Relationship between biofilm formation and antibiotic resistance of Klebsiella pneumoniae and updates on antibiofilm therapeutic strategies.

Klebsiella pneumoniae is a Gram-negative bacterium within the Enterobacteriaceae family that can cause multiple systemic infections, such as respiratory, blood, liver abscesses and urinary systems. Antibiotic resistance is a global health threat and K. pneumoniae warrants special attention due to its resistance to most modern day antibiotics. Biofilm formation is a critical obstruction that enhances the antibiotic resistance of K. pneumoniae. However, knowledge on the molecular mechanisms of biofilm formation and its relation with antibiotic resistance in K. pneumoniae is limited. Understanding the molecular mechanisms of biofilm formation and its correlation with antibiotic resistance is crucial for providing insight for the design of new drugs to control and treat biofilm-related infections. In this review, we summarize recent advances in genes contributing to the biofilm formation of K. pneumoniae, new progress on the relationship between biofilm formation and antibiotic resistance, and new therapeutic strategies targeting biofilms. Finally, we discuss future research directions that target biofilm formation and antibiotic resistance of this priority pathogen.

Review of cardiac-coronary interaction and insights from mathematical modeling.

Cardiac-coronary interaction is fundamental to the function of the heart. As one of the highest metabolic organs in the body, the cardiac oxygen demand is met by blood perfusion through the coronary vasculature. The coronary vasculature is largely embedded within the myocardial tissue which is continually contracting and hence squeezing the blood vessels. The myocardium-coronary vessel interaction is two-ways and complex. Here, we review the different types of cardiac-coronary interactions with a focus on insights gained from mathematical models. Specifically, we will consider the following: (1) myocardial-vessel mechanical interaction; (2) metabolic-flow interaction and regulation; (3) perfusion-contraction matching, and (4) chronic interactions between the myocardium and coronary vasculature. We also provide a discussion of the relevant experimental and clinical studies of different types of cardiac-coronary interactions. Finally, we highlight knowledge gaps, key challenges, and limitations of existing mathematical models along with future research directions to understand the unique myocardium-coronary coupling in the heart. This article is categorized under: Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Biomedical Engineering Cardiovascular Diseases > Molecular and Cellular Physiology.

Functions of Representative Terpenoids and Their Biosynthesis Mechanisms in Medicinal Plants.

Terpenoids are the broadest and richest group of chemicals obtained from plants. These plant-derived terpenoids have been extensively utilized in various industries, including food and pharmaceuticals. Several specific terpenoids have been identified and isolated from medicinal plants, emphasizing the diversity of biosynthesis and specific functionality of terpenoids. With advances in the technology of sequencing, the genomes of certain important medicinal plants have been assembled. This has improved our knowledge of the biosynthesis and regulatory molecular functions of terpenoids with medicinal functions. In this review, we introduce several notable medicinal plants that produce distinct terpenoids (e.g., Cannabis sativa, Artemisia annua, Salvia miltiorrhiza, Ginkgo biloba, and Taxus media). We summarize the specialized roles of these terpenoids in plant-environment interactions as well as their significance in the pharmaceutical and food industries. Additionally, we highlight recent findings in the fields of molecular regulation mechanisms involved in these distinct terpenoids biosynthesis, and propose future opportunities in terpenoid research, including biology seeding, and genetic engineering in medicinal plants.

Neurobiological Dysfunctional Substrates for the Self-Medication Hypothesis in Adult Individuals with Attention-Deficit Hyperactivity Disorder and Cocaine Use Disorder: A Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography Study.

