Envelope Dynamics Research Articles

Claudin-4 remodeling of nucleus-cell cycle crosstalk maintains ovarian tumor genome stability and drives resistance to genomic instability-inducing agents.

During cancer development, the interplay between the nucleus and the cell cycle leads to a state of genomic instability, often accompanied by observable morphological aberrations. These aberrations can be controlled by tumor cells to evade cell death, either by preventing or eliminating genomic instability. In epithelial ovarian cancer (EOC), overexpression of the multifunctional protein claudin-4 is a key contributor to therapy resistance through mechanisms associated with genomic instability. However, the molecular mechanisms underlying claudin-4 overexpression in EOC remain poorly understood. Here, we altered claudin-4 expression and employed a unique claudin-4 targeting peptide (CMP) to manipulate the function of claudin-4. We found that claudin-4 facilitates genome maintenance by linking the nuclear envelope and cytoskeleton dynamics with cell cycle progression. Claudin-4 caused nuclei constriction by excluding lamin B1 and promoting perinuclear F-actin accumulation, associated with remodeling nuclear architecture, thus altering nuclear envelope dynamics. Consequently, cell cycle modifications due to claudin-4 overexpression resulted in fewer cells entering the S-phase and reduced genomic instability. Importantly, disrupting biological interactions of claudin-4 using CMP and forskolin altered oxidative stress cellular response and increased the efficacy of PARP inhibitor treatment. Our data indicate that claudin-4 protects tumor genome integrity by remodeling the crosstalk between the nuclei and the cell cycle, leading to resistance to genomic instability formation and the effects of genomic instability-inducing agents.

Imbalance in positive and negative acceleration ratio of alpha oscillation in patients with complex regional pain syndrome

ObjectivesTo elucidate the functional characteristics of the brain in the presence of chronic pain using electroencephalography (EEG), with a focus on the dynamics of neural excitation and inhibition. MethodsResting-state EEG was performed in: 17 patients with complex regional pain syndrome (CRPS) who exhibited chronic pain higher than 20 on the visual analogue scale (VAS), 6 patients with reduced CRPS symptoms and chronic pain less than 20 on VAS, and healthy age-matched controls. For the analysis, 50 s of electroencephalogram (EEG) signals were extracted from EEG recordings during wakefulness and rest with eyes closed. The envelope of the alpha frequency band was calculated by examining the positive and negative accelerations of the envelope oscillation, ratio of positive (Ap) to negative (An) accelerations (Ap-An ratio), and mean amplitude of the envelope. Comparisons were made between patients and controls, and correlations between these EEG measures and the subjective pain VAS were evaluated.Significant differences in the value of Ap, An and Ap-An ratio were observed at temporal and central electrodes between patients with pain symptoms and controls. Those with reduced CRPS symptoms exhibited a distinct Ap-An ratio at the majority of electrodes when compared with those exhibiting chronic pain. ConclusionsDistinct patterns in alpha wave envelope dynamics, reflecting excitatory and inhibitory activities, were associated with chronic pain in patients with CRPS. The pain-relieved state of CRPS suggested that a new balance of activities was established. This relationship indicated a potential association between altered alpha oscillation characteristics and the subjective experience of pain. SignificanceThis study introduces a novel method for analyzing alpha oscillation envelopes, providing new insights into the neural pathophysiology of chronic pain in CRPS patients. This approach has the potential to enhance our understanding of the alterations in brain function that occur under chronic pain conditions.

LEMD2-associated progeroid syndrome: Expanding the phenotype of the nuclear envelopathy caused by a defect in LEMD2 gene.

