Changes of Motor and Sensory Asymmetries in Highly Trained Athletes

Data about peculiarities of organization of motor control and brain functional asymmetry pattern in highly trained judo wrestlers are presented. It has been shown that in athletes the right hemisphere is predominant in processing of both speech and visual-spatial information, while high competition results in wrestlers with left-side stand correlates with prevalence of the left hemisphere in speech perception. It is suggested that high sport results in wrestlers are due to formation of novel long-term skills, reorganization of motor control, and interhemispheric interaction.     

独脚金内酯信号途径的新发现——抑制子也是转录因子

植物激素信号传导途径中的抑制子(repressor) DELLA、AUX/IAA、JAZ和D53/SMXL均结合下游转录因子并抑制其转录活性, 从而阻遏激素响应基因的表达; 激素分子则激活信号传导链降解抑制子、释放转录因子, 从而诱导响应基因表达并介导相应的生物学功能。中国科学院遗传与发育生物学研究所李家洋研究团队最新的研究发现, 独脚金内酯(SL)信号途径中的SMXL6、SMXL7和SMXL8是具有抑制子和转录因子双重功能的新型抑制子, 他们还通过研究SL转录调控网络发现了大量新的SL响应基因, 揭示了SL调控植物分枝、叶片伸长和花色素苷积累的分子机制。这些重要发现为探索植物激素作用机理提供了新思路, 具有重要科学意义和应用前景。     

New Insight into Neurodegeneration: the Role of Proteomics

Recent advances within the field of proteomics, including both upstream and downstream protocols, have fuelled a transition from simple protein identification to functional analysis. A battery of proteomics approaches is now being employed for the analysis of protein expression levels, the monitoring of cellular activities and for gaining an increased understanding into biochemical pathways. Combined, these approaches are changing the way we study disease by allowing accurate and targeted, large scale protein analysis, which will provide invaluable insight into disease pathogenesis. Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), prion disease, and other diseases that affect the neuromuscular system, are a leading cause of disability in the aging population. There are no effective intervention strategies for these disorders and diagnosis is challenging as it relies primarily on clinical symptomatic features, which often overlap at early stages of disease. There is, therefore, an urgent need to develop reliable biomarkers to improve early and specific diagnosis, to track disease progression, to measure molecular responses towards treatment regimes and ultimately devise new therapeutic strategies. To accomplish this, a better understanding of disease mechanisms is needed. In this review we summarize recent advances in the field of proteomics applicable to neurodegenerative disorders, and how these advances are fueling our understanding, diagnosis, and treatment of these complex disorders.     

Lizard and Frog Prestin: Evolutionary Insight into Functional Changes

The plasma membrane of mammalian cochlear outer hair cells contains prestin, a unique motor protein. Prestin is the fifth member of the solute carrier protein 26A family. Orthologs of prestin are also found in the ear of non-mammalian vertebrates such as zebrafish and chicken. However, these orthologs are electrogenic anion exchangers/transporters with no motor function. Amphibian and reptilian lineages represent phylogenic branches in the evolution of tetrapods and subsequent amniotes. Comparison of the peptide sequences and functional properties of these prestin orthologs offer new insights into prestin evolution. With the recent availability of the lizard and frog genome sequences, we examined amino acid sequence and function of lizard and frog prestins to determine how they are functionally and structurally different from prestins of mammals and other non-mammals. Somatic motility, voltage-dependent nonlinear capacitance (NLC), the two hallmarks of prestin function, and transport capability were measured in transfected human embryonic kidney cells using voltage-clamp and radioisotope techniques. We demonstrated that while the transport capability of lizard and frog prestin was compatible to that of chicken prestin, the NLC of lizard prestin was more robust than that of chicken’s and was close to that of platypus. However, unlike platypus prestin which has acquired motor capability, lizard or frog prestin did not demonstrate motor capability. Lizard and frog prestins do not possess the same 11-amino-acid motif that is likely the structural adaptation for motor function in mammals. Thus, lizard and frog prestins appear to be functionally more advanced than that of chicken prestin, although motor capability is not yet acquired.     

