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PubMed2006

Responses of Purkinje-cells of the cerebellar anterior vermis to stimulation of vestibular and somatosensory receptors.

In decerebrate cats, sinusoidal rotation of the forepaw around the wrist modifies the activity of the ipsilateral forelimb extensor triceps brachii (TB) and leads to plastic changes of adaptive nature in the gain of vestibulospinal (VS) reflexes (VSRs). Both effects are depressed by functional inactivation of the cerebellar anterior vermis, which also decreases the gain of VSRs. In order to better understand the mechanisms of these phenomena, the simple spike activity of Purkinje (P-) cells was recorded from the vermal cortex of the cerebellar anterior lobe during individual and/or combined stimulation of somatosensory wrist, neck and vestibular receptors. About one third of the recorded units were affected by sinusoidal rotation of the ipsilateral forepaw around the wrist axis (0.16 Hz, +/-10 degrees ). Most of these neurons ( approximately 60%) increased their activity during ventral flexion of the wrist and decreased it during the oppositely directed movement, with an average phase lag of -141 degrees with respect to the position of maximal dorsiflexion. The remaining cells ( approximately 40%) were excited during dorsiflexion of the wrist, with an average phase lead of 59 degrees with respect to the extreme dorsal flexion. Both populations showed comparable response gains, with an average value of 0.42+/-0.52, S.D., imp/s/deg. About half of the recorded units were also tested during sinusoidal roll tilt of the animal around the longitudinal axis (0.16 Hz, +/-10 degrees ), leading to stimulation of labyrinthine receptors. When both stimuli were applied simultaneously, the responses to combined stimulation usually corresponded to the sum of individual responses. While the phase distribution of somatosensory responses was clearly bimodal, vestibular responses showed phase angle values uniformly scattered between +/-180 degrees and 0 degrees , so that, during combined stimulation, each neuron could be maximally activated by coupling the two stimuli with a particular phase relation. Finally, a proportion of the recorded neurons was also tested during sinusoidal rotation of the body around its longitudinal axis, with the head fixed in space, leading to stimulation of neck receptors. The proportion of neurons affected by individual stimulation of vestibular or neck receptors (81% and 72%, respectively) was larger than that of wrist-driven neurons. Convergence of signals from vestibular, somatosensory wrist and neck receptors was found in 18% of the neurons analyzed. In conclusion, the results of this study show that somatosensory signals from the forelimb: i) modulate the activity of a sizeable proportion of neurons located within the cerebellar anterior vermis and ii) interact widely with labyrinthine and neck signals at this level. Moreover, iii) this corticocerebellar region is largely dominated by vestibular and neck signals that may be utilized to build up a neuronal representation of the position of body in space. These findings suggest that: 1) the modulation of TB activity induced by rotation of the ipsilateral wrist may at least partially depend upon the simultaneous changes in P-cell activity and 2) the interaction of vestibular and somatosensory wrist signals at P-cell level may represent the substrate of the plastic changes that affect the VSR when animal tilt and wrist rotation are driven together. A preliminary report of these data has been presented [ Responses of cerebellar Purkinje cells to forepaw rotation in decerebrate cat. Pflügers Arch 440:R31].

Action Potentials↗

PubMed2003

Dynamic properties of nucleosomes during thermal and ATP-driven mobilization.

The fundamental subunit of chromatin, the nucleosome, is not a static entity but can move along DNA via either thermal or enzyme-driven movements. Here we have monitored the movements of nucleosomes following deposition at well-defined locations on mouse mammary tumor virus promoter DNA. We found that the sites to which nucleosomes are deposited during chromatin assembly differ from those favored during thermal equilibration. Taking advantage of this, we were able to track the movement of nucleosomes over 156 bp and found that this proceeds via intermediate positions spaced between 46 and 62 bp. The remodeling enzyme ISWI was found to direct the movement of nucleosomes to sites related to those observed during thermal mobilization. In contrast, nucleosome mobilization driven by the SWI/SNF and RSC complexes were found to drive nucleosomes towards sites up to 51 bp beyond DNA ends, with little respect for the sites favored during thermal repositioning. The dynamic properties of nucleosomes we describe are likely to influence their role in gene regulation.

Adenosine Triphosphatases↗

PubMed2003

Relay of visual information to the lateral geniculate nucleus and the visual cortex in albino ferrets.

