Oxidative stress,DNA damage,and the telomeric complex as therapeutic targets in acute neurodegeneration

Oxidative stress has been identified as an important contributor to neurodegeneration associated with acute CNS injuries and diseases such as spinal cord injury (SCI), traumatic brain injury (TBI), and ischemic stroke. In this review, we briefly detail the damaging effects of oxidative stress (lipid peroxidation, protein oxidation, etc.) with a particular emphasis on DNA damage. Evidence for DNA damage in acute CNS injuries is presented along with its downstream effects on neuronal viability. In particular, unchecked oxidative DNA damage initiates a series of signaling events (e.g. activation of p53 and PARP-1, cell cycle re-activation) which have been shown to promote neuronal loss following CNS injury. These findings suggest that preventing DNA damage might be an effective way to promote neuronal survival and enhance neurological recovery in these conditions. Finally, we identify the telomere and telomere-associated proteins (e.g. telomerase) as novel therapeutic targets in the treatment of neurodegeneration due to their ability to modulate the neuronal response to both oxidative stress and DNA damage.     

福建漳江口红树林鹭科鸟类巢址选择

2011年4～5月、2012年4～5月,采用样线调查和样方调查相结合的方法对福建漳江口红树林国家级自然保护区内鹭科鸟类巢址与影响其选择的因子进行研究.t-检验结果显示,红树基径、盖度、距地面平均高度、植株密度及秋茄比5个参数在巢区样方(n=23)与对照样方(n=37)之间存在显著差异(P＜0.05),桐花比、距道路距离、距村庄距离与距池塘距离4个参数存在极其显著差异(P＜0.01).主成分分析表明,植被结构和干扰条件是影响鹭科鸟类巢址选择的主要因子,植被结构不仅能够影响鹭科鸟类群落结构,还受到鹭科鸟类集群繁殖影响.     

The Global Sequence Signature algorithm unveils a structural network surrounding heavy chain CDR3 loop in Camelidae variable domains

Background

A large fraction of camelid (camels and llamas) antibodies is composed of heavy chain-only homodimers, able to recognise antigens with their variable domain. Events in somatic assembly and maturation of antibodies such as hypermutations and rearrangement of variable loops (CDRs — complementary determining regions) and selection among a wide range of framework variants are generally considered to be random processes.

Methods

An original algorithmic approach (Global Sequence Signature—GSS) was developed, able to take into account multiple functional and/or local sequence properties to detect scattered evolutionary constraints into sequences.

Results

Using the GSS approach, we show that the length of the main hypervariable loop (CDR3) is linked to the nature of 19 surrounding residues on the scaffold. Surprisingly, the relation between CDR3 size and scaffold residues strongly depends on the considered species, illustrating either significant differences in selection mechanisms or functional constraints during antibody maturation.

Conclusions

Combined with the statistical coupling analysis (SCA) approach at the level of scaffold residues, this study has unravelled a robust interaction network on antibody structure surrounding the CDR3 loop.

General significance

In addition to the general applicability of the GSS algorithm, which can bring together functional and sequence data to locate hot spots of constrained evolution, the relationship between CDR3 and scaffold discussed here should be taken into account in protein engineering when designing antibody libraries.     

Genetic structure of Mexican Mestizos with type 2 diabetes mellitus based on three STR loci

Background

The aims of this population genetics study were: 1) to ascertain whether Mexicans with type 2 diabetes mellitus (DM) were genetically homogeneous and 2) to compare the genetic structure of this selected population with the previously reported data of four random populations (Nuevo León, Hispanics, Chihuahua, and Central Region of Mexico).

Methods

A sample of 103 unrelated individuals with DM and whose 4 grandparents were born in five zones of Mexico was interviewed in 32 Medical Units in the Mexican Institute of Social Security (IMSS). The non-coding STRs D16S539, D7S820, and D13S317 were analyzed.