New Insight into the Biochemical Pathology of Liver in Choline Deficiency

Abstract

A diet deficient in choline can cause liver cancer in rats. The previous work since 1932 emphasized the fat-removing ability of choline from the liver. There are other dietary factors, including methionine, which, like choline, can remove fat from the liver. These factors were termed as lipotropes. Since then, choline deficiency and lipotrope deficiency are used synonoumously. Recent work since 1980 has clearly demonstrated that choline deficiency (CD) and lipotrope deficiency (LD) are not the same. Generation of free radicals, DNA alterations, liver cell death, and liver cancer that occur due to CD are not generated by LD. Generation of free radicals due to CD diet and some of the agents that counteract free radical action also prevent CD effects except for lipid accumulation in the liver. Despite the recent observations on the role of phospholipase A, (PLA) as the protector of the membranes, it has been found that by preventing the rise of PLA, in the liver, cell death can be prevented. These new findings give choline a distinct role in liver cell death and cancer rather than the role of lipotrope. A new hypothesis linking dietary choline deficiency and liver cancer has been discussed.     

New Insight into the Interactions of Arbutin with Mushroom Tyrosinase

The Protein Journal - As a safe substitute for hydroquinone, β-arbutin, a natural plant substance, and its synthetic counterpart, α-arbutin, are used in depigmentation formulations....     

iTBS-Induced LTP-Like Plasticity Parallels Oscillatory Activity Changes in the Primary Sensory and Motor Areas of Macaque Monkeys

Recently, neuromodulation techniques based on the use of repetitive transcranial magnetic stimulation (rTMS) have been proposed as a non-invasive and efficient method to induce in vivo long-term potentiation (LTP)-like aftereffects. However, the exact impact of rTMS-induced perturbations on the dynamics of neuronal population activity is not well understood. Here, in two monkeys, we examine changes in the oscillatory activity of the sensorimotor cortex following an intermittent theta burst stimulation (iTBS) protocol. We first probed iTBS modulatory effects by testing the iTBS-induced facilitation of somatosensory evoked potentials (SEP). Then, we examined the frequency information of the electrocorticographic signal, obtained using a custom-made miniaturised multi-electrode array for electrocorticography, after real or sham iTBS. We observed that iTBS induced facilitation of SEPs and influenced spectral components of the signal, in both animals. The latter effect was more prominent on the θ band (4–8 Hz) and the high γ band (55–90 Hz), de-potentiated and potentiated respectively. We additionally found that the multi-electrode array uniformity of β (13–26 Hz) and high γ bands were also afflicted by iTBS. Our study suggests that enhanced cortical excitability promoted by iTBS parallels a dynamic reorganisation of the interested neural network. The effect in the γ band suggests a transient local modulation, possibly at the level of synaptic strength in interneurons. The effect in the θ band suggests the disruption of temporal coordination on larger spatial scales.     

MicroRNAs: A New Insight into Cancer Genome

Cancer is a disease involving multi-step dynamic changes in the genome. However, studies on cancer genome so far have focused most heavily on protein-coding genes, and our knowledge on alterations of the functional non-coding sequences in cancer is largely absent. MicroRNAs (miRNA) are ~22 nt non-coding RNAs, which regulate gene expression in a sequence-specific manner via translational inhibition or mRNA degradation. Mounting evidence is showing that miRNAs may play important roles in tumor development, and a better understanding of their alteration in cancer genome and oncogenic property should contribute to the diagnosis and treatment of cancer.     