Objectives: Attention-deficit hyperactivity disorder (ADHD) in adulthood shows high co-occurrence rates with cocaine use disorder (CoUD). The self-medication hypothesis (SMH) provides a theoretical explanation for this comorbidity. This study investigates the neurobiological mechanisms that could support SMH in adult patients with attention-deficit hyperactivity disorder with cocaine use disorder (ADHD-CoUD). Materials and Methods: We included 19 ADHD-CoUD patients (84.2% male; age: 32.11 years [7.18]) and 16 CoUD patients (68.7% male; age: 36.63 years [8.12]). All subjects underwent a fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) brain scan. We tested brain metabolism differences between ADHD-CoUD and CoUD patients using voxel-based and regions of interest (ROIs)-based analyses. The correlation between dependence/abstinence duration and regional brain metabolism was also assessed in the two groups. Lastly, we investigated the integrity of brain metabolic connectivity of mesocorticolimbic and nigrostriatal dopaminergic systems, and large-scale brain networks involved in ADHD and addictions. Results: The voxel-wise and ROIs-based approaches showed that ADHD-CoUD patients had a lower metabolism in the thalamus and increased metabolism in the amygdala and parahippocampus, bilaterally, than CoUD subjects and healthy controls (HCs). Metabolism in the thalamus negatively correlated with years of dependence in ADHD-CoUD patients. Moreover, connectivity analyses revealed that ADHD-CoUD patients had a more preserved metabolic connectivity than CoUD patients in the dopaminergic networks and large-scale networks involved in self-regulation mechanisms of attention and behaviors (i.e., anterior default mode network [ADMN], executive network [ECN], and anterior salience network [aSAN]). Conclusions: We demonstrated distinct neuropathological substrates underlying substance-use behaviors in ADHD-CoUD and CoUD patients. Furthermore, we provided neurobiological evidence in support of SMH, demonstrating that ADHD-CoUD patients might experience short-term advantages of cocaine assumption (i.e., compensation of dopaminergic deficiency and related cognitive-behavioral deficits).

Generation, secretion and degradation of cancer immunotherapy target PD-L1.

Cancer immunotherapy is a rapidly developing and effective method for the treatment of a variety of malignancies in recent years. As a significant immune checkpoint, programmed cell death 1 ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) play the most significant role in cancer immune escape and cancer immunotherapy. Though PD-L1 have become an important target for drug development and there have been various approved drugs and clinic trials targeting it, and various clinical response rate and adverse reactions prevent many patients from benefiting from it. In recent years, combination trials have become the main direction of PD-1/PD-L1 antibodies development. Here, we summarized PD-L1 biofunctions and key roles in various cancers along with the development of PD-L1 inhibitors. The regulators that are involved in controlling PD-L1 expression including post-translational modification, mRNA level regulation as well as degradation and exosome secretory pathway of PD-L1 were focused. This systematic summary may provide comprehensive understanding of different regulations on PD-L1 as well as a broad prospect for the search of the important regulator of PD-L1. The regulatory factors of PD-L1 can be potential targets for immunotherapy and increase strategies of immunotherapy in combination.

Current understanding and future perspectives on the extraction, structures, and regulation of muscle function of tea pigments.

With the aggravating aging of modern society, the sarcopenia-based aging syndrome poses a serious potential threat to the health of the elderly. Natural dietary supplements show great potential to reduce muscle wasting and enhance muscle performance. Tea has been widely recognized for its health-promoting effects. which contains active ingredients such as tea polyphenols, tea pigments, tea polysaccharides, theanine, caffeine, and vitamins. In different tea production processes, the oxidative condensation and microbial transformation of catechins and other natural substances from tea promotes the production of various tea pigments, including theaflavins (TFs), thearubigins (TRs), and theabrownins (TBs). Tea pigments have shown a positive effect on maintaining muscle health. Nevertheless, the relationship between tea pigments and skeletal muscle function has not been comprehensively elucidated. In addition, the numerous research on the extraction and purification of tea pigments is disordered with the limited recent progress due to the complexity of species and molecular structure. In this review, we sort out the strategies for the separation of tea pigments, and discuss the structures of tea pigments. On this basis, the regulation mechanisms of tea pigments on muscle functional were emphasized. This review highlights the current understanding on the extraction methods, molecular structures and regulation mechanisms of muscle function of tea pigments. Furthermore, main limitations and future perspectives are proposed to provide new insights into broadening theoretical research and industrial applications of tea pigments in the future.

