Beclin 1-Vps34 complex architecture： Understanding the nuts and bolts of therapeutic targets

Autophagy is an important lysosomal degradation pathway that aids in the maintenance of cellular homeostasis by breaking down and recycling intracellular contents. Dysregulation of autophagy is linked to a growing number of human diseases. The Beclin 1-Vps34 protein-protein interaction network is critical for autophagy regulation and is therefore essential to cellular integrity. Manipulation of autophagy, in particular via modulation of the action of the Beclin I-Vps34 complexes, is considered a promising route to combat autophagy-related diseases. Here we summarize recent findings on the core components and structural architecture of the Beclin 1-Vps34 complexes, and how these findings provide valuable insights into the molecular mechanisms that underlie the multiple functions of these complexes and for devising therapeutic strategies.

Progress in Brucella vaccine development

Brucella spp. are zoonotic, facultative intracellular pathogens, which cause animal and human disease. Animal disease results in abortion of fetuses; in humans, it manifests flu-like symptoms with an undulant fever, with osteoarthritis as a common complication of infection. Antibiotic regimens for human brucellosis patients may last several months and are not always completely effective. While there are no vaccines for humans, several licensed live Brucella vaccines are available for use in livestock. The performance of these animal vaccines is dependent upon the host species, dose, and route of immunization. Newly engineered live vaccines, lacking well-defined virulence factors, retain low residual virulence, are highly protective, and may someday replace currently used animal vaccines. These also have possible human applications. Moreover, due to their enhanced safety and efficacy in animal models, subunit vaccines for brucellosis show great promise for their application in livestock and humans. This review summarizes the progress of brucellosis vaccine development and presents an overview of candidate vaccines.

A review of target gene specificity of flavonoid R2R3-MYB transcription factors and a discussion of factors contributing to the target gene selectivity

Flavonoid biosynthetic genes are often coordinately regulated in a temporal manner during flower or fruit development, resulting in specific accumulation profiles of flavonoid compounds. R2R3-MYB-type transcription factors （TFs） ＂recruit＂ a set of biosynthetic genes to produce flavonoids, and, therefore, R2R3-MYBs are responsible for the coordinated expression of structural genes. Although a wealth of information regarding the identified and functionally characterized R2R3-MYBs that are involved in flavonoid accumulation is available to date, this is the first review on the global regulation of MYB factors in the flavonoid pathway. The data presented in this review demonstrate that anthocyanin, flavone/flavonol/3-deoxyflavonoid （FFD）, proanthocyanidin （PA）, and isoflavonoid are independently regulated by different subgroups of R2R3-MYBs. Furthermore, FFD-specific R2R3-MYBs have a preference for early biosynthetic genes （EBGs） as their target genes; anthocyanin-specific R2R3-MYBs from dicot species essentially regulate late biosynthetic genes （LBGs）; the remaining R2R3-MYBs have a wider range of target gene specificity. To elucidate the nature of the differential target gene specificity between R2R3-MYBs, we analyzed the DNA binding domain （also termed the MYB-domain） of R2R3-MYBs and the distribution of the recognition cis-elements. We identified four conserved amino acid residues located in or just before helix-3 of dicot anthocyanin R2R3-MYBs that might account for the different recognition DNA sequence and subsequently the different target gene specificity to the remaining R2R3-MYB TFs.

Lattice Boltzmann modeling and simulation of compressible flows

In this mini-review we summarize the progress of Lattice Boltzmann （LB） modeling and simulating compressible flows in our group in recent years. Main contents include （i） Single-Relaxation-Time （SRT） LB model supplemented by additional viscosity, （ii） Multiple-Relaxation-Time （MRT） LB model, and （iii） LB study on hydrodynamic instabilities. The former two belong to improvements of physical modeling and the third belongs to simulation or application. The SRT-LB model sup- plemented by additional viscosity keeps the original framework of Lattice Bhatnagar-Gross Krook （LBGK）. So, it is easier and more convenient for previous SRT-LB users. The MRT-LB is a com- pletely new framework for physical modeling. It significantly extends the range of LB applications. The cost is longer computational time. The developed SRT-LB and MRT-LB are complementary from the sides of convenience and applicability.