Gastric Motor and Sensory Functions in Obesity

In the vast majority of affected individuals, obesity involves overconsumption of food relative to calorie requirements. The sensory function of the stomach may play a key role in the cessation of food ingestion. This sensation of the stomach is, in part, determined by its motor functions, such as tone and compliance and the rate of emptying. However, studies of gastric emptying in normal‐weight and obese persons have shown inconsistent results. Gastric capacity was larger in obese persons when tested with an intragastric latex balloon filled with water. In contrast, other studies using the barostat or imaging (single‐photon emission computed tomography) techniques reported no differences in gastric volume or compliance between obese and lean subjects. On the other hand, increased body mass and fasting gastric volume are independently associated with delayed satiation under standard laboratory conditions of food ingestion. These data suggest that changes in gastric motor and sensory functions in obesity may present useful targets to prevent and treat obesity. Further well‐controlled, validated studies are needed to clarify the potential role of altering the stomach's function as a means of controlling food intake in obesity.     

An Insight into the Changes in Human Plasma Proteome on Adaptation to Hypobaric Hypoxia

Adaptation to hypobaric hypoxia is required by animals and human in several physiological and pathological situations. Hypobaric hypoxia is a pathophysiological condition triggering redox status disturbances of cell organization leading, via oxidative stress, to proteins, lipids, and DNA damage. Identifying the molecular variables playing key roles in this process would be of paramount importance to shed light on the mechanisms known to counteract the negative effects of oxygen lack. To obtain a molecular signature, changes in the plasma proteome were studied by using proteomic approach. To enrich the low-abundance proteins in human plasma, two highly abundant proteins, albumin and IgG, were first removed. By comparing the plasma proteins of high altitude natives with those of a normal control group, several proteins with a significant alteration were found. The up-regulated proteins were identified as vitamin D-binding protein, hemopexin, alpha-1–antitrypsin, haptoglobin β-chain, apolipoprotein A1, transthyretin and hemoglobin beta chain. The down-regulated proteins were transferrin, complement C3, serum amyloid, complement component 4A and plasma retinol binding protein. Among these proteins, the alterations of transthyretin and transferrin were further confirmed by ELISA and Western blotting analysis. Since all the up- and down- regulated proteins identified above are well-known inflammation inhibitors and play a positive anti-inflammatory role, these results show that there is some adaptive mechanism that sustains the inflammation balance in high altitude natives exposed to hypobaric hypoxia.     

New Insight into the Thermal Properties and the Biological Behaviour of the Bacterial Spores

The physicochemical properties of spores were studied in relationship of their structure, which was modulated by chemical or genetic methods. The Bacillus subtilis spores were equilibrated at different water activities (from 0.113 to ~1) and investigated by differential scanning calorimetry (DSC). The isothermal sorptions at 25 °C of the native and the modified spores were also used to analyse the DSC results. As already reported in literature, an endothermic peak in DSC was found at about 70 °C, but a previously unreported baseline shift, a ∆Cp step, was also observed at −69 °C. The endothermic peak found at 70 °C was assigned to a material relaxation which corresponded to a structure change from a less mobile state to a more mobile state. The spore cortex material seems to be mainly implicated in this event. The ∆Cp step observed at −69 °C was identified as a glass transition of the water in the spore protoplast. These results showed that at room temperature, the physical state of the components within B. subtilis spores equilibrated at water activity levels below 0.3 was different: The cortex material is in a low mobility state whereas confined structure of protoplast and its internal hydration level allow a certain mobility of water molecules.     

New Insight into the Structure and Regulation of the Plant Vacuolar H+-ATPase

Plant cells are characterized by a highly active secretory system that includes the large central vacuole found in most differentiated tissues. The plant vacuolar H⁺-ATPase plays an essential role in maintaining the ionic and metabolic gradients across endomembranes, in activating transport processes and vesicle dynamics, and, hence, is indispensable for plant growth, development, and adaptation to changing environmental conditions. The review summarizes recent advances in elucidating the structure, subunit composition, localization, and regulation of plant V-ATPase. Emerging knowledge on subunit isogenes from Arabidopsis and rice genomic sequences as well as from Mesembryanthemum illustrates another level of complexity, the regulation of isogene expression and function of subunit isoforms. To this end, the review attempts to define directions of future research on plant V-ATPase.     