The extraction and isolation methods of tea pigments are detailedly introduced.The structural research progress of tea pigments are summarized.The effects of tea pigments in the prevention of muscle diseases are introduced.The mechanism of tea pigments in enhancing skeletal muscle function are proposed.

Regulation of the generation of reactive oxygen species during photosynthetic electron transport.

Light capture by chlorophylls and photosynthetic electron transport bury the risk of the generation of reactive oxygen species (ROS) including singlet oxygen, superoxide anion radicals and hydrogen peroxide. Rapid changes in light intensity, electron fluxes and accumulation of strong oxidants and reductants increase ROS production. Superoxide is mainly generated at the level of photosystem I while photosystem II is the main source of singlet oxygen. ROS can induce oxidative damage of the photosynthetic apparatus, however, ROS are also important to tune processes inside the chloroplast and participate in retrograde signalling regulating the expression of genes involved in acclimation responses. Under most physiological conditions light harvesting and photosynthetic electron transport are regulated to keep the level of ROS at a non-destructive level. Photosystem II is most prone to photoinhibition but can be quickly repaired while photosystem I is protected in most cases. The size of the transmembrane proton gradient is central for the onset of mechanisms that protect against photoinhibition. The proton gradient allows dissipation of excess energy as heat in the antenna systems and it regulates electron transport. pH-dependent slowing down of electron donation to photosystem I protects it against ROS generation and damage. Cyclic electron transfer and photoreduction of oxygen contribute to the size of the proton gradient. The yield of singlet oxygen production in photosystem II is regulated by changes in the midpoint potential of its primary quinone acceptor. In addition, numerous antioxidants inside the photosystems, the antenna and the thylakoid membrane quench or scavenge ROS.

Research advances in function and regulation mechanisms of plant small heat shock proteins (sHSPs) under environmental stresses.

Plants respond to various stresses by triggering the expression of genes that encode proteins involved in plant growth, fruit ripening, cellular protein homeostasis, and tolerance systems. sHSPs, a subfamily of heat shock proteins (HSPs), can be expressed in plants to inhibit abnormal aggregation of proteins and protect normal proteins by interacting with folding target proteins, protect cell integrity, and improve resistance under various adverse conditions. Thus, sHSPs have significant influences on seed germination and plant development. In this review, the classification, structure, and functions of sHSP family members in plants are systematically summarized, with emphasis on their roles in promoting fruit ripening and plant growth by reducing the accumulation of ROS, improving the survival rate of plants and the antioxidant activity, and protecting photosynthesis under biotic and abiotic stresses. Meanwhile, the production and regulatory mechanisms of sHSPs are described in detail. Heat shock factors, long non-coding RNA (lncRNAs), microRNA (miRNAs), and FK506 binding proteins are related to the production process of sHSPs. Molecular chaperone complex HSP70/100, plastidic proteins, and abscisic acid (ABA) are involved in the regulatory mechanisms of sHSPs. Besides, scientific efforts and practices for improving plant stress resistance have carried out the constitutive expression of sHSPs in transgenic plants in recent years. It is a powerful path for inducing the protective mechanisms of plants under various stresses. Therefore, exploring the role of sHSPs in the plant defense system paves a way for comprehensively unraveling plant tolerance in response to biotic and abiotic stress.

Diversity in Genetic Regulation of Bacterial Fimbriae Assembled by the Chaperone Usher Pathway.