The abnormal organization of the central visual pathways in the albino ferret has been characterized anatomically and physiologically. Recordings in dorsal lateral geniculate nucleus of the albino ferret show that lamina A1, which receives an aberrant projection from the contralateral eye, contains an extensive representation of the ipsilateral visual hemifield with receptive fields located up to 35 degrees from the vertical meridian. This is not the case in pigmented ferrets, for which the vast majority of units, activated through either the contralateral or ipsilateral eye, have receptive fields confined to the contralateral hemifield. The few fields found in the ipsilateral hemifield are driven through the contralateral eye and none is more than 10 degrees from the midline. Cortical topography was studied by making closely spaced electrode penetrations across the area 17/18 border. In pigmented animals, the reversal of topography at the border is characterized by units with receptive fields centered a few degrees into the ipsilateral hemifield. In 22 of 25 albinos, the "Boston" aberrant topography was found: the representation of the vertical meridian is within area 17, rather than at the area 17/18 border. Instead, at the area 17/18 border, there is a reversal in the topographic progression at up to 30 degrees into the ipsilateral hemifield. This pattern was most pronounced in the upper visual field. In agreement with the "Boston" physiology, injections of retrograde tracer made in area 17 usually label neurons in either lamina A or the part of lamina A1 that is aberrantly innervated by the contralateral eye. A column of labeled cells extending through all geniculate layers is rarely seen in albinos, although this is commonly the pattern in pigmented ferrets.

Action Potentials↗

PubMed2000

T-cell-dependent fibrosis in the mdx dystrophic mouse.

In Duchenne muscular dystrophy patients, the pathological hallmark of the disease, namely, the chronic accumulation of sclerotic scar tissue in the interstitial space of skeletal muscle is attributed to manifestation of secondary pathological processes. Such anomalous generation of matrix protein is thought to be driven by the continuous degeneration and regeneration of muscle both in Duchenne Muscular Dystrophy and in the mdx mouse homolog. We examined mdx and the control strain C57bl/10 mice over a range of ages with respect to the amounts of collagen present in muscles and other organs, finding that the mdx have significantly higher collagen content at later time points in their kidney and lung as well as their muscles. Surprisingly, when we bred the mdx mice on the nu/nu background, the time course of fibrogenesis was modified depending on the tissue and the collagen content was significantly different in age-matched mice. Transplantation of normal thymic tissue into the mdx-nu/nu mice replenished their T-cells and concomitantly altered the collagen content in their tissues to levels comparable with those in immunocompetent mdx mice. This suggests that T-cells play a role in the onset of the fibrotic events that undermines the ability of dystrophic muscle to regenerate.

Aging↗

PubMed2003

Atomically detailed folding simulation of the B domain of staphylococcal protein A from random structures.

The conformational space of the 10-55 fragment of the B-domain of staphylococcal protein A has been investigated by using the electrostatically driven Monte Carlo (EDMC) method. The ECEPP/3 (empirical conformational energy program for peptides) force-field plus two different continuum solvation models, namely SRFOPT (Solvent Radii Fixed with atomic solvation parameters OPTimized) and OONS (Ooi, Oobatake, Némethy, and Scheraga solvation model), were used to describe the conformational energy of the chain. After an exhaustive search, starting from two different random conformations, three of four runs led to native-like conformations. Boltzmann-averaged root-mean-square deviations (RMSD) for all of the backbone heavy atoms with respect to the native structure of 3.35 A and 4.54 A were obtained with SRFOPT and OONS, respectively. These results show that the protein-folding problem can be solved at the atomic detail level by an ab initio procedure, starting from random conformations, with no knowledge except the amino acid sequence. To our knowledge, the results reported here correspond to the largest protein ever folded from a random conformation by an initial-value formulation with a full atomic potential, without resort to knowledge-based information.

Hydrogen Bonding↗

PubMed2006

Influence of classical resonances on chaotic tunneling.

Dynamical tunneling between symmetry-related stable modes is studied in the periodically driven pendulum. We present strong evidence that the tunneling process is governed by nonlinear resonances that manifest within the regular phase-space islands on which the stable modes are localized. By means of a quantitative numerical study of the corresponding Floquet problem, we identify the trace of such resonances not only in the level splittings between near-degenerate quantum states, where they lead to prominent plateau structures, but also in overlap matrix elements of the Floquet eigenstates, which reveal characteristic sequences of avoided crossings in the Floquet spectrum. The semiclassical theory of resonance-assisted tunneling yields good overall agreement with the quantum-tunneling rates, and indicates that partial barriers within the chaos might play a prominent role.