Nuclear envelopathies are rare genetic diseases that compromise the integrity of the nuclear envelope. Patients with a defect in LEM domain nuclear envelope protein 2 (LEMD2) leading to LEMD2-associated progeroid syndrome are exceedingly scarce in number, yet they exhibit shared clinical features including skeletal abnormalities and a prematurely-aged appearance. Our study broadens the understanding of LEMD2-associated progeroid syndrome by detailing its phenotypic and molecular characteristics in the first female and fourth reported case, highlighting a distinct impact on metabolic functions. The patient's history revealed growth delay, facial and skeletal abnormalities, and recurrent abdominal pain crises caused by hepatomegaly. Comparisons with the previously documented cases emphasized similarities in skeletal and facial features while showcasing unique variations, notably in cardiac and hepatic manifestations. Invitro experiments conducted on patient-derived peripheral blood and urinary epithelial cells and LEMD2-downregulated HepG2 cells confirmed abnormalities in the structure of the nuclear envelope in all three tissue-types. Overall, our work offers a comprehensive profile of a patient with LEMD2-related syndrome, emphasizing the hepatic involvement in the disease and broadening our understanding of clinical and molecular implications. This study not only contributes specific insights into LEMD2-related conditions but also underscores potential therapeutic paths for disorders affecting nuclear envelope dynamics.

The nexus of nuclear envelope dynamics, circular economy and cancer cell pathophysiology

The nuclear envelope (NE) is a critical component in maintaining the function and structure of the eukaryotic nucleus. The NE and lamina are disassembled during each cell cycle to enable an open mitosis. Nuclear architecture construction and deconstruction is a prime example of a circular economy, as it fulfills a highly efficient recycling program bound to continuous assessment of the quality and functionality of the building blocks. Alterations in the nuclear dynamics and lamina structure have emerged as important contributors to both oncogenic transformation and cancer progression. However, the knowledge of the NE breakdown and reassembly is still limited to a fraction of participating proteins and complexes. As cancer cells contain highly diverse nuclei in terms of DNA content, but also in terms of nuclear number, size, and shape, it is of great interest to understand the intricate relationship between these nuclear features in cancer cell pathophysiology. In this review, we provide insights into how those NE dynamics are regulated, and how lamina destabilization processes may alter the NE circular economy. Moreover, we expand the knowledge of the lamina-associated domain region by using strategic algorithms, including Artificial Intelligence, to infer protein associations, assess their function and location, and predict cancer-type specificity with implications for the future of cancer diagnosis, prognosis and treatment. Using this approach we identified NUP98 and MECP2 as potential proteins that exhibit upregulation in Acute Myeloid Leukemia (LAML) patients with implications for early diagnosis.

Loss of the mitochondrial protein SPD-3 elevates PLK-1 levels and dysregulates mitotic events.

In metazoans, Polo-like kinase (PLK1) controls several mitotic events including nuclear envelope breakdown, centrosome maturation, spindle assembly and progression through mitosis. Here we show that a mutation in the mitochondria-localized protein SPD-3 affects mitotic events by inducing elevated levels of PLK-1 in early Caenorhabditis elegans embryos. SPD-3 mutant embryos contain abnormally positioned mitotic chromosomes, show a delay in anaphase onset and asymmetrically disassemble the nuclear lamina. We found that more PLK-1 accumulated on centrosomes, nuclear envelope, nucleoplasm, and chromatin before NEBD, suggesting that PLK-1 overexpression is responsible for some of the observed mitotic phenotypes. In agreement with this, the chromosome positioning defects of the spd-3(oj35) mutant could be rescued by reducing PLK-1 levels. Our data suggests that the mitochondrial SPD-3 protein affects chromosome positioning and nuclear envelope integrity by up-regulating the endogenous levels of PLK-1 during early embryogenesis in C. elegans This finding suggests a novel link between mitochondria and nuclear envelope dynamics and chromosome positioning by increasing the amount of a key mitotic regulator, PLK-1, providing a novel link between mitochondria and mitosis.

Nuclear envelope dynamics in connection to chromatin remodeling.