Bacteria express different types of hair-like proteinaceous appendages on their cell surface known as pili or fimbriae. These filamentous structures are primarily involved in the adherence of bacteria to both abiotic and biotic surfaces for biofilm formation and/or virulence of non-pathogenic and pathogenic bacteria. In pathogenic bacteria, especially Gram-negative bacteria, fimbriae play a key role in bacteria-host interactions which are critical for bacterial invasion and infection. Fimbriae assembled by the Chaperone Usher pathway (CUP) are widespread within the Enterobacteriaceae, and their expression is tightly regulated by specific environmental stimuli. Genes essential for expression of CUP fimbriae are organised in small blocks/clusters, which are often located in proximity to other virulence genes on a pathogenicity island. Since these surface appendages play a crucial role in bacterial virulence, they have potential to be harnessed in vaccine development. This review covers the regulation of expression of CUP-assembled fimbriae in Gram-negative bacteria and uses selected examples to demonstrate both dedicated and global regulatory mechanisms.

tRNA-derived fragments as New Hallmarks of Aging and Age-related Diseases.

tRNA-derived fragments (tRFs), which are non-coding RNAs produced via tRNA cleavage with lengths of 14 to 50 nucleotides, originate from precursor tRNAs or mature tRNAs and exist in a wide range of organisms. tRFs are produced not by random fracture of tRNAs but by specific mechanisms. Considerable evidence shows that tRFs are detectable in model organisms of different ages and are associated with age-related diseases in humans, such as cancer and neurodegenerative diseases. In this literature review, the origin and classification of tRFs and the regulatory mechanisms of tRFs in aging and age-related diseases are summarized. We also describe the available tRF databases and research techniques and lay a foundation for the exploration of tRFs as biomarkers for the diagnosis and treatment of aging and age-related diseases.

Moonlighting Proteins: The Case of the Hexokinases.

Moonlighting proteins are defined as proteins with two or more functions that are unrelated and independent to each other, so that inactivation of one of them should not affect the second one and vice versa. Intriguingly, all the glycolytic enzymes are described as moonlighting proteins in some organisms. Hexokinase (HXK) is a critical enzyme in the glycolytic pathway and displays a wide range of functions in different organisms such as fungi, parasites, mammals, and plants. This review discusses HXKs moonlighting functions in depth since they have a profound impact on the responses to nutritional, environmental, and disease challenges. HXKs' activities can be as diverse as performing metabolic activities, as a gene repressor complexing with other proteins, as protein kinase, as immune receptor and regulating processes like autophagy, programmed cell death or immune system responses. However, most of those functions are particular for some organisms while the most common moonlighting HXK function in several kingdoms is being a glucose sensor. In this review, we also analyze how different regulation mechanisms cause HXK to change its subcellular localization, oligomeric or conformational state, the response to substrate and product concentration, and its interactions with membrane, proteins, or RNA, all of which might impact the HXK moonlighting functions.

Regulatory mechanisms, functions, and clinical significance of CircRNAs in triple-negative breast cancer.

Circular RNAs (circRNAs) are a new class of endogenous regulatory RNAs characterized by covalently closed cyclic structure lacking poly-adenylated tails, and are capable of regulating gene expression at transcription or post-transcription levels. Recently, plentiful circRNAs have been discovered in breast cancer and some circRNAs expression profiles are specifically involved in the triple-negative breast cancer (TNBC). TNBC is a type of malignant tumor defined by the lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Considering its clinical characteristics of high invasion, metastasis, poor prognosis, and lack of effective response to conventional chemotherapies or targeted therapies, it could be a promosing option to discover specific circRNAs as new targets for TNBC treatment. Meanwhile, accumulating evidence has demonstrated that circRNAs are dysregulated in TNBC tissues and are correlated with clinicopathological features and prognosis of TNBC patients. Furthermore, looking for circRNAs with high specificity and sensitivity will provide a new opportunity for the early diagnosis, clinical treatment, and prognosis monitoring of TNBC. Herein, we reviewed the biogenesis, regulatory mechanisms, and biological functions of circRNAs in TNBC and summarized the relationship between circRNAs expression and the clinicopathology, diagnosis, and prognosis of patients with TNBC.

Kaolinite weakens the co-stress of ampicillin and tetracycline on Escherichia coli through multiple pathways.

