-liquid phase separation (LLPS), known as condensates, also facilitate compartmentalization of cellular functions. Emerging evidence shows that these two organelle types interact in many biological processes. Membranes modulate the biogenesis and dynamics of phase-separated condensates by serving as assembly platforms or by forming direct contacts. Phase separation of membrane-associated proteins participates in various trafficking events, such as clustering of vesicles for temporally controlled fusion and storage, and transport of membraneless condensates on membrane-bound organelles. Phase separation also acts in cargo trafficking pathways by sorting and docking cargos for translocon-mediated transport across membranes, by shuttling cargos through the nuclear pore complex, and by triggering the formation of surrounding autophagosomes for delivery to lysosomes. The coordinated actions of membrane-bound and membraneless organelles ensure spatiotemporal control of various cellular functions.
Zhao and Zhang summarize the coordinated interactions between membrane-bound organelles and membraneless condensates in various biological processes. Membranes provide surfaces for assembling condensates and also modulate their dynamics and transport, while protein phase separation regulates the storage and trafficking of membrane-bound organelles and also facilitates protein translocation across membranes.
Macroautophagy involves the sequestration of cytoplasmic contents in a double-membrane autophagosome and their delivery to lysosomes for degradation. In multicellular organisms, nascent ...autophagosomes fuse with vesicles originating from endolysosomal compartments before forming degradative autolysosomes, a process known as autophagosome maturation. ATG8 family members, tethering factors, Rab GTPases, and SNARE proteins act coordinately to mediate fusion of autophagosomes with endolysosomal vesicles. The machinery mediating autophagosome maturation is under spatiotemporal control and provides regulatory nodes to integrate nutrient availability with autophagy activity. Dysfunction of autophagosome maturation is associated with various human diseases, including neurodegenerative diseases, Vici syndrome, cancer, and lysosomal storage disorders. Understanding the molecular mechanisms underlying autophagosome maturation will provide new insights into the pathogenesis and treatment of these diseases.
Autophagy is a versatile degradation system for maintaining cellular homeostasis whereby cytosolic materials are sequestered in a double-membrane autophagosome and subsequently delivered to ...lysosomes, where they are broken down. In multicellular organisms, newly formed autophagosomes undergo a process called 'maturation', in which they fuse with vesicles originating from endolysosomal compartments, including early/late endosomes and lysosomes, to form amphisomes, which eventually become degradative autolysosomes. This fusion process requires the concerted actions of multiple regulators of membrane dynamics, including SNAREs, tethering proteins and RAB GTPases, and also transport of autophagosomes and late endosomes/lysosomes towards each other. Multiple mechanisms modulate autophagosome maturation, including post-translational modification of key components, spatial distribution of phosphoinositide lipid species on membranes, RAB protein dynamics, and biogenesis and function of lysosomes. Nutrient status and various stresses integrate into the autophagosome maturation machinery to coordinate the progression of autophagic flux. Impaired autophagosome maturation is linked to the pathogenesis of various human diseases, including neurodegenerative disorders, cancer and myopathies. Furthermore, invading pathogens exploit various strategies to block autophagosome maturation, thus evading destruction and even subverting autophagic vacuoles (autophagosomes, amphisomes and autolysosomes) for survival, growth and/or release. Here, we discuss the recent progress in our understanding of the machinery and regulation of autophagosome maturation, the relevance of these mechanisms to human pathophysiology and how they are harnessed by pathogens for their benefit. We also provide perspectives on targeting autophagosome maturation therapeutically.
Efficient delivery and endo-lysosomal release of active proteins in living cells remain a challenge in protein-based theranostics. We report a novel protein delivery platform using ...protein-encapsulating biomineralized metal-organic framework (MOF) nanoparticles (NPs). This platform introduces an adapted biomimetic mineralization method for facile synthesis of MOF NPs with high protein encapsulation efficiency and a new polymer coating strategy to confer the NPs with long-term stability. In vitro results show that protein-encapsulating MOF NPs have the advantages of preserving protein activity for months and protecting proteins from enzyme-mediated degradation. Live cell studies reveal that MOF NPs enable rapid cellular uptake, efficient release and escape of proteins from endo-lysosomes, and preservation of protein activity in living cells. Moreover, the developed platform is demonstrated to enable easy encapsulation of multiple proteins in single MOF NPs for efficient protein co-delivery. To our knowledge, it is the first time that protein-encapsulating MOF NPs have been developed as a generally applicable strategy for intracellular delivery of native active proteins. The developed protein-encapsulating biomineralized MOF NPs can provide a valuable platform for protein-based theranostic applications.
