Daniel Peterson

MEGA5: Molecular Evolutionary Genetics Analysis Using Maximum Likelihood, Evolutionary Distance, and Maximum Parsimony Methods

Comparative analysis of molecular sequence data is essential for reconstructing the evolutionary histories of species and inferring the nature and extent of selective forces shaping the evolution of genes and species. Here, we announce the release of Molecular Evolutionary Genetics Analysis version 5 (MEGA5), which is a user-friendly software for mining online databases, building sequence alignments and phylogenetic trees, and using methods of evolutionary bioinformatics in basic biology, biomedicine, and evolution. The newest addition in MEGA5 is a collection of maximum likelihood (ML) analyses for inferring evolutionary trees, selecting best-fit substitution models (nucleotide or amino acid), inferring ancestral states and sequences (along with probabilities), and estimating evolutionary rates site-by-site. In computer simulation analyses, ML tree inference algorithms in MEGA5 compared favorably with other software packages in terms of computational efficiency and the accuracy of the estimates of phylogenetic trees, substitution parameters, and rate variation among sites. The MEGA user interface has now been enhanced to be activity driven to make it easier for the use of both beginners and experienced scientists. This version of MEGA is intended for the Windows platform, and it has been configured for effective use on Mac OS X and Linux desktops. It is available free of charge from http://www.megasoftware.net.

MEGA6: Molecular Evolutionary Genetics Analysis Version 6.0

We announce the release of an advanced version of the Molecular Evolutionary Genetics Analysis (MEGA) software, which currently contains facilities for building sequence alignments, inferring phylogenetic histories, and conducting molecular evolutionary analysis. In version 6.0, MEGA now enables the inference of timetrees, as it implements the RelTime method for estimating divergence times for all branching points in a phylogeny. A new Timetree Wizard in MEGA6 facilitates this timetree inference by providing a graphical user interface (GUI) to specify the phylogeny and calibration constraints step-by-step. This version also contains enhanced algorithms to search for the optimal trees under evolutionary criteria and implements a more advanced memory management that can double the size of sequence data sets to which MEGA can be applied. Both GUI and command-line versions of MEGA6 can be downloaded from www.megasoftware.net free of charge.

MEGA-MD: molecular evolutionary genetics analysis software with mutational diagnosis of amino acid variation

Computational diagnosis of amino acid variants in the human exome is the first step in assessing the disruptive impacts of non-synonymous single nucleotide variants (nsSNVs) on human health and disease. The Molecular Evolutionary Genetics Analysis software with mutational diagnosis (MEGA-MD) is a suite of tools developed to forecast the deleteriousness of nsSNVs using multiple methods and to explore nsSNVs in the context of the variability permitted in the long-term evolution of the affected position. In its graphical interface for use on desktops, it enables interactive computational diagnosis and evolutionary exploration of nsSNVs. As a web service, MEGA-MD is suitable for diagnosing variants on an exome scale. The MEGA-MD suite intends to serve the needs for conducting low- and high-throughput analysis of nsSNVs in diverse applications.

The Effect of Levodopa on Improvements in Protective Stepping in People with Parkinson's Disease

Background. The effect of levodopa on postural motor learning in people with Parkinson’s disease is poorly understood. In particular, it is unknown whether levodopa affects improvement in protective postural responses after external perturbations such as a slip or trip, a critical aspect of fall prevention. Objective. Determine the effect of levodopa on postural motor learning in people with Parkinson’s disease. Methods. We assessed improvement in protective postural responses in people with Parkinson’s disease over short-term (1 day) perturbation training on and off levodopa. We also assessed retention and generalization of improvement. Participants were 22 individuals with Parkinson’s disease. The primary outcome was total center of mass (COM) displacement after perturbation. Secondary outcomes assessed first step performance and included margin of stability at first foot contact. Results. People with Parkinson’s disease improved COM displacement (P = .011) and margin of stability (P = .016) over training. Improvements in these outcomes were more pronounced after training while on levodopa than off levodopa. Levodopa State × Training interactions were not observed for other step performance variables (eg, step latency, length, total number of steps). Improvements were retained for 24 hours, and for margin of stability, retention was more pronounced while on levodopa than off (P = .018). Conclusions. Individuals with Parkinson’s disease are able to improve protective postural responses through short-term perturbation training, and improvements were more pronounced when on levodopa for some variables. Perturbation training may be more effective if completed while optimally medicated with levodopa.

Anticipatory Postural Adjustment During Self-Initiated, Cued, and Compensatory Stepping in Healthy Older Adults and Patients With Parkinson Disease

OBJECTIVE To characterize anticipatory postural adjustments (APAs) across a variety of step initiation tasks in people with Parkinson disease (PD) and healthy subjects. DESIGN Cross-sectional study. Step initiation was analyzed during self-initiated gait, perceptual cued gait, and compensatory forward stepping after platform perturbation. People with PD were assessed on and off levodopa. SETTING University research laboratory. PARTICIPANTS People (N=31) with PD (n=19) and healthy aged-matched subjects (n=12). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Mediolateral (ML) size of APAs (calculated from center of pressure recordings), step kinematics, and body alignment. RESULTS With respect to self-initiated gait, the ML size of APAs was significantly larger during the cued condition and significantly smaller during the compensatory condition (P<.001). Healthy subjects and patients with PD did not differ in body alignment during the stance phase prior to stepping. No significant group effect was found for ML size of APAs between healthy subjects and patients with PD. However, the reduction in APA size from cued to compensatory stepping was significantly less pronounced in PD off medication compared with healthy subjects, as indicated by a significant group by condition interaction effect (P<.01). No significant differences were found comparing patients with PD on and off medications. CONCLUSIONS Specific stepping conditions had a significant effect on the preparation and execution of step initiation. Therefore, APA size should be interpreted with respect to the specific stepping condition. Across-task changes in people with PD were less pronounced compared with healthy subjects. Antiparkinsonian medication did not significantly improve step initiation in this mildly affected PD cohort.