Surgical decompression in acute spinal cord injury： A review of clinical evidence, animal model studies, and potential future directions of investigation

The goal for treatment in acute spinal cord injury （SCI） is to reduce the extent of secondary damage and facilitate neurologic regeneration and functional recovery. Although multiple studies have investigated potential new therapies for the treatment of acute SCI, outcomes and management protocols aimed at ameliorating neurologic injury in patients remain ineffective. More recent clinical and basic science research have shown surgical interventions to be a potentially valuable modality for treatment; however, the role and timing of surgical decompression, in addition to the optimal surgical intervention, remain one of the most controversial topics pertaining to surgical treatment of acute SCI. As an increasing number of potential treatment modalities emerge, animal models are pivotal for investigating its clinical application and translation into human trials. This review critically appraises the available literature for both clinical and basic science studies to highlight the extent of investigation that has occurred, specific therapies considered, and potential areas for future research.

PTEN/PI3K and MAPK signaling in protection and pathology following CNS injuries

Brain and spinal cord injuries initiate widespread temporal and spatial neurodegeneration, through both necrotic and programmed cell death mechanisms. Inflammation, reactive oxidation, excitotoxicity and cell-specific dysregulation of metabolic processes are instigated by traumatic insult and are main contributors to this cumulative damage. Successful treatments rely on prevention or reduction of the magnitude of disruption, and interfering with injurious cellular responses through modulation of signaling cascades is an effective approach. Two intracellular signaling pathways, the phosphatase and tensin homolog （PTEN）/phosphatidylinositol 3-kinase （PI3K） and mitogen- activated protein kinase （MAPK） signaling cascades play various cellular roles under normal and pathological conditions. Activation of both pathways can influence anatomical and functional outcomes in multiple CNS disorders. However, some mechanisms involve inhibiting or enhancing one pathway or the other, or both, in propagating specific downstream effects. Though many intraceHular mechanisms contribute to cell responses to insult, this review examines the evidence exploring PTEN/PI3K and MAPK signaling influence on pathology, neuroprotection, and repair and how these pathways may be targeted for advancing knowledge and improving neurological outcome after injury to the brain and spinal cord.

Growth arrest signaling of the Raf/MEK/ERK pathway in cancer

The Raf/MEK/extraceUular signal-regulated kinase （ERK） pathway has a pivotal role in facilitating cell proliferation, and its deregulated activation is a central signature of many epithelial cancers. However paradoxically, sustained activity of Raf/MEK/ERK can also result in growth arrest in many different cell types. This anti-proliferative Raf/MEK/ERK signaling also has physiological significance, as exemplified by its potential as a tumor suppressive mechanism. Therefore, significant questions include in which cell types and by what mechanisms this pathway can mediate such an opposing context of signaling. Particularly, our understating of the role of ERK1 and ERK2, the focal points of pathway signaling, in growth arrest signaling is still limited. This review discusses these aspects of Raf/MEK/ ERK-mediated growth arrest signaling.

Plant calcium oxalate crystal formation, function, and its impact on human health

Crystals of calcium oxalate have been observed among members from most taxonomic groups of photosynthetic organisms ranging from the smallest algae to the largest trees. The biological roles for calcium oxalate crystal formation in plant growth and development include high-capacity calcium regulation, protection against herbivory, and tolerance to heavy metals. Using a variety of experimental approaches researchers have begun to unravel the complex mechanisms controlling formation of this biomineral. Given the important roles for calcium oxalate formation in plant survival and the antinutrient and pathological impact on human health through its presence in plant foods, researchers are avidly seeking a more comprehensive understanding of how these crystals form. Such an understanding will be useful in efforts to design strategies aimed at improving the nutritional quality and production of plant foods.

Receptor-like kinases and receptor-like proteins： keys to pathogen recognition and defense signaling in plant innate immunity

Plants have evolved multiple layers of defense against various pathogens in the environment. Receptor-like kinases/proteins （RLKs/RLPs） are on the front lines of the battle between plants and pathogens since they are present at the plasma membrane and perceive signature molecules from either the invading pathogen or damaged plant tissue. With a few notable exceptions, most RLKs/RLPs are positive regulators of plant innate immunity. In this review, we summarize recently discovered RLKs/RLPs that are involved in plant defense responses against various classes of pathogens, We also describe what is currently known about the mechanisms of RLK-mediated initiation of signaling via protein-protein interactions and phosphorylation.