Journal Article↗

PubMed2000

A two-frequency acoustic technique for bubble resonant oscillation studies

A two-frequency acoustic apparatus has been developed to study the dynamics of a single gas or vapor bubble in water. An advantage of the apparatus is its capability of trapping a bubble by an ultrasonic standing wave while independently driving it into oscillations by a second lower frequency acoustic wave. For a preliminary application, the apparatus is used to study resonant oscillations. First, near-resonant coupling between the volume and the n = 3 shape oscillation modes of air bubbles at room temperature is studied, where n is the mode number. The stability boundary, amplitude versus frequency, of the volume oscillation forms a wedge centered at the resonant frequency, which qualitatively agrees with a theoretical prediction based on a phase-space analysis. Next, the resonant volume oscillations of vapor bubbles are studied. The resonant radius of vapor bubbles at 80 degrees C driven at 1682 Hz is determined to be 0.7 mm, in agreement with a prediction obtained by numerical simulation.

Journal Article↗

PubMed2026

Artificial intelligence for translational personalized neoantigen cancer vaccine development.

Personalized neoantigen cancer vaccine is a promising strategy for precision immunotherapy by targeting patient-specific and mutation-derived tumor antigens. Early clinical studies have demonstrated the feasibility, safety, and immunogenicity of these vaccines across multiple solid tumors, with encouraging outcomes particularly when combined with immune checkpoint blockade. However, broader clinical translation remains limited by sequential bottlenecks across the vaccine development pipeline, including false-positive neoantigen selection,  imperfect modeling of antigen processing and HLA presentation, limited prediction of T-cell receptor recognition, and challenges in formulation, delivery, and manufacturing. Artificial intelligence and advanced computational workflows are increasingly integrated into this pipeline to improve candidate prioritization and support more reproducible decision-making. In this review, we summarize clinical progress and key translational barriers in personalized neoantigen vaccination, and discuss how AI-enabled approaches may contribute across four major stages: multi-omics integration for neoantigen discovery, processing-aware HLA presentation prediction, structure-aware and TCR-informed immunogenicity modeling, and data-driven formulation optimization, particularly for lipid nanoparticle-based delivery systems. These approaches are able to help narrow biological and chemical search spaces, improve prioritization, and provide mechanistic insights into antigen presentation and immune recognition rather than replacing experimental validation. This articlefurther addresses future implementation challenges, including dataset diversity, model interpretability, prospective benchmarking, manufacturing traceability, and evolving regulatory frameworks for individualized mRNA cancer immunotherapies. Integrating computational innovation with rigorous immunological validation, scalable manufacturing, and regulatory oversight will be essential for advancing personalized neoantigen vaccines toward broader clinical implementation.

Cancer Vaccines↗

PubMed2002

Can we fulfil even the basics of endodontic therapy?

Micro-organisms and lipopolysaccharides (LPS) are involved in inducing periapical inflammation. Therefore, it is important to eliminate them from the complex root canal system and seal the endodontic space as accurately as possible. This is possible with a combination of the following: instrumentation of the canal, eventually with new, motor driven instruments, abundant rinsing with NaOCl, dressing preferably with Ca(OH)2, sealing the root canal and incorporating the permanent restoration within three months after root canal filling to avoid reinfection.

Humans↗

PubMed1988

[A theoretical model of the transition phase in human locomotion].

In this study we examine the bifurcation of the transition between walking and running. Beuter and Lalonde (1986) have conjectured that the pertinent parameters separating walking and running can be described by a cusp singularity (Thom, 1972). In this model, the unidimensional state space is characterized by support duration and the bidimensional parameter space is characterized by the subject's weight and speed. To test this model eight males walked and ran on a motor driven treadmill at an increasing or decreasing speed with or without additional loads corresponding to 0%, 7% and 14% of their body weight. Velocities corresponding to transitions between the two modes of locomotion indicate that on the average the walk-run transition occurs at higher speed than the run-walk transition illustrating an hysteresis effect. In addition, the average difference between the transitions decreases as the load increases [mean 0 = 0.235 m/s, +/- 0.09 m/s, mean 7 = 0.104 m/s, +/- 0.07 m/s and mean 14 = 0.041 m/s, +/- 0.06 m/s] corresponding to an F ratio of F = 2.72, 0.05 less than p less than 0.1. A comparison of the differences in transition velocity at 0% and 14% is statistically different (t = 2.8, p less than 0.025). These results tend to support the existence of an elementary cusp singularity separating the two locomotion modes and suggest that the mechanisms controlling these transitions can be described by a hysterisis cycle and a small number of parameters.

Adipose Tissue↗

PubMed1997

Bcl-2 and the outer mitochondrial membrane in the inactivation of cytochrome c during Fas-mediated apoptosis.