Helicase-appended Topoisomerases: New Insight into the Mechanism of Directional Strand Transfer

DNA strand passage through an enzyme-mediated gate is a key step in the catalytic cycle of topoisomerases to produce topological transformations in DNA. In most of the reactions catalyzed by topoisomerases, strand passage is not directional; thus, the enzyme simply provides a transient DNA gate through which DNA transport is allowed and thereby resolves the topological entanglement. When studied in isolation, the type IA topoisomerase family appears to conform to this rule. Interestingly, type IA enzymes can carry out directional strand transport as well. We examined here the biochemical mechanism for directional strand passage of two type IA topoisomerases: reverse gyrase and a protein complex of topoisomerase IIIα and Bloom helicase. These enzymes are able to generate vectorial strand transport independent of the supercoiling energy stored in the DNA molecule. Reverse gyrase is able to anneal single strands, thereby increasing linkage number of a DNA molecule. However, topoisomerase IIIα and Bloom helicase can dissolve DNA conjoined with a double Holliday junction, thus reducing DNA linkage. We propose here that the helicase or helicase-like component plays a determinant role in the directionality of strand transport. There is thus a common biochemical ground for the directional strand passage for the type IA topoisomerases.     

New Insight into Ki67 Expression at the Invasive Front in Breast Cancer

Purpose

To investigate the distribution of Ki67+ cells in breast cancer in relation to clinical-pathological parameters and prognosis.

Materials and Methods

Ki67 expression status was detected in 1,086 breast cancer specimens using immunohistochemistry staining and examining the relationship between the Ki67+ cells'' location. Subsequently, clinical-pathological parameters and prognosis were determined.

Results

In total, Ki67 protein expression was found in 781 (71.92%) of the 1,086 breast cancer specimens. Among the 781 Ki67+ cases, 461 were defined as diffuse type and 320 were defined as borderline type. After universal correlation analysis, significant differences were observed in age, histological grade, metastatic nodes, postoperative distant metastasis, and molecular subtype between Ki67+ and Ki67− cases (P = 0.01, 0.001, 0.001, 0.001, and 0.001, respectively). After subgroup analysis, the borderline cases were found to be characterized by a high distant metastasis rate compared to the diffuse cases as well as the Ki67− cases (P = 0.001). No differences were observed between diffuse type or Ki67− cases (P = 0.105). Multivariate analysis showed that age, tumor size, histological grade, lymph node metastasis, molecular subtype, and the Ki67 distribution pattern were observed to be related to postoperative distant metastasis (all P<0.05). Furthermore, borderline type was shown to attain a significantly more distant bone and liver metastasis and worse disease-specific survival than the other types (P = 0.001). In the Cox regression test, the Ki67 distribution pattern was detected as an independent prognostic factor (P = 0.001).

Conclusion

The distribution pattern of Ki67 may be a new independent prognostic factor for breast cancer.     

Molecular Time-Course and the Metabolic Basis of Entry into Dauer in Caenorhabditis elegans

When Caenorhabditis elegans senses dauer pheromone (daumone), signaling inadequate growth conditions, it enters the dauer state, which is capable of long-term survival. However, the molecular pathway of dauer entry in C. elegans has remained elusive. To systematically monitor changes in gene expression in dauer paths, we used a DNA microarray containing 22,625 gene probes corresponding to 22,150 unique genes from C. elegans. We employed two different paths: direct exposure to daumone (Path 1) and normal growth media plus liquid culture (Path 2). Our data reveal that entry into dauer is accomplished through the multi-step process, which appears to be compartmentalized in time and according to metabolic flux. That is, a time-course of dauer entry in Path 1 shows that dauer larvae formation begins at post-embryonic stage S4 (48 h) and is complete at S6 (72 h). Our results also suggest the presence of a unique adaptive metabolic control mechanism that requires both stage-specific expression of specific genes and tight regulation of different modes of fuel metabolite utilization to sustain the energy balance in the context of prolonged survival under adverse growth conditions. It is apparent that worms entering dauer stage may rely heavily on carbohydrate-based energy reserves, whereas dauer larvae utilize fat or glyoxylate cycle-based energy sources. We created a comprehensive web-based dauer metabolic database for C. elegans (www.DauerDB.org) that makes it possible to search any gene and compare its relative expression at a specific stage, or evaluate overall patterns of gene expression in both paths. This database can be accessed by the research community and could be widely applicable to other related nematodes as a molecular atlas.     