Ampicillin and tetracycline are common antibiotics and can threaten humans by inducing antibiotic resistance in bacteria. Microorganisms are usually exposed to a mixed antibiotic system in the environment. However, there are few researches on the specific regulatory mechanisms of clay on microorganisms under the stress of complex antibiotics. In this study, tandem mass tag-based coupled with two-dimensional liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) was employed to recognize and quantify changes in protein expression of Escherichia coli (E. coli) after culture for 15 days, with or without kaolinite in the co-stress of ampicillin and tetracycline. The results indicated that kaolinite could activate metabolic pathways of E. coli such as the energy metabolism, the biosynthesis of other secondary metabolites, and the metabolism of cofactors and vitamins. Particularly, the fatty acid degradation pathway has also been promoted, indicating that in the same unfavorable environment, kaolinite might influence the composition of E. coli cell membranes. This might be due to the change in membrane composition that was a kind of adaptive strategy of bacterial evolution. Moreover, kaolinite could promote multidrug efflux system to export the bacterial intracellular toxic substances, making E. coli survive better in an adverse environment. Consequently, this study not only disclosed the regulation of kaolinite on E. coli in a complex antibiotic environment but also provided new insights into the environmental process of antibiotic resistance.

Lack of visual avoidance in patients with unilateral brain damage: New perspectives from old, unexpected, neglected data.

The present commentary revisits some old data, concerning the same kind of visual avoidance behaviors described by Otero and Levenson's (2019) in their target paper and proposes a new perspective on the neural underpinnings of such behaviors. A lack of visual avoidance in response to a shocking film clip had been unexpectedly observed during a study of emotional expression in patients with unilateral brain damage (Mammucari et al., 1988). This lack of visual avoidance in subjects with right hemisphere brain lesions was attributed to the emotional indifference of these patients. These results could be complementary to those obtained by Otero and Levenson (2019) for two main reasons: (1) they concerned the inter-hemispheric, rather than the intra-hemispheric organization of emotional functions; (2) they could be replicated in FTD patients. Atrophy is, in fact, often asymmetrical in these subjects and several investigations have recently shown that emotional disorders can be on the foreground when atrophy prevails in the right frontal or temporal lobes. The present commentary suggests that a fruitful integration is possible between these two previously independent lines of neuropsychological research.

The Anti-lipopolysaccharide Factors in Crustaceans.

Anti-lipopolysaccharide factors (ALFs) are a type of antimicrobial peptide (AMP) which show broad-spectrum antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, fungi and viruses. In this chapter, we review the discovery and classification of this kind of antimicrobial peptide in crustaceans. The structure and function, as well as the mechanism of antibacterial and antiviral activities of ALFs will be summarized and discussed. We will then describe the expression and regulation of various ALF genes in different crustacean species. Finally, the application prospects of ALFs in drug development and disease-resistant genetic breeding will be pointed out and discussed. The review will also discuss several key questions such as the systematic classification and expression regulation of the ALF genes, as well as the future application of ALFs and ALF-derived peptides.

Experimental study of the synergistic effect and network regulation mechanisms of an applied combination of BMP-2, VEGF, and TGF-ß1 on osteogenic differentiation.

The study aimed to explore the osteogenic effect induced by the combined use of bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF), and transforming growth factor-ß1 (TGF-ß1), attain the best combination for osteogenic quality and efficiency, and explore the network regulation mechanisms of induced osteogenesis. MC3T3-E1 cells were cultured in vitro, and BMP-2, VEGF, and TGF ß1 were added to osteogenic induction mediums in different combinations to conduct experiments. At 7 and 14 days, the alkaline phosphatase (ALP) and Alizarin Red S (ARS) staining of the applied BMP-2 and VEGF combination were deeper and the quantitative analysis were higher than those of the other groups. After optimizing the time-effect relationship of the combined application, with BMP-2, VEGF, and TGF-ß1 adding in the early stage and BMP-2 and VEGF adding in the late, the ALP and ARS staining of these groups were deeper and the quantitative analyses were meaningfully higher than the BMP-2 and VEGF combination group at 7 and 14 days. The expression of the RUNX2 gene and the Smad1 signaling pathway in the optimized combination group was also significantly higher. The results demonstrate that the combination of BMP-2, VEGF, and TGF-ß1 applied according to the time-effect relationship can significantly promote osteogenic differentiation mainly through the classical BMP-receptor-Smad signal pathway.