Source-sink landscape theory and its ecological significance

Exploring the relationships between landscape pattern and ecological processes is the key topic of landscape ecology,for which,a large number of indices as well as landscape pattern analysis model were developed.However,one problem faced by landscape ecologists is that it is hard to link the landscape indices with a specific ecological process.Linking landscape pattern and ecological processes has become a challenge for landscape ecologists.“Source”and“sink”are common concepts used in air pollution research,by which the movement direction and pattern of different pollutants in air can be clearly identified.In fact,for any ecological process,the research can be considered as a balance between the source and the sink in space.Thus,the concepts of“source”and“sink”could be implemented to the research of landscape pattern and ecological processes.In this paper,a theory of sourcesink landscape was proposed,which include:(1)In the research of landscape pattern and ecological process,all landscape types can be divided into two groups,“source”landscape and“sink”landscape.“Source”landscape contributes positively to the ecological process,while“sink”landscape is unhelpful to the ecological process.(2)Both landscapes are recognized with regard to the specific ecological process.“Source”landscape in a target ecological process may change into a“sink”landscape as in another ecological process.Therefore,the ecological process should be determined before“source”or“sink”landscape were defined.(3)The key point to distinguish“source”landscape from“sink”landscape is to quantify the effect of landscape on ecological process.The positive effect is made by“source”landscape,and the negative effect by“sink”landscape.(4)For the same ecological process,the contribution of“source”landscapes may vary,and it is the same to the“sink”landscapes.It is required to determine the weight of each landscape type on ecological processes.(5)The sourcesink principle can be applied to non-point source pollution control,biologic diversity protection,urban heat island effect mitigation,etc.However,the landscape evaluation models need to be calibrated respectively,because different ecological processes correspond with different source-sink landscapes and evaluation models for the different study areas.This theory is helpful to further study landscape pattern and ecological process,and offers a basis for new landscape index design.

Emerging roles of autophagy in metabolism and metabolic disorders

The global prevalence of metabolic disorders is an immediate threat to human health. Genetic features, environmental aspects and lifestyle changes are the major risk factors determining metabolic dysfunction in the body. Autophagy is a housekeeping stress-induced lysosomal degradation pathway, which recycles macromolecules and metabolites for new protein synthesis and energy production and regulates cellular homeostasis by clearance of damaged protein or organelles. Recently, a dramatically increasing number of literatures has shown that defects of the autophagic machinery is associated with dysfunction of multiple metabolic tissues including pancreatic β cells, liver, adipose tissue and muscle, and is implicated in metabolic disorders such as obesity and insulin resistance. Here in this review, we summarize the representative works on these topics and discuss the versatile roles of autophagy in the regulation of cellular metabolism and its possible implication in metabolic diseases.

An overview of inflammation: mechanism and consequences

Inflammation is an essential response provided by the immune systems that ensures the survival duringinfection and tissue injury. Inflammatory responses are essential for the maintenance of normal tissue homeostasis. Themolecular mechanism of inflammation is quite a complicated process which is initiated by the recognition of specificmolecular patterns associated with either infection or tissue injury. The entire process of the inflammatory response ismediated by several key regulators involved in the selective expression of proinflammatory molecules. Prolongedinflammations are often associated with severe detrimental side effects on health. Alterations in inflammatory responsesdue to persistent inducers or genetic variations are on the rise over the last couple of decades, causing a variety ofinflammatory diseases and pathophysiological conditions.

Insights into the role of jasmonic acid-mediated defenses against necrotrophic and biotrophic fungal pathogens

Jasmonic acid （JA） is a natural hormone regulator involved in development, responses against woundingand pathogen attack. Upon perception of pathogens, JA is synthesized and mediates a signaling cascade initiating various defense responses. Traditionally, necrotrophic fungi have been shown to be the primary activators of JA- dependent defenses through the JA-receptor, COIl. Conversely, plants infected with biotrophic fungi have classically been associated with suppressing JA-mediated responses. However, recent evidence has shown that certain biotrophic fungal species also trigger activation of JA-mediated responses and mutants deficient in JA signaling show an increase in susceptibility to certain biotrophic fungal pathogens. These findings suggest a new role for JA in defense against fungal biotrophs. This review will focus on recent research advancing our knowledge of JA-dependant responses involved in defense against both biotrophic and necrotrophic fungi.