Fas-driven apoptosis in Jurkat cells results in the inactivation of cytochrome c with cessation of oxygen consumption. Overexpression of Bcl-2 was found to protect against acidification and apoptosis mediated by Fas ligation in these cells. Bcl-2 is present in the outer mitochondrial membrane, but the molecular mechanism by which it protects cells is unknown. Because Bcl-2 projects into the mitochondrial intermembrane space and cytochrome c is located in the intermembrane space, we considered the possibility that Bcl-2 might protect cytochrome c from inactivation during Fas-mediated apoptosis. The present study shows that 1) in Jurkat cells, cytochrome c inactivation during Fas-driven apoptosis requires the permeabilization of the outer mitochondrial membrane; and 2) the post-mitochondrial fraction from CEM cells that overexpress Bcl-2 both prevents and reverses cytochrome c inactivation.

Apoptosis↗

PubMed1997

Closely spaced tandem arrangement of AQP2, AQP5, and AQP6 genes in a 27-kilobase segment at chromosome locus 12q13.

The aquaporins (AQPs) are a family of water-transporting proteins that facilitate osmotically driven water movement across cell plasma membranes. Among the seven human aquaporins cloned to date (AQPs 0-6), genes encoding the four most closely related aquaporins (AQP0, AQP2, AQP5, and AQP6) have been mapped to chromosome band 12q13, suggesting an aquaporin family gene cluster at this locus. To construct a physical map and identify novel aquaporin gene members on this cluster, a human CEPH B yeast artificial chromosome (YAC) library was screened by PCR using primers derived from exon 4 of AQP2 and AQP0 genes. A YAC clone with 200 kb of human DNA was isolated and analyzed. Primary pulsed-field gel electrophoresis and Southern blot analysis indicated the presence of AQP2, AQP5, and AQP6 genes, but not AQP0. Restriction mapping and PCR analysis yielded a precise physical map in which the three aquaporin genes span only approximately 27 kb in the order, transcriptional orientation, and spacer length 5'-AQP2-5 kb spacer-AQP5-7 kb spacer-AQP6-3'.

Aquaporin 5↗

PubMed1992

A reduced set of coordinates for modeling DNA structures: (I). A B-to-A transition pathway driven by pseudorotational angle.

The A-DNA and the B-DNA are two well characterized polymorphous forms of DNA duplex. By using Metropolis Monte Carlo Simulations in a reduced coordinate space, we have shown that the B in equilibrium with A transitions can be induced by forcing pseudorotational angle (W) to change between C3'-endo and C2'-endo puckerings. The energy barrier for the transition pathway is less than 10 Kcal.mol-1. Base-pair parameters x-displacement (Dx) and roll (rho), which have the largest differences between the two forms of structures, cannot drive the transition. Our results support the view that the bistable states of the DNA duplex are due to the bistable structures of the sugar ring.

Computer Simulation↗

PubMed2006

Determinants of CCL5-driven mononuclear cell migration across the blood-brain barrier. Implications for therapeutically modulating neuroinflammation.

Chemokine receptors and adhesion molecules are used selectively for the transmigration of leukocytes across the blood-brain barrier (BBB) during neuroinflammation. We established an activated in vitro BBB (aIVBBB) using physiological concentrations of cytokines. We studied CCL5-driven migration as a model to determine how chemokine receptors and adhesion molecules regulate T-cell and monocyte migration across the aIVBBB. Increased expression of CCL5 and its receptors, CCR1 and CCR5 have been described in the perivascular space of multiple sclerosis (MS) lesions. Elucidating the determinants of CCL5-mediated mononuclear cell migration may clarify appropriate targets for therapeutic modulation in neuroinflammatory conditions. In response to CCL5, there was a significant increase in total mononuclear cell migration across the aIVBBB. Neutralizing monoclonal antibodies to CCR1 and CCR5 abrogated CCL5-driven transmigration, suggestive of non-redundant receptor usage in mononuclear cell migration to this chemokine in vitro. CCL5-driven transmigration was also dependent on alpha(4)beta(1) integrin/fibronectin connecting segment-1 (FN CS-1) and alpha(L)beta(2) integrin/intercellular adhesion molecule (ICAM-1) interactions. Monocyte migration to CCL5 was solely dependent on alpha(4)beta(1) integrin/FN CS-1 while T-cell migration required both alpha(L)beta(2) integrin/ICAM-1 and alpha(4)beta(1) integrin/FN CS-1 interactions. These findings provide plausible molecular targets for the selective inhibition of mononuclear cell trafficking during the acute immune effector phases of MS and other neuroinflammatory diseases.