The nucleus is a central organelle of eukaryotic cells undergoing dynamic structural changes during cellular fundamental processes such as proliferation and differentiation. These changes rely on the integration of developmental and stress signals at the nuclear envelope (NE), orchestrating responses at the nucleo-cytoplasmic interface for efficient genomic functions such as DNA transcription, replication and repair. While in animals, correlation has already been established between NE dynamics and chromatin remodeling using last-generation tools and cutting-edge technologies, this topic is just emerging in plants, especially in response to mechanical cues. This review summarizes recent data obtained in this field with more emphasis on the mechanical stress response. It also highlights similarities/differences between animal and plant cells at multiples scales, from the structural organization of the nucleo-cytoplasmic continuum to the functional impacts of NE dynamics.

Observation of coherent oscillations in the association of dimers from a thermal gas of ultracold atoms

We report the observation of coherent oscillations in conversion efficiency of weakly-bound dimers formed from a thermal gas of ultracold atoms. Finite thermal energy of the gas causes loss of coherence when a broad continuum is resonantly coupled to a discrete bound state. Restoration of the coherence can be achieved through non-adiabatic transitions of the dressed molecular energy level that are induced by a strong modulation pulse with fast envelope dynamics. Conditions to observe coherent oscillations are verified, and control of their properties is demonstrated. The main experimental findings are supported by theoretical modeling and numerical calculations. The observed results may lead to a renewed interest in general studies of a discrete energy level coupled to a broadband continuum when the properties of both are fully controlled.

Azido Inositol Probes Enable Metabolic Labeling of Inositol-Containing Glycans and Reveal an Inositol Importer in Mycobacteria.

Bacteria from the genus Mycobacterium include pathogens that cause serious diseases in humans and remain as difficult infectious agents to treat. Central to these challenges are the composition and organization of the mycobacterial cell envelope, which includes unique and complex glycans. Inositol is an essential metabolite for mycobacteria due to its presence in the structural core of the immunomodulatory cell envelope glycolipids phosphatidylinositol mannoside (PIM) and PIM-anchored lipomannan (LM) and lipoarabinomannan (LAM). Despite their importance to mycobacterial physiology and pathogenesis, many aspects of PIM, LM, and LAM construction and dynamics remain poorly understood. Recently, probes that allow metabolic labeling and detection of specific mycobacterial glycans have been developed to investigate cell envelope assembly and dynamics. However, these tools have been limited to peptidoglycan, arabinogalactan, and mycolic acid-containing glycolipids. Herein, we report the development of synthetic azido inositol (InoAz) analogues as probes that can metabolically label PIMs, LM, and LAM in intact mycobacteria. Additionally, we leverage an InoAz probe to discover an inositol importer and catabolic pathway in Mycobacterium smegmatis. We anticipate that in the future, InoAz probes, in combination with bioorthogonal chemistry, will provide a valuable tool for investigating PIM, LM, and LAM biosynthesis, transport, and dynamics in diverse mycobacterial organisms.

SMPD4 regulates mitotic nuclear envelope dynamics and its loss causes microcephaly and diabetes.

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder with progressive congenital microcephaly and early death. SMPD4 encodes a sphingomyelinase that hydrolyses sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes (NPC). We refine the clinical phenotype of loss-of-function SMPD4 variants by describing five individuals from three unrelated families with longitudinal data due to prolonged survival. All individuals surviving beyond infancy developed insulin-dependent diabetes, besides presenting with a severe neurodevelopmental disorder and microcephaly, making diabetes one of the most frequent age-dependent non-cerebral abnormalities. We studied the function of SMPD4 at the cellular and organ levels. Knock-down of SMPD4 in human neural stem cells causes reduced proliferation rates and prolonged mitosis. Moreover, SMPD4 depletion results in abnormal nuclear envelope breakdown and reassembly during mitosis and decreased post-mitotic NPC insertion. Fibroblasts from affected individuals show deficient SMPD4-specific neutral sphingomyelinase activity, without changing (sub)cellular lipidome fractions, which suggests a local function of SMPD4 on the nuclear envelope. In embryonic mouse brain, knockdown of Smpd4 impairs cortical progenitor proliferation and induces premature differentiation by altering the balance between neurogenic and proliferative progenitor cell divisions. We hypothesize that, in individuals with SMPD4-related disease, nuclear envelope bending, which is needed to insert NPCs in the nuclear envelope, is impaired in the absence of SMPD4 and interferes with cerebral corticogenesis and survival of pancreatic beta cells.