How changes in brain activity and connectivity are associated with motor performance in people with MS

People with multiple sclerosis (MS) exhibit pronounced changes in brain structure, activity, and connectivity. While considerable work has begun to elucidate how these neural changes contribute to behavior, the heterogeneity of symptoms and diagnoses makes interpretation of findings and application to clinical practice challenging. In particular, whether MS related changes in brain activity or brain connectivity protect against or contribute to worsening motor symptoms is unclear. With the recent emergence of neuromodulatory techniques that can alter neural activity in specific brain regions, it is critical to establish whether localized brain activation patterns are contributing to (i.e. maladaptive) or protecting against (i.e. adaptive) progression of motor symptoms. In this manuscript, we consolidate recent findings regarding changes in supraspinal structure and activity in people with MS and how these changes may contribute to motor performance. Furthermore, we discuss a hypothesis suggesting that increased neural activity during movement may be either adaptive or maladaptive depending on where in the brain this increase is observed. Specifically, we outline preliminary evidence suggesting sensorimotor cortex activity in the ipsilateral cortices may be maladaptive in people with MS. We also discuss future work that could supply data to support or refute this hypothesis, thus improving our understanding of this important topic.

Motor learning in people with Parkinson’s disease: Implications for fall prevention across the disease spectrum

BACKGROUND Falls are a significant burden for people with Parkinsons disease (PD), however, individuals across the spectrum of disease severity respond differently to fall prevention interventions. Despite the multifactorial causes of falls in people with PD, recent work has provided insight into interventions that hold promise for fall prevention. Further, studies have begun to identify patient characteristics that may predict responsiveness to such interventions. RESEARCH QUESTION We discuss (i) the postural motor learning abilities of people with mild versus severe PD that could affect their ability to benefit from fall prevention interventions, (ii) how people with different severity of PD respond to such interventions, and (iii) the practical considerations of providing effective fall prevention interventions for people with PD across the spectrum of disease severity. METHODS This narrative review consolidates recent work on postural motor learning and fall prevention rehabilitation involving exercise in people with PD. RESULTS People with PD are able to improve postural motor control through practice, enabling them to benefit from exercise which challenges their gait and balance to reduce falling. Worsening of axial and cognitive symptoms may result in diminished learning, and those with more severe PD may require fully supervised, high intensity programs to reduce falls. SIGNIFICANCE Understanding how people with PD across the spectrum of disease severity differ in their postural motor learning ability and response to different fall prevention interventions will enable researchers and clinicians to refine such interventions and their delivery to minimize falls and their negative sequelae in people with PD.

Relating Anticipatory Postural Adjustments to Step Outcomes During Loss of Balance in People With Parkinson’s Disease

Background. Effective protective steps are critical for fall prevention, and anticipatory postural adjustments (APAs) after a perturbation but prior to protective steps affect step performance. Although APAs prior to protective steps are altered in people with Parkinson’s disease (PD), whether these changes affect subsequent step performance is poorly understood. Objective. Characterize the relationship between mediolateral APA size and protective step outcomes in response to anteroposterior balance perturbations in people with PD. Methods. Twenty-eight individuals with PD completed 25 forward and 25 backward protective steps in response to support surface translations. Multilevel linear models related mediolateral APA size to protective step outcomes. Results. During forward protective stepping, larger mediolateral APAs were associated with delayed (P < .001) and larger (P = .004) steps. Larger APAs were also associated with smaller mediolateral (P < .001) but larger anterior-posterior center of mass movement at foot off (P < .001). During backward stepping, larger APAs were associated with later steps (P < .001) and smaller anterior-posterior margin of stability at first foot contact (P < .001). During backward stepping, larger APAs were also associated with worse clinical (ie, UPDRS [Unified Parkinson’s Disease Rating Scale]; P = .005) and balance (ie, MiniBEST [Mini-Balance Evaluation Systems Test]; P = .021) outcomes. Conclusions. During forward protective stepping, larger APAs were associated with larger and later steps, suggesting APA size may have mixed effects on the subsequent step. During backward stepping, larger APAs were associated with worse stepping outcomes (ie, later steps, smaller anterior-posterior margin of stability, worse clinical outcomes). Interventions aimed at improving APAs in PD should monitor spatial and temporal protective step outcomes to ensure treatment does not negatively affect protective steps, particularly for forward stepping.

Destabilization of the Upright Posture Through Elevation of the Center of Mass

The inverted pendulum model predicts that the major challenge for neural control of the upright posture is the inherent instability of the body due to the center of mass (COM) being above the base of support (BOS). If so, even slight elevation of the COM may substantially destabilize posture. The destabilizing effect of heavy load positioned above the COM has been demonstrated. We examined sensitivity of posture to light (1–5% of body weight) load by placing weights on the shoulders and assessing functional reach distance in the forward, right, and left directions and postural sway during quiet stance. At each load level, the quiet stance task was tested with and without vision. The 1% of body weight load significantly shortened reach distance in the forward direction. It also increased postural sway. Interestingly, additional weight did not result in further deficits. The results support high sensitivity of postural stability to COM elevation that increases the challenge for neural control of posture and that can potentially be used for early detection of declines in postural stability.