Results

Genotype distribution was in agreement with Hardy–Weinberg expectations for all three markers. Allele frequencies were found to be similar between the selected population and the four random populations. Gene diversity analysis suggested that more than 99.57% of the total gene diversity could be attributed to variation between individuals within the population and 0.43% between the populations.

Conclusions

According to the present and previous studies using molecular and non-molecular nuclear DNA markers not associated with any disease, the Mexican Mestizo population is found to be genetically homogeneous and therefore the genetic causes of DM are less heterogeneous, thereby simplifying genetic epidemiological studies as has been found in a previous study with the same design in Mexican women with breast cancer.     

Comparative structural analysis of two proteins belonging to quorum sensing system in Vibrio cholerae

Vibrio cholerae uses quorum sensing communication system to interact with other bacteria and for gauzing environmental parameters. This organism dwells equally well in both human host and aquatic environments. Quorum sensing regulates multitude of activities and is one of the lucrative targets presently pursued for drug design in bacteria to encounter virulence. Histidine phosphotransfer protein LuxU and response regulator LuxO of V. cholerae are known to play important roles in biofilms and virulence machinery. In the present study, we used computational methods to model LuxU and LuxO and simulated the interactions of LuxO and LuxU. Since no structural details of the proteins were available, we employed homology modeling to construct the three-dimensional structures and then performed molecular dynamics simulations to study dynamic behavior of the LuxO and LuxU from V. cholerae. The modeled proteins were validated and subjected to molecular docking analyses. This allowed us to predict the binding modes of the proteins to elucidate probable sites of interference.     

Multifrequency Infradian Variation of Blood Pressure During and After Human Pregnancy

We used a chronobiologic approach to explore the possibility that there may be -7-day (circaseptan) and -30-day (circatrigintan) components in blood pressure during a healthy human pregnancy, the amenorrhea of this status notwithstanding. The results were compared with those obtained from data longitudinally monitored on the same subject at a time when she was not pregnant. The woman under study used an ABPM-630 Colin (Komaki, Japan) device to monitor her blood pressures and heart rates at half to 1-h intervals, with few interruptions. During pregnancy, starting during the first gestational week, she monitored herself for 2 of each 6-day span for the entire duration of pregnancy (a total of 76 days of monitoring). Additionally, with a monitoring protocol similar to that during pregnancy, the subject used the same blood pressure monitor for a total of 78 days during 9.6 months and starting 1 year after delivery. The data obtained oscillometrically for both longitudinal profiles were analyzed separately by multiple-component linear least-squares rhythmometry, a procedure used to describe the periodic waveform of nonsinusoidal rhythms. The analysis of blood pressure variability during pregnancy allows the identification not only of the circadian (with a period of 24 h), but also of other statistically significant components with periods of 156 (6.5 days, apparently free-running from the social week) and of 720 h (30 days) for both systolic and diastolic blood pressure. This multiharmonic time structure is somewhat different during menstruation in the same woman and during a similar time span, with statistically significant components of 96 h (4 days), 192 h (8 days), and 960 h (40 days) for both systolic and diastolic blood pressure. Moreover, the ratio between the amplitudes of the infradian components identified during pregnancy in clinical health is reversed from that obtained in women with preeclampsia. The complex time-structure of blood pressure during pregnancy offers new endpoints to be taken into account for an early identification of gestational hypertension or even preeclampsia.     

Conformational changes and allosteric communications in human serum albumin due to ligand binding

It is well recognized that knowledge of structure alone is not sufficient to understand the fundamental mechanism of biomolecular recognition. Information of dynamics is necessary to describe motions involving relevant conformational states of functional importance. We carried out principal component analysis (PCA) of structural ensemble, derived from 84 crystal structures of human serum albumin (HSA) with different ligands and/or different conditions, to identify the functionally important collective motions, and compared with the motions along the low-frequency modes obtained from normal mode analysis of the elastic network model (ENM) of unliganded HSA. Significant overlap is observed in the collective motions derived from PCA and ENM. PCA and ENM analysis revealed that ligand selects the most favored conformation from accessible equilibrium structures of unliganded HSA. Further, we analyzed dynamic network obtained from molecular dynamics simulations of unliganded HSA and fatty acids- bound HSA. Our results show that fatty acids-bound HSA has more robust community network with several routes to communicate among different parts of the protein. Critical nodes (residues) identified from dynamic network analysis are in good agreement with allosteric residues obtained from sequence-based statistical coupling analysis method. This work underscores the importance of intrinsic structural dynamics of proteins in ligand recognition and can be utilized for the development of novel drugs with optimum activity.     