Dictyostelium spastin is involved in nuclear envelope dynamics during semi-closed mitosis

ABSTRACT Dictyostelium amoebae perform a semi-closed mitosis, in which the nuclear envelope is fenestrated at the insertion sites of the mitotic centrosomes and around the central spindle during karyokinesis. During late telophase the centrosome relocates to the cytoplasmic side of the nucleus, the central spindle disassembles and the nuclear fenestrae become closed. Our data indicate that Dictyostelium spastin (DdSpastin) is a microtubule-binding and severing type I membrane protein that plays a role in this process. Its mitotic localization is in agreement with a requirement for the removal of microtubules that would hinder closure of the fenestrae. Furthermore, DdSpastin interacts with the HeH/ LEM-family protein Src1 in BioID analyses as well as the inner nuclear membrane protein Sun1, and shows subcellular co-localizations with Src1, Sun1, the ESCRT component CHMP7 and the IST1-like protein filactin, suggesting that the principal pathway of mitotic nuclear envelope remodeling is conserved between animals and Dictyostelium amoebae.

Comparative Dynamics and Envelope Theorems of Open-Loop Stackelberg Equilibria in Differential Games

A direct proof of the envelope theorems and intrinsic comparative dynamics of locally differentiable open-loop Stackelberg equilibria (OLSE) is given using an extended primal-dual method. It is shown that the follower’s envelope and comparative dynamics results agree in form with those of any player in an open-loop Nash equilibrium, while those of the leader differ. This difference allows, in principle, an empirical test of the leader–follower role in a differential game. Separability conditions are identified on the instantaneous payoff and transition functions under which, for certain parameters, the intrinsic comparative dynamics of the leader’s time-inconsistent OSLE and those in the corresponding optimal control problem are qualitatively identical. However, similar conditions do not exist for time-consistent OSLE.

HIV-1 Envelope Conformation, Allostery, and Dynamics.

The HIV-1 envelope glycoprotein (Env) mediates host cell fusion and is the primary target for HIV-1 vaccine design. The Env undergoes a series of functionally important conformational rearrangements upon engagement of its host cell receptor, CD4. As the sole target for broadly neutralizing antibodies, our understanding of these transitions plays a critical role in vaccine immunogen design. Here, we review available experimental data interrogating the HIV-1 Env conformation and detail computational efforts aimed at delineating the series of conformational changes connecting these rearrangements. These studies have provided a structural mapping of prefusion closed, open, and transition intermediate structures, the allosteric elements controlling rearrangements, and state-to-state transition dynamics. The combination of these investigations and innovations in molecular modeling set the stage for advanced studies examining rearrangements at greater spatial and temporal resolution.

Cortical Responses to the Amplitude Envelopes of Sounds Change with Age.

