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At least 487 records · Page 27Linked to original sources
PubMed2026

Genotype-structure-phenotype correlations define divergent natural history in early-onset spastic paraplegia type 4.

Hereditary spastic paraplegia type 4 (SPG4), caused by variants in SPAST, is the most common form of HSP and exhibits a remarkable phenotypic heterogeneity ranging from late-onset pure presentations to severe, early-onset complex disease. Robust genotype-phenotype correlations and detailed natural history data are lacking, limiting clinical trial readiness. We analyzed 206 patients with genetically confirmed SPG4 enrolled across seven international centers, complemented by high-quality literature-derived cases. Deep phenotyping included standardized motor scales, spasticity ratings, developmental milestones, and patient-reported outcomes. We developed an extended essentiality-mapping framework to classify SPAST missense variants by integrating in silico pathogenicity predictions, evolutionary constraint, physicochemical residue connectivity, and variant enrichment within the human spastin hexamer structure. Plasma neurofilament light chain (pNfL) using was quantified using Simoa in 26 patients and 101 controls. We identified 136 distinct SPAST variants, including 10 novel variants. Variant class segregated strongly by inheritance, with de novo cases enriched for missense variants and inherited cases showing a variety of variant classes with enrichment for truncating variants. Longitudinal analysis revealed two latent trajectories: a rapidly progressive severe subgroup enriched for de novo missense variants, and a biphasic moderate subgroup enriched for inherited truncating variants. Patient stratification integrating spastin essentiality mapping (missense variants affecting essential, neutral, or context-dependent residues) with established genetic modifiers (biallelic pathogenic variants or modifier variants in trans) classified patients into predicted severe and moderate subgroups with divergent age at onset and clinical disease progression. The severe subgroup showed early developmental delays, rapid loss of ambulation, and declining quality of life, while the moderate subgroup displayed delayed but accelerating disease progression. pNfL levels were elevated in both subgroups, most pronounced in severe early disease. This study provides the most detailed natural history of SPG4 to date and introduces a biologically informed stratification framework that links variant class and location to divergent clinical trajectories. These data establish clinically meaningful benchmarks and offer a genotype-based framework to improve anticipatory care and optimize trial design for SPG4.

SPAST↗
PubMed1988

Influence of system parameter settings on human sperm motility analysis using CellSoft.

The effect of changing CellSoft system parameter settings on measurements of motile sperm concentration and sperm movement characteristics (curvilinear and linear velocities, amplitude of lateral head displacement and beat/cross frequency) was investigated in semen. Specifically, the use of either four or 15 frames to distinguish motile from immotile cells was used in conjunction with a threshold curvilinear velocity of either 10 or 20 micron/s (recommended values: 4 and 10). In addition, a threshold for progressive motility based on linear velocity was also used by manual re-analysis of CellSoft Individual Cell Data printouts. Known reliable semen analysis methods or the analysis of manually reconstructed trajectories from videotape were used as standard methods for comparison. A curvilinear velocity threshold of 20 micron/s gave improved correspondence between CellSoft and standard methods for all characteristics evaluated. Whether a four or 15 frame setting was better varied with the measurement being made. However, using a linear velocity threshold to define the progressively motile sperm population provided the most acceptable values for sperm movement characteristics. Consequently, while substantial improvements in the measurements made by CellSoft can be obtained using different system parameters to those usually recommended, more reliable and certainly more useful information could probably be obtained if all analyses were performed on a defined population of progressively motile, and therefore potentially functional, spermatozoa.

Humans↗
PubMed2004

Ray and wave instabilities in twisted graded-index optical fibers.

We study ray and wave propagation in an elliptical graded-index optical fiber or lens with a twisted axis and show analytically the existence of an instability for both ray trajectories and beam moments in a finite range of axis twist rate embedded within the spatial frequencies of periodically focused rays for the untwisted fiber. By considering the paraxial ray equations and the paraxial wave dynamics in a rotating frame that follows the fiber axis twist, we reduce the dynamical problem of ray trajectories to the classical Blackburn's pendulum, which shows a dynamical instability, corresponding to classical diverging trajectories, due to the competing effects of confining potential, Coriolis force, and centrifugal force. A closed set of linear evolution equations for generalized beam moments are also derived from the paraxial wave equation in the rotating reference frame, revealing the existence of a dynamical moment instability in addition to the trajectory instability. A detailed analysis of beam propagation is presented in case of a Gaussian beam, and different dynamical regimes are discussed.