Mechanical Roles of F-Actin in the Differentiation of Stem Cells: A Review.

In the development and differentiation of stem cells, mechanical forces associated with filamentous actin (F-actin) play a crucial role. The present review aims to reveal the relationship among the chemical components, microscopic structures, mechanical properties, and biological functions of F-actin. Particular attention is given to the functions of the cytoplasmic and nuclear microfilament cytoskeleton and their regulation mechanisms in the differentiation of stem cells. The distributions of different types of actin monomers in mammal cells and the functions of actin-binding proteins are summarized. We discuss how the fate of stem cells is regulated by intra/extracellular mechanical and chemical cues associated with microfilament-related proteins, intercellular adhesion molecules, etc. In addition, we also address the differentiation-induced variation in the stiffness of stem cells and the correlation between the fate and geometric shape change of stem cells. This review not only deepens our understanding of the biophysical mechanisms underlying the fates of stem cells under different culture conditions but also provides inspirations for the tissue engineering of stem cells.

Alternative mechanisms for Gaia.

A long-standing objection to the Gaia hypothesis has been a perceived lack of plausible mechanisms by which life on Earth could come to regulate its abiotic environment. A null hypothesis is survival by pure chance, by which any appearance of regulation on Earth is illusory and the persistence of life simply reflects the weak anthropic principle - it must have occurred for intelligent observers to ask the question. Recent work has proposed that persistence alone increases the chance that a biosphere will acquire further persistence-enhancing properties. Here we use a simple quantitative model to show that such 'selection by survival alone' can indeed increase the probability that a biosphere will persist in the future, relative to a baseline of pure chance. Adding environmental feedback to this model shows either an increased or decreased survival probability depending on the initial conditions. Feedback can hinder early life becoming established if initial conditions are poor, but feedback can also prevent systems from diverging too far from optimum environmental conditions and thus increase survival rates. The outstanding question remains the relative importance of each mechanism for the historical and continued persistence of life on Earth.

Differential networking meta-analysis of gastric cancer across Asian and American racial groups.

BACKGROUND: Gastric Carcinoma is one of the most lethal cancer around the world, and is also the most common cancers in Eastern Asia. A lot of differentially expressed genes have been detected as being associated with Gastric Carcinoma (GC) progression, however, little is known about the underlying dysfunctional regulation mechanisms. To address this problem, we previously developed a differential networking approach that is characterized by involving differential coexpression analysis (DCEA), stage-specific gene regulatory network (GRN) modelling and differential regulation networking (DRN) analysis. RESULT: In order to implement differential networking meta-analysis, we developed a novel framework which integrated the following steps. Considering the complexity and diversity of gastric carcinogenesis, we first collected three datasets (GSE54129, GSE24375 and TCGA-STAD) for Chinese, Korean and American, and aimed to investigate the common dysregulation mechanisms of gastric carcinogenesis across racial groups. Then, we constructed conditional GRNs for gastric cancer corresponding to normal and carcinoma, and prioritized differentially regulated genes (DRGs) and gene links (DRLs) from three datasets separately by using our previously developed differential networking method. Based on our integrated differential regulation information from three datasets and prior knowledge (e.g., transcription factor (TF)-target regulatory relationships and known signaling pathways), we eventually generated testable hypotheses on the regulation mechanisms of two genes, XBP1 and GIF, out of 16 common cross-racial DRGs in gastric carcinogenesis. CONCLUSION: The current cross-racial integrative study from the viewpoint of differential regulation networking provided useful clues for understanding the common dysfunctional regulation mechanisms of gastric cancer progression and discovering new universal drug targets or biomarkers for gastric cancer.