DISC1 genetics, biology and psychiatric illness

Psychiatric disorders arc highly heritable, and in many individuals likely arise from the combined effects of genes and the environment. A substantial body of evidence points toward D1SCI being one of the genes that influence risk of schizophrenia, bipolar disorder and depression, and functional studies of DISC1 consequently have the potential to reveal much about the pathways that lead to major mental illness. Here, we review the evidence that DISC1 influences disease risk through effects upon multiple critical pathways in the developing and adult brain.

Cellular, physiological and pathological aspects of the long non-coding RNA NEAT1

BACKGROUND： The majority of mammalian genomes have been found to be transcribed into non-coding RNAs. One category of non-coding RNAs is classified as long non-coding RNAs （lncRNAs） based on their transcript sizes larger than 200 nucleotides. Growing evidence has shown that lncRNAs are not junk transcripts and play regulatory roles in multiple aspects of biological processes. Dysregulation of lncRNA expression has also been linked to diseases, in particular cancer. Therefore, studies of lncRNAs have attracted significant interest in the field of medical research. Nuclear enriched abundant transcript 1 （NEAT1）, a nuclear lncRNA, has recently emerged as a key regulator involved in various cellular processes, physiological responses, developmental processes, and disease development and progression. OBJECTIVE： This review will summarize and discuss the most recent findings with regard to the roles of NEAT1 in the function of the nuclear paraspeckle, cellular pathways, and physiological responses and processes. Particularly, the most recently reported studies regarding the pathological roles of deregulated NEAT1 in cancer are highlighted in this review. METHODS： We performed a systematic literature search using the Pubmed search engine. Studies published over the past 8 years （between January 2009 and August 2016） were the sources of literature review. The following keywords were used： ＂Nuclear enriched abundant transcript 1,＂ ＂NEATI,＂ and ＂paraspeckles.＂ RESULTS： The Pubmed search identified 34 articles related to the topic of the review. Among the identified literature, 13 articles report findings related to cellular functions of NEAT1 and eight articles are the investigations of physiological functions of NEAT1. The remaining 13 articles are studies of the roles of NEAT1 in cancers. CONCLUSION： Recent advances in NEAT1 studies reveal the multifimctional roles of NEAT1 in various biological processes, which are beyond its role in nuclear paraspeckles. Recent studies also indicate that dysregulation of NEAT1 function contributes to the development and progression of various cancers. More investigations will be needed to address the detailed mechanisms regarding how NEAT1 executes its cellular and physiological functions and how NEAT1 dysregulation results in tumorigenesis, and to explore the potential of NEAT1 as a target in cancer diagnosis, prognosis and therapy.

Mass spectrometry-based proteomics and peptidomics for systems biology and biomarker discovery

The scientific community has shown great interest in the field of mass spectrometry-based proteomics and peptidomics for its applications in biology. Proteomics technologies have evolved to produce large data sets of proteins or peptides involved in various biologic and disease progression processes generating testable hypothesis for complex biologic questions. This review provides an introduction to relevant topics in proteomics and peptidomics including biologic material selection, sample preparation, separation techniques, peptide fragmentation, post-translational modifications, quantification, bioinformatics, and biomarker discovery and validation. In addition, current literature, remaining challenges, and emerging technologies for proteomics and peptidomics are presented.