Blood-Brain Barrier↗

PubMed2005

Effects of hunger and visuo-spatial interference on imagery-induced food cravings.

The present study investigated the effects of hunger and visuo-spatial interference on imagery-induced food cravings. Forty-two women were randomly assigned to a hungry (no food for prior 4h) or not hungry condition. Participants were asked to form and maintain images of desired foods while looking at a blank computer screen (control condition) or performing a task designed to load the visuo-spatial sketchpad of working memory (dynamic visual noise). They then rated the vividness of their images and their craving intensity. Although hungry participants reported stronger food cravings, dynamic visual noise made images less vivid and cravings less intense, irrespective of participant hunger status. Thus concurrent visuo-spatial processing may offer a useful technique for treating problematic food cravings that are predominantly psychological in origin, as well as those that are hunger-driven.

Adolescent↗

PubMed1999

Role of the feedforward command and reafferent information in the coordination of a passing prehension task.

The performances of a deafferented patient and five control subjects have been studied during a self-driven passing task in which one hand has to grasp an object transported by the other hand and in a unimanual reach-to-grasp task. The kinematics of the reach and grasp components and the scaling of the grip aperture recorded for the self-driven passing task were very similar in controls and the deafferented subject (GL). In contrast, for the unimanual task when vision was absent, GL's coordination between reaching and grasping was delayed in space and time compared with the control subjects. In addition, frequent reopening of the grip was observed in GL during the final closure phase of the unimanual prehension task. These results support the notion that afferent proprioceptive information resulting from the reaching movement - which seemed to be used to coordinate reaching and grasping commands in the unimanual task - is no longer necessary in the self-induced passing task. Finally, for the externally driven passing task, when the object was passively transported by the experimenter, the coordination was consistently modified in all subjects; grip aperture onset was delayed, thus asserting a specific contribution of the central command or feedforward mechanisms into the anticipation of the grasp onset observed in the self-driven passing task. The origin and nature of the information necessary for building up the feedforward mechanisms remains to be elucidated.

Adult↗

PubMed1992

Steady-state fluctuations of human walking.

In steady-state walking, fluctuations in space-time behavior are observed for normal adult subjects. In the present study, the intrinsic fluctuations of gait have been analyzed when walking on a subject-driven treadmill (with adjustable inertial forces). Furthermore, these intrinsic fluctuations have been compared with those observed in natural overground locomotion which involves a real subject's displacement and thus an optical flow. Four adult subjects participated in both experimental sessions. It was found that the frequency and amplitude of the instantaneous fluctuations of leg movement were weak and of equal magnitude with or without optical flow. This was also the case for instantaneous fluctuations in displacement speed. Secondly, a low-frequency fluctuation in walking speed was observed when no optical flow information was available to the subject. This fluctuation results from the addition of a series of leg-movement fluctuations, whose values are all either positive or negative. As the optical flow provides information about the displacement speed, it allows the subject to avoid such addition, and thus plays a role in maintaining steady leg movement. Theoretical models linking space-time behavior of rhythmic movement with stiffness strongly suggest that the observed low-frequency fluctuations in speed result from fluctuations in stiffness.

Adult↗

PubMed2006

Involvement of axonal guidance proteins and their signaling partners in the developing mouse mammary gland.

Mammary morphogenesis in the mouse is driven by specialized structures at the ends of the developing ducts, the terminal end buds (TEB). The mechanisms controlling the precise branching and spacing of the ducts are, as yet, unknown. To identify genes that are associated with migration of TEB and differentiation of the subtending ducts, we developed a novel method of isolating TEB and ducts free of stroma, and compared the gene expression profiles of these two isolates using oligonucleotide microarrays. Ninety one genes were upregulated in TEB compared to ducts. Three of these genes, Sprr1A, Sema3B, and BASP1, are associated with axonal growth and guidance. Two additional members of the Sprr family, Sprr2A and 2B, not previously associated with axonal growth, were also highly expressed in TEB. Expression of these genes was confirmed by RT-PCR and Western blotting, and the cellular distribution of Sprr1A and BASP1 was demonstrated by immunohistochemistry. Other semaphorins, including Sema3C, 4A, 4F and the cancer invasion associated Sema 4D were also expressed in the mouse mammary gland along with the semaphorin receptors, Plexins A2, A3, B2, and D1, and Neuropilins 1 and 2. These results are discussed in the context of other proteins expressed in the developing gland that are known to be downstream effectors of these signaling molecules. We suggest that these genes may influence ductal growth and morphogenesis in the developing mammary gland.

Animals↗