Journal Article↗
PubMed2001

Dependence of the dust-particle charge on its size in a glow-discharge plasma.

Measurements of the charge of dust grains have been performed in a quasineutral plasma over a wide range of grain sizes. A new method was established for measuring the charge on grains levitating in the striations of a dc glow discharge. A single dust particle is moved out of a dust cloud with the help of a focused laser beam. When it leaves the beam it returns back to the cloud, and the charge on the grain is derived from the analysis of the returning trajectory. The obtained dependence of the dust-grain charge on its size was found to be strongly nonlinear in the experimental conditions.

Journal Article↗
PubMed2004

Regge oscillations in integral cross sections for proton impact on atomic hydrogen.

The integral cross sections for elastic scattering and spin exchange for proton impact on atomic hydrogen show several oscillations in the energy range 0.01-1.0 eV that cannot be associated with resonances or the glory effect. A complex angular momentum analysis using computed Regge trajectories shows that each peak of the oscillatory structure is predominantly associated with at most three trajectories. In this way, the peaks are related to the L=0 bound states of H+ 2. The complex angular momentum theory for integral cross sections that we introduce shows that such oscillations are a general feature of potential scattering.

Journal Article↗
PubMed2026

Metabolic Stress Testing Reveals Persistent Lipid-Handling Dysfunction in Women With Polycystic Ovary Syndrome Despite Exercise Training.

AIM: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and metabolic dysfunction, yet baseline metabolomic studies show inconsistent findings. We investigated whether metabolic abnormalities in PCOS emerge under physiological stress and how these responses are modified by exercise training. MATERIALS AND METHODS: Twelve women with PCOS and 10 controls completed hyperinsulinaemic-euglycaemic clamps with randomised saline or lipid infusion, before and after 8 weeks of supervised exercise. Plasma metabolomics (163 metabolites) were measured at baseline, post-infusion and post-clamp. Linear mixed-effects models assessed Group × Timepoint × Intervention interactions. RESULTS: No baseline metabolite differences were observed between groups. A significant three-way interaction (p = 0.008) indicated condition-dependent trajectory divergence. Post hoc analysis revealed a specific divergence during post-exercise lipid challenge (p = 0.048). Women with PCOS showed reduced suppression of ether-linked phosphatidylcholines during insulin-stimulated lipid loading (PC ae C44:4, p = 0.031), despite exercise-induced improvements in fitness and normalisation of amino acid profiles. Exploratory metabolite ratios suggested impaired substrate coordination under stress. CONCLUSIONS: Metabolic defects in PCOS are stress-dependent and not detectable at rest. Exercise training improves resting metabolism but reveals persistent impairment in adaptive lipid handling during combined insulin and lipid challenges, suggesting impaired coordination of substrate supply during metabolic stress. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ISRCTN42448814.

Humans↗
PubMed1985

Dynamics and conformational energetics of a peptide hormone: vasopressin.

A theoretical methodology for use in conjunction with experiment was applied to the neurohypophyseal hormone lysine vasopressin for elucidation of its accessible molecular conformations and associated flexibility, conformational transitions, and dynamics. Molecular dynamics and energy minimization techniques make possible a description of the conformational properties of a peptide in terms of the precise positions of atoms, their fluctuations in time, and the interatomic forces acting on them. Analysis of the dynamic trajectory of lysine vasopressin shows the ability of a flexible peptide hormone to undergo spontaneous conformational transitions. The excursions of an individual phenylalanine residue exemplify the dynamic flexibility and multiple conformational states available to small peptide hormones and their component residues, even within constraints imposed by a cyclic hexapeptide ring.

Chemical Phenomena↗
PubMed2005

Asynchrony between position and motion signals in the saccadic system.