Intracellular Signaling in Primary Sensory Neurons and Persistent Pain

During evolution, living organisms develop a specialized apparatus called nociceptors to sense their environment and avoid hazardous situations. Intense stimulation of high threshold C- and Aδ-fibers of nociceptive primary sensory neurons will elicit pain, which is acute and protective under normal conditions. A further evolution of the early pain system results in the development of nociceptor sensitization under injury or disease conditions, leading to enhanced pain states. This sensitization in the peripheral nervous system is also called peripheral sensitization, as compared to its counterpart, central sensitization. Inflammatory mediators such as proinflammatory cytokines (TNF-α, IL-1β), PGE₂, bradykinin, and NGF increase the sensitivity and excitability of nociceptors by enhancing the activity of pronociceptive receptors and ion channels (e.g., TRPV1 and Na_v1.8). We will review the evidence demonstrating that activation of multiple intracellular signal pathways such as MAPK pathways in primary sensory neurons results in the induction and maintenance of peripheral sensitization and produces persistent pain. Targeting the critical signaling pathways in the periphery will tackle pain at the source. Special issue article in honor of Dr. Ji-Sheng Han.     

Vitamin Pharmacogenomics: New Insight into Individual Differences in Diseases and Drug Responses

Vitamins are vital to sustain normal physiological function, metabolism, and growth for all living organisms. Being an integral component of coenzyme, vitamins can affect the catalytic activities of many enzymes and the expression of drug transporters. Genetic variations in metabolism and/or transporter genes of drugs can influence the exposure of the human body to drugs and/or their active metabolites, thus contributing to the variations in drug responses and toxicities. Nonetheless, pharmacogenomics studies on nutrients have been rarely summarized. In this article, we reviewed recent progress on vitamin pharmacogenomics, for a better understanding on the influence of vitamin-related gene polymorphisms on inter-individual differences in diseases and drug efficacy and safety.     

Modeling and Analysis of the Molecular Basis of Pain in Sensory Neurons

Intracellular calcium dynamics are critical to cellular functions like pain transmission. Extracellular ATP plays an important role in modulating intracellular calcium levels by interacting with the P2 family of surface receptors. In this study, we developed a mechanistic mathematical model of ATP-induced P2 mediated calcium signaling in archetype sensory neurons. The model architecture, which described 90 species connected by 162 interactions, was formulated by aggregating disparate molecular modules from literature. Unlike previous models, only mass action kinetics were used to describe the rate of molecular interactions. Thus, the majority of the 252 unknown model parameters were either association, dissociation or catalytic rate constants. Model parameters were estimated from nine independent data sets taken from multiple laboratories. The training data consisted of both dynamic and steady-state measurements. However, because of the complexity of the calcium network, we were unable to estimate unique model parameters. Instead, we estimated a family or ensemble of probable parameter sets using a multi-objective thermal ensemble method. Each member of the ensemble met an error criterion and was located along or near the optimal trade-off surface between the individual training data sets. The model quantitatively reproduced experimental measurements from dorsal root ganglion neurons as a function of extracellular ATP forcing. Hypothesized architecture linking phosphoinositide regulation with P2X receptor activity explained the inhibition of P2X-mediated current flow by activated metabotropic P2Y receptors. Sensitivity analysis using individual and the whole system outputs suggested which molecular subsystems were most important following P2 activation. Taken together, modeling and analysis of ATP-induced P2 mediated calcium signaling generated qualitative insight into the critical interactions controlling ATP induced calcium dynamics. Understanding these critical interactions may prove useful for the design of the next generation of molecular pain management strategies.