Novel functions of GABA signaling in adult neurogenesis

Neurotransmitter gamma-aminobutiric acid （GABA） through ionotropic GABAA and metabotropic GABAB receptors plays key roles in modulating the development, plasticity and function of neuronal networks. GABA is inhibitory in mature neurons but excitatory in immature neurons, neuroblasts and neural stem/progenitor cells （NSCs/ NPCs）. The switch from excitatory to inhibitory occurs following the development of glutamatergic synaptic input and results from the dynamic changes in the expression of Na＋/K＋/2CF co-transporter NKCC1 driving CF influx and neuron-specific K＋/Cl co-transporter KCC2 driving Cl efflux. The developmental transition of KCC2 expression is regulated by Disrupted-in-Schizophrenia 1 （DISC1） and brain-derived neurotrophic factor （BDNF） signaling. The excitatory GABA signaling during early neurogenesis is important to the activity/experience-induced regulation of NSC quiescence, NPC proliferation, neuroblast migration and new-born neuronal maturation/functional integration. The inhibitory GABA signaling allows for the sparse and static functional networking essential for learning/memory development and maintenance.

Rice allelopathy and its properties of molecular ecology

Crop allelopathy is a promising and environmentally friendly method in weed control;however,the inducible genetic trait for allelopathy in the suppression of weeds needs to be overcome for practical use.Further study needs to be directed to this end to elucidate the molecular genetics and its physiologic mechanism.In this paper,the authors review recent advances in the investigation of rice allelopathy and its molecular regulatory mechanism,especially in responses to stressful conditions including biotic and abiotic factors in China.Previous studies show that rice allelopathy could be enhanced when the rice accession was exposed to stressful conditions,and further analysis by the transcriptomics and proteomics approaches conducted in our laboratory indicated that the increase in allelopathic potential of rice,when exposed to the stresses,was attributed to increased expression level of genes involved in phenolic synthetic metabolism.The increasing phenolic compounds have been confirmed as the main allelochemicals and they jointly act to suppress the target,especially in responses to stressful condition,but it seems to be the primary effect in phenolic allelopathy.We still wonder how the exudates from rice root,which were released into rhizosphere soil,are transformed by soil microorganism to produce the higher secondary effect of phenolic allelopathy in the suppression of weeds.Therefore,the authors suggest that rhizosphere biologic properties of allelopathy in rice and its mechanism are being the key research areas in the world now,and systems biology and its approaches,such as metagenomics and metaproteomics,would be helpful to reveal the process and its molecular ecological mechanism regarding rhizospheric biology of rice allelopathy.

Heat shock proteins: Molecules with assorted functions

Heat shock proteins (Hsps) or molecular chaperones, are highly conserved protein families present in allstudied organisms. Following cellular stress, the intracellular concentration of Hsps generally increases several folds.Hsps undergo ATP-driven conformational changes to stabilize unfolded proteins or unfold them for translocationacross membranes or mark them for degradation. They are broadly classified in several families according to theirmolecular weights and functional properties. Extensive studies during the past few decades suggest that Hsps play avital role in both normal cellular homeostasis and stress response. Hsps have been reported to interact with numeroussubstrates and are involved in many biological functions such as cellular communication, immune response, proteintransport, apoptosis, cell cycle regulation, gametogenesis and aging. The present review attempts to provide a briefoverview of various Hsps and summarizes their involvement in diverse biological activities.

RasGRP Ras guanine nucleotide exchange factors in cancer

RasGRP proteins are activators of Ras and other related small GTPases by the virtue of functioning as guanine nucleotide exchange factors （GEFs）. In vertebrates, four RasGRP family members have been described. RasGRP-1 through -4 share many structural domains but there are also subtle differences between each of the different family members. Whereas SOS RasGEFs are ubiquitously expressed, RasGRP proteins are expressed in distinct patterns, such as in different cells of the hematopoietic system and in the brain. Most studies have concentrated on the role of RasGRP proteins in the development and function of immune cell types because of the predominant RasGRP expression profiles in these cells and the immune phenotypes of mice deficient for Rasgrp genes. However, more recent studies demonstrate that RasGRPs also play an important role in tumorigenesis. Examples are skin- and hematological- cancers but also solid malignancies such as melanoma or prostate cancer. These novel studies bring up many new and unanswered questions related to the molecular mechanism of RasGRP-driven oncogenesis, such as new receptor systems that RasGRP appears to respond to as well as regulatory mechanisms for RasGRP expression that appear to be perturbed in these cancers. Here we will review some of the known aspects of RasGRP biology in lymphocytes and will discuss the exciting new notion that RasGRP Ras exchange factors play a role in oncogenesis downstream of various growth factor receptors.