The influence of position and motion signals on saccades was studied in two dimensions (2D) using a double step-ramp paradigm. We showed the presence of a predictive component in 2D catch-up saccade programming that is based on motion signals and influences both saccade amplitude and orientation. Interestingly, a significant proportion of catch-up saccades was characterized by a large curvature or a sudden change of direction in midflight for large values of retinal slip. For these saccades, a quantitative analysis showed that their trajectory could be explained by an asynchrony between position and motion signals in saccade programming. When the saccade trajectory was not straight, position error was always available first and influenced the initial orientation of the saccade, whereas retinal slip determined the final orientation. This new paradigm could be used in electrophysiological experiments, where it should prove to be very useful to study position and motion pathways separately in catch-up saccades.

Acceleration↗
PubMed2000

In ovo time-lapse analysis of chick hindbrain neural crest cell migration shows cell interactions during migration to the branchial arches.

Hindbrain neural crest cells were labeled with DiI and followed in ovo using a new approach for long-term time-lapse confocal microscopy. In ovo imaging allowed us to visualize neural crest cell migration 2-3 times longer than in whole embryo explant cultures, providing a more complete picture of the dynamics of cell migration from emergence at the dorsal midline to entry into the branchial arches. There were aspects of the in ovo neural crest cell migration patterning which were new and different. Surprisingly, there was contact between neural crest cell migration streams bound for different branchial arches. This cell-cell contact occurred in the region lateral to the otic vesicle, where neural crest cells within the distinct streams diverted from their migration pathways into the branchial arches and instead migrated around the otic vesicle to establish a contact between streams. Some individual neural crest cells did appear to cross between the streams, but there was no widespread mixing. Analysis of individual cell trajectories showed that neural crest cells emerge from all rhombomeres (r) and sort into distinct exiting streams adjacent to the even-numbered rhombomeres. Neural crest cell migration behaviors resembled the wide diversity seen in whole embryo chick explants, including chain-like cell arrangements; however, average in ovo cell speeds are as much as 70% faster. To test to what extent neural crest cells from adjoining rhombomeres mix along migration routes and within the branchial arches, separate groups of premigratory neural crest cells were labeled with DiI or DiD. Results showed that r6 and r7 neural crest cells migrated to the same spatial location within the fourth branchial arch. The diversity of migration behaviors suggests that no single mechanism guides in ovo hindbrain neural crest cell migration into the branchial arches. The cell-cell contact between migration streams and the co-localization of neural crest cells from adjoining rhombomeres within a single branchial arch support the notion that the pattern of hindbrain neural crest cell migration emerges dynamically with cell-cell communication playing an important guidance role.

Animals↗
PubMed2004

Nucleotide-dependent conformational changes in HisP: molecular dynamics simulations of an ABC transporter nucleotide-binding domain.

ATP-binding cassette (ABC) transporters mediate the movement of molecules across cell membranes in both prokaryotes and eukaryotes. In ABC transporters, solute translocation occurs after ATP is either bound or hydrolyzed at the intracellular nucleotide-binding domains (NBDs). Molecular dynamics (MD) simulations have been employed to study the interactions of nucleotide with NBD. The results of extended (approximately 20 ns) MD simulations of HisP (total simulation time approximately 80 ns), the NBD of the histidine transporter HisQMP2J from Salmonella typhimurium, are presented. Analysis of the MD trajectories reveals conformational changes within HisP that are dependent on the presence of ATP in the binding pocket of the protein, and are sensitive to the presence/absence of Mg ions bound to the ATP. These changes are predominantly confined to the alpha-helical subdomain of HisP. Specifically there is a rotation of three alpha-helices within the subdomain, and a movement of the signature sequence toward the bound nucleotide. In addition, there is considerable conformational flexibility in a conserved glutamine-containing loop, which is situated at the interface between the alpha-helical subdomain and the F1-like subdomain. These results support the mechanism for ATP-induced conformational transitions derived from the crystal structures of other NBDs.

ATP-Binding Cassette Transporters↗
PubMed2006

Molecular basis for the Cu2+ binding-induced destabilization of beta2-microglobulin revealed by molecular dynamics simulation.