Many older listeners have difficulty understanding speech in noise, when cues to speech-sound identity are less redundant. The amplitude envelope of speech fluctuates dramatically over time, and features such as the rate of amplitude change at onsets (attack) and offsets (decay), signal critical information about the identity of speech sounds. Aging is also thought to be accompanied by increases in cortical excitability, which may differentially alter sensitivity to envelope dynamics. Here, we recorded electroencephalography in younger and older human adults (of both sexes) to investigate how aging affects neural synchronization to 4 Hz amplitude-modulated noises with different envelope shapes (ramped: slow attack and sharp decay; damped: sharp attack and slow decay). We observed that subcortical responses did not differ between age groups, whereas older compared with younger adults exhibited larger cortical responses to sound onsets, consistent with an increase in auditory cortical excitability. Neural activity in older adults synchronized more strongly to rapid-onset, slow-offset (damped) envelopes, was less sinusoidal, and was more peaked. Younger adults demonstrated the opposite pattern, showing stronger synchronization to slow-onset, rapid-offset (ramped) envelopes, as well as a more sinusoidal neural response shape. The current results suggest that age-related changes in the excitability of auditory cortex alter responses to envelope dynamics. This may be part of the reason why older adults experience difficulty understanding speech in noise.SIGNIFICANCE STATEMENT Many middle-aged and older adults report difficulty understanding speech when there is background noise, which can trigger social withdrawal and negative psychosocial health outcomes. The difficulty may be related to age-related changes in how the brain processes temporal sound features. We tested younger and older people on their sensitivity to different envelope shapes, using EEG. Our results demonstrate that aging is associated with heightened sensitivity to sounds with a sharp attack and gradual decay, and sharper neural responses that deviate from the sinusoidal features of the stimulus, perhaps reflecting increased excitability in the aged auditory cortex. Altered responses to temporal sound features may be part of the reason why older adults often experience difficulty understanding speech in social situations.

Brain rhythm bursts are enhanced by multiplicative noise.

Many healthy and pathological brain rhythms, including beta and gamma rhythms and essential tremor, are suspected to be induced by noise. This yields randomly occurring, brief epochs of higher amplitude oscillatory activity known as "bursts," the statistics of which are important for proper neural function. Here, we consider a more realistic model with both multiplicative and additive noise instead of only additive noise, to understand how state-dependent fluctuations further affect rhythm induction. For illustrative purposes, we calibrate the model at the lower end of the beta band that relates to movement; parameter tuning can extend the relevance of our analysis to the higher frequency gamma band or to lower frequency essential tremors. A stochastic Wilson-Cowan model for reciprocally as well as self-coupled excitatory (E) and inhibitory (I) populations is analyzed in the parameter regime where the noise-free dynamics spiral in to a fixed point. Noisy oscillations known as quasi-cycles are then generated by stochastic synaptic inputs. The corresponding dynamics of E and I local field potentials can be studied using linear stochastic differential equations subject to both additive and multiplicative noises. As the prevalence of bursts is proportional to the slow envelope of the E and I firing activities, we perform an envelope-phase decomposition using the stochastic averaging method. The resulting envelope dynamics are uni-directionally coupled to the phase dynamics as in the case of additive noise alone but both dynamics involve new noise-dependent terms. We derive the stationary probability and compute power spectral densities of envelope fluctuations. We find that multiplicative noise can enhance network synchronization by reducing the magnitude of the negative real part of the complex conjugate eigenvalues. Higher noise can lead to a "virtual limit cycle," where the deterministically stable eigenvalues around the fixed point acquire a positive real part, making the system act more like a noisy limit cycle rather than a quasi-cycle. Multiplicative noise can thus exacerbate synchronization and possibly contribute to the onset of symptoms in certain motor diseases.

Speech Envelope Dynamics for Noise-Robust Auditory Scene Analysis in Robotics

Humans make extensive use of auditory cues to interact with other humans, especially in challenging real-world acoustic environments. Multiple distinct acoustic events usually mix together in a complex auditory scene. The ability to separate and localize mixed sound in complex auditory scenes remains a demanding skill for binaural robots. In fact, binaural robots are required to disambiguate and interpret the environmental scene with only two sensors. At the same time, robots that interact with humans should be able to gain insights about the speakers in the environment, such as how many speakers are present and where they are located. For this reason, the speech signal is distinctly important among auditory stimuli commonly found in human-centered acoustic environments. In this paper, we propose a Bayesian method of selectively processing acoustic data that exploits the characteristic amplitude envelope dynamics of human speech to infer the location of speakers in the complex auditory scene. The goal was to demonstrate the effectiveness of this speech-specific temporal dynamics approach. Further, we measure how effective this method is in comparison with more traditional methods based on amplitude detection only.