Simulating nanoscale functional motions of biomolecules

We are describing efficient dynamics simulation methods for the characterization of functional motion of biomolecules on the nanometer scale. Multivariate statistical methods are widely used to extract and enhance functional collective motions from molecular dynamics (MD) simulations. A dimension reduction in MD is often realized through a principal component analysis (PCA) or a singular value decomposition (SVD) of the trajectory. Normal mode analysis (NMA) is a related collective coordinate space approach, which involves the decomposition of the motion into vibration modes based on an elastic model. Using the myosin motor protein as an example we describe a hybrid technique termed amplified collective motions (ACM) that enhances sampling of conformational space through a combination of normal modes with atomic level MD. Unfortunately, the forced orthogonalization of modes in collective coordinate space leads to complex dependencies that are not necessarily consistent with the symmetry of biological macromolecules and assemblies. In many biological molecules, such as HIV-1 protease, reflective or rotational symmetries are present that are broken using standard orthogonal basis functions. We present a method to compute the plane of reflective symmetry or the axis of rotational symmetry from the trajectory frames. Moreover, we develop an SVD that best approximates the given trajectory while respecting the symmetry. Finally, we describe a local feature analysis (LFA) to construct a topographic representation of functional dynamics in terms of local features. The LFA representations are low-dimensional, and provide a reduced basis set for collective motions, but unlike global collective modes they are sparsely distributed and spatially localized. This yields a more reliable assignment of essential dynamics modes across different MD time windows.     

Does local adaptation along a latitudinal cline shape plastic responses to combined thermal and nutritional stress?

Thermal and nutritional stress are commonly experienced by animals. This will become increasingly so with climate change. Whether populations can plastically respond to such changes will determine their survival. Plasticity can vary among populations depending on the extent of environmental heterogeneity. However, theory conflicts as to whether environmental heterogeneity should increase or decrease plasticity. Using three locally adapted populations of Drosophila melanogaster sampled from a latitudinal gradient, we investigated whether plastic responses to combinations of nutrition and temperature increase or decrease with latitude for four traits: egg-adult viability, egg-adult development time, and two body size traits. Employing nutritional geometry, we reared larvae on 25 diets varying in protein and carbohydrate content at two temperatures: 18 and 25°C. Plasticity varied among traits and across the three populations. Viability was highly canalized in all three populations. The tropical population showed the least plasticity for development time, the sub-tropical showed the highest plasticity for wing area, and the temperate population showed the highest plasticity for femur length. We found no evidence of latitudinal plasticity gradients in either direction. Our data highlight that differences in thermal variation and resource predictability experienced by populations along a latitudinal cline are not sufficient to predict their plasticity.     

Simultaneous confidence corridors for mean functions in functional data analysis of imaging data

Motivated by recent work involving the analysis of biomedical imaging data, we present a novel procedure for constructing simultaneous confidence corridors for the mean of imaging data. We propose to use flexible bivariate splines over triangulations to handle an irregular domain of the images that is common in brain imaging studies and in other biomedical imaging applications. The proposed spline estimators of the mean functions are shown to be consistent and asymptotically normal under some regularity conditions. We also provide a computationally efficient estimator of the covariance function and derive its uniform consistency. The procedure is also extended to the two-sample case in which we focus on comparing the mean functions from two populations of imaging data. Through Monte Carlo simulation studies, we examine the finite sample performance of the proposed method. Finally, the proposed method is applied to analyze brain positron emission tomography data in two different studies. One data set used in preparation of this article was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.