According to experimental data, binding of the Cu(2+) ions destabilizes the native state of beta2-microglobulin (beta2m). The partial unfolding of the protein was generally considered an early step toward fibril formation in dialysis-related amyloidosis. Recent NMR studies have suggested that the destabilization of the protein might be achieved through increased flexibility upon Cu(2+) binding. However, the molecular mechanism of destabilization due to Cu(2+), its role in amyloid formation, and the relative contributions of different potential copper-binding sites remain unclear. To elucidate the effect of ion ligation at atomic detail, a series of molecular dynamics simulations were carried out on apo- and Cu(2+)-beta2m systems in explicit aqueous solutions, with varying numbers of bound ions. Simulations at elevated temperatures (360 K) provide detailed pictures for the process of Cu(2+)-binding-induced destabilization of the native structure at the nanosecond timescale, which are in agreement with experiments. Conformational transitions toward partially unfolded states were observed in protein solutions containing bound copper ions at His-31 and His-51, which is marked by an increase in the protein vibrational entropy, with TDeltaS(vibr) ranging from 30 to 69 kcal/mol. The binding of Cu(2+) perturbs the secondary structure and the hydrogen bonding pattern disrupts the native hydrophobic contacts in the neighboring segments, which include the beta-strand D2 and part of the beta-strand E, B, and C and results in greater exposure of the D-E loop and the B-C loop to the water environment. Analysis of the MD trajectories suggests that the changes in the hydrophobic environment near the copper-binding sites lower the barrier of conformational transition and stabilize the more disordered conformation. The results also indicate that the binding of Cu(2+) at His-13 has little effect on the conformational stability, whereas the copper-binding site His-31, and to a lesser extent His-51, are primarily responsible for the observed changes in the protein conformation and dynamics.

Cations, Divalent↗
PubMed2005

Comparison of mode analyses at different resolutions applied to nucleic acid systems.

More than two decades of different types of mode analyses has shown that these techniques can be useful in describing large-scale motions in protein systems. A number of mode analyses are available and include quasiharmonics, classical normal mode, block normal mode, and the elastic network model. Each of these methods has been validated for protein systems and this variety allows researchers to choose the technique that gives the best compromise between computational cost and the level of detail in the calculation. These same techniques have not been systematically tested for nucleic acid systems, however. Given the differences in interactions and structural features between nucleic acid and protein systems, the validity of these techniques in the protein regime cannot be directly translated into validity in the nucleic acid realm. In this work, we investigate the usefulness of the above mode analyses as applied to two RNA systems, i.e., the hammerhead ribozyme and a guanine riboswitch. We show that classical normal-mode analysis can match the magnitude and direction of residue fluctuations from the more detailed, anharmonic technique, quasiharmonic analysis of a molecular dynamics trajectory. The block normal-mode approximation is shown to hold in the nucleic acid systems studied. Only the mode analysis at the lowest level of detail, the elastic network model, produced mixed results in our calculations. We present data that suggest that the elastic network model, with the popular parameterization, is not best suited for systems that do not have a close packed structure; this observation also hints at why the elastic network model has been found to be valid for many globular protein systems. The different behaviors of block normal-mode analysis and the elastic network model, which invoke similar degrees of coarse-graining to the dynamics but use different potentials, suggest the importance of applying a heterogeneous potential function in a robust analysis of the dynamics of biomolecules, especially those that are not closely packed. In addition to these comparisons, we briefly discuss insights into the conformational space available to the hammerhead ribozyme.

Algorithms↗
PubMed2005

Capturing intervention effects over time: reanalysis of a critical time intervention for homeless mentally ill men.

OBJECTIVES: We analyzed whether a method for identifying latent trajectories--latent class growth analysis (LCGA)--was useful for understanding outcomes for individuals subject to an intervention. METHODS: We used LCGA to reanalyze data from a published study of mentally ill homeless men in a critical time intervention (CTI) program. In that study, 96 men leaving a shelter's on-site psychiatric program were randomly assigned to experimental and control groups. The former received CTI services and the latter usual services. Each individual's housing circumstances were observed for 18 months after program initiation. Our outcome measure was monthly homelessness: a person was considered homeless in a month if he was homeless for even 1 night that month. RESULTS: Four latent classes were found among the control group, but just 3 among the experimental group. Control, but not experimental, group individuals showed a small class of chronically homeless men. The size of the never-homeless class was 19 percentage points larger for the experimental than for the control group. J- and inverted-U-shaped patterns were also found among both groups, but with important differences in timing of patterns. CONCLUSIONS: Our results reveal effects not apparent in the original analysis, suggesting that latent class growth models improve intervention evaluation.