Metal–organic frameworks (MOFs) have recently emerged as a type of uniformly and periodically atom‐distributed precursor and efficient self‐sacrificial template to fabricate hierarchical ...porous‐carbon‐related nanostructured functional materials. For the first time, a Cu‐based MOF, i.e., Cu‐NPMOF is used, whose linkers contain nitrogen and phosphorus heteroatoms, as a single precursor and template to prepare novel Cu3P nanoparticles (NPs) coated by a N,P‐codoped carbon shell that is extended to a hierarchical porous carbon matrix with identical uniform N and P doping (termed Cu3P@NPPC) as an electrocatalyst. Cu3P@NPPC demonstrates outstanding activity for both the hydrogen evolution and oxygen reduction reaction, representing the first example of a Cu3P‐based bifunctional catalyst for energy‐conversion reactions. The high performances are ascribed to the high specific surface area, the synergistic effects of the Cu3P NPs with intrinsic activity, the protection of the carbon shell, and the hierarchical porous carbon matrix doped by multiheteroatoms. This strategy of using a diverse MOF as a structural and compositional material to create a new multifunctional composite/hybrid may expand the opportunities to explore highly efficient and robust non‐noble‐metal catalysts for energy‐conversion reactions.
Cu3P nanoparticles coated by a N,P‐codoped carbon shell (hierarchical porous carbon matrix) are prepared using a novel Cu‐based metal–organic framework (MOF) containing dual linkers as a template and single precursor. The Cu3P@NPPC catalyst demonstrates a high specific surface area and affords remarkable bifunctional electrocatalytic performance for hydrogen evolution reaction and oxygen reduction reaction with long‐term durability for both reactions.
The novel coronavirus disease (COVID-19) has been rapidly transmitted in China, Macau, Hong Kong, and other Asian and European counterparts. This COVID-19 epidemic has aroused increasing attention ...nationwide. Patients, health professionals, and the general public are under insurmountable psychological pressure which may lead to various psychological problems, such as anxiety, fear, depression, and insomnia. Psychological crisis intervention plays a pivotal role in the overall deployment of the disease control. The National Health Commission of China has summoned a call for emergency psychological crisis intervention and thus, various mental health associations and organizations have established expert teams to compile guidelines and public health educational articles/videos for mental health professionals and the general public alongside with online mental health services. In addition, mental health professionals and expert groups are stationed in designated isolation hospitals to provide on-site services. Experts have reached a consensus on the admission of patients with severe mental illness during the COVID-19 outbreak in mental health institutions. Nevertheless, the rapid transmission of the COVID-19 has emerged to mount a serious challenge to the mental health service in China.
Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia in the elderly. Patients with AD suffer a gradual deterioration of memory and other cognitive functions, ...which eventually leads to a complete incapacity and death. A complicated array of molecular events has been implicated in the pathogenesis of AD. The major pathological characteristics of AD brains are the presence of senile plaques, neurofibrillary tangles, and neuronal loss. Growing evidence has demonstrated that oxidative stress is an important factor contributing to the initiation and progression of AD. However, the mechanisms that lead to the disruption of redox balance and the sources of free radicals remain elusive. The excessive reactive oxygen species may be generated from mechanisms such as mitochondria dysfunction and/or aberrant accumulation of transition metals, while the abnormal accumulation of Abeta and tau proteins appears to promote the redox imbalance. The resulted oxidative stress has been implicated in Abeta- or tau-induced neurotoxicity. In addition, evidence has suggested that oxidative stress may augment the production and aggregation of Abeta and facilitate the phosphorylation and polymerization of tau, thus forming a vicious cycle that promotes the initiation and progression of AD.
Herein we reported a direct synthesis series of indolines through cyclization of tertiary aryl amines with iodonium ylides. This cyclization reaction occurred under sole visible‐light irradiation at ...room temperature without the addition of any photocatalysts and additives. Preliminary mechanism studies revealed that an electron donor‐acceptor (EDA) complex between iodonium ylides and tertiary aryl amines should be formed during the reaction.
Fossil pollen records from 20 sites with reliable chronologies and high-resolution data in the East Asian monsoon margin region were synthesized to document Holocene vegetation and climate change and ...to understand the large-scale controls. The vegetation experienced different changes over the Holocene in various sub-regions. (1) Near the boundary between modern forest and temperate steppe in Northeast China, forest showed clear expansion in the middle Holocene. (2) In central China near the boundary between steppe/forest and desert, vegetation showed various patterns at different sites. (3) Further west on the Tibetan Plateau near the boundary between highland meadow/steppe and semi-desert/desert, forest expanded at most sites during the early and middle Holocene. Our synthesis indicates that climate in the margin region was slightly moist in the early Holocene, wettest in the middle Holocene, and dry in the late Holocene, though there are regional differences as reflected by vegetation change. This general pattern is very different from either monsoon- or westerly-dominated regions. The maximum moisture occurred during the early Holocene in the monsoon region, while the arid central Asia dominated by the westerlies was driest in the early Holocene and wettest in the mid-Holocene. The interplay of the Asian summer monsoon, westerlies, topography and regional vegetation factors might have contributed to this spatial complexity.
Recently, more than 300 Chinese patients with psychiatric disorders were diagnosed with the 2019 novel coronavirus disease (COVID-19). Possible reasons quoted in the report were the lack of caution ...regarding the COVID-19 outbreak in January and insufficient supplies of protective gear. We outlined major challenges for patients with psychiatric disorders and mental health professionals during the COVID-19 outbreak, and also discussed how to manage these challenges through further mental health service reform in China.
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