Adult↗
PubMed2002

Rational design and development of RDP58.

We used a novel rational design approach in the development of novel immunomodulatory peptides, in particular RDP58, with at least two primary biological activities, inhibition of TNF production and upregulation of heme oxygenase-1 (HO-1) activity. The design strategy used a variety of topological and shape descriptors in combination with an analysis of molecular dynamics trajectories to identify potential drug candidates. The process was initiated using a panel of 19 lead molecules derived from a functionally-important region of HLA I, on the premise that the peptides might modulate immune responses by blocking HLA/T lymphocyte interactions. Each of these 19 peptides was tested in vivo for potential cardiac allograft protection in a mouse model. Outcome of graft survival was the primary data available to describe nine of the peptides as active and ten as inactive. A virtual combinatorial library of 279,936 peptides was then generated, based on physical properties associated with efficacy in the original learning set of 19 peptides--in particular, the distribution of lipophilic residues. The library was screened using descriptors that fell into 2 categories: static (physico-chemical) and dynamic (conformational). The screenings identified 5 peptides with theoretic potential efficacy. These were synthesized and tested for activity in vitro and in vivo. Besides prolonging graft survival in rodents, RDP58 was found to inhibit TNF and increase HO-1 activity; these biological activities were tested exhaustively in various in vivo disease models. RDP58 demonstrated convincing potential to alleviate disease symptoms in many of the experimental diseases.

Animals↗
PubMed2001

Determination of functional rotation axes during elevation of the shoulder complex.

STUDY DESIGN: A cross-sectional, descriptive study of shoulder movements conducted on nonimpaired subjects. OBJECTIVE: To investigate whether a single functional rotation axis about the shoulder complex can be determined during elevation in the coronal or sagittal planes, and to identify their location. BACKGROUND: Accurate measurement of isokinetic torques about a joint requires alignment of the dynamometer axis with an assumed rotation axis of the joint. To assess shoulder function on a dynamometer, the location of a single rotation axis is not evident because the shoulder joint motion is based on several anatomical joints. Therefore, the rotation axis where humerothoracic movements occur should be judged as a functional rotation axis. METHODS AND MEASURES: During slow elevation movements in the sagittal and coronal plane, the position of the epicondyle and acromion were recorded with a motion analysis system. The motion trajectory of the elbow coordinates was fitted to a circle and considered an estimate of the functional shoulder joint rotation axis in the specified plane. RESULTS: The fitted trajectory appeared to be very accurate (root-mean-square error < 2%; N = 7). In the sagittal plane, the estimated functional rotation axis was found at the humeral head; in the coronal plane, it was located about 13 centimeters medial relative to the acromion. CONCLUSION: The shoulder complex of nonimpaired subjects can act as a hinge joint of the upper arm relative to the thorax during elevation in each measured plane.

Adult↗
PubMed1994

Long interfascicular axon growth from embryonic neurons transplanted into adult myelinated tracts.

In a previous study we used the species-specific marker M6 to demonstrate that transplanted mouse embryonic hippocampal neurons grow axons at a rate of at least 1 mm/d for a distance of at least 10 mm along the longitudinal axis of the fimbria in immunosuppressed adult rat hosts. We now show that hippocampal neurons are able to grow comparably long interfascicular axons in two other myelinated adult fiber tracts, the corpus callosum and the cingulum. Moreover, suspensions of cells from embryonic neocortex and superior colliculus transplanted into each of these three adult host sites also give interfascicular axon growth whose speed, intensity, and pattern of distribution are identical to those of transplanted hippocampal neurons. The axons of the donor cells grow in both directions along the longitudinal axis of the host tracts, where they are interspersed in parallel among the normal host axons, the rows of host interfascicular glial nuclei, and the longitudinal processes of host tract astrocytes. Serial section analysis through the complex trajectories of the host fiber bundles of the fimbria and corpus callosum shows that the course of the donor axons conforms to the underlying orientation of the axonal and glial structures of the host fiber tract. These observations indicate that long interfascicular axon growth can occur in several different adult myelinated fiber tracts. The donor axons become integrated with the host tract fibers and glia, and they respect intertract boundaries. Growth is not restricted to the types of axons normally present in the tracts.

Animals↗