An observational correlation between magnetic field, angular momentum and fragmentation in the envelopes of Class 0 protostars?

Aims. The main goal of the following analysis is to assess the potential role of magnetic fields in regulating the envelope rotation, the formation of disks and the fragmentation of Class 0 protostars in multiple systems. Methods. We use the Submillimeter Array to carry out observations of the dust polarized emission at 0.87 mm, in the envelopes of a large sample of 20 Class 0 protostars. We estimate the mean magnetic field orientation over the central 1000 au envelope scales to characterize the orientation of the main component of the organized magnetic field at the envelope scales in these embedded protostars. This direction is compared to that of the protostellar outflow in order to study the relation between their misalignment and the kinematics of the circumstellar gas. The latter is traced via velocity gradient observed in the molecular line emission (mainly N2H+) of the gas at intermediate envelope scales. Results. We discover a strong relationship between the misalignment of the magnetic field orientation with the outflow and the amount of angular momentum observed at similar scales in the protostellar envelope, revealing a potential link between the kinetic and the magnetic energy at envelope scales. The relation could be driven by favored B-misalignments in more dynamical envelopes or a dependence of the envelope dynamics with the large-scale B initial configuration. Comparing the trend with the presence of fragmentation, we observe that single sources are mostly associated with conditions of low angular momentum in the inner envelope and good alignment of the magnetic field with protostellar outflows, at intermediate scales. Our results suggest that the properties of the magnetic field in protostellar envelopes bear a tight relationship with the rotating-infalling gas directly involved in the star and disk formation: we find that it may not only influence the fragmentation of protostellar cores into multiple stellar systems, but also set the conditions establishing the pristine properties of planet-forming disks.

Scattering of The Vector Soliton in Coupled Nonlinear Schrödinger Equation with Gaussian Potential

Nonlinear Schrodinger equation (NLSE) is the fundamental equation which describes the wave field envelope dynamics in a nonlinear and dispersive medium. However, if the fields have many components, one should consider the Coupled Nonlinear Schrodinger equation (CNLSE). We considered the interactions of orthogonally polarized and equal-amplitude vector solitons with two polarization directions. In this paper, we focused on the effect of Gaussian potential on the scattering of the vector soliton in CNLSE. The scattering process was investigated by the variational approximation method and direct numerical solution of CNLSE. Analytically, we analyzed the dynamics of the width and center of mass position of a soliton by the variational approximation method. Soliton may be reflected from each other or transmitted through or trapped. Initially, uncoupled solitons may form the coupled state if the kinetic energy of solitons less than the potential of attractive interaction between solitons but when its’ velocity above the critical velocity, the soliton will pass through each other easily. Meanwhile, a direct numerical simulation of CNLSE had been run to check the accuracy of the approximation. The result of the variational model gives a slightly similar pattern with direct numerical simulation of CNLSE by fixing the parameters for both solutions with the same value. The interaction of the vector soliton with Gaussian potential depends on the initial velocity and amplitude of the soliton and the strength of the external potential.

Comparing mesoscopic models for dendritic growth

We present a quantitative benchmark of multiscale models for dendritic growth simulations. We focus on approaches based on phase-field, dendritic needle network, and grain envelope dynamics. As a first step, we focus on isothermal growth of an equiaxed grain in a supersaturated liquid in three dimensions. A quantitative phase-field formulation for solidification of a dilute binary alloy is used as the reference benchmark. We study the effect of numerical and modeling parameters in both needle-based and envelope-based approaches, in terms of their capacity to quantitatively reproduce phase-field reference results. In light of this benchmark, we discuss the capabilities and limitations of each approach in quantitatively and efficiently predicting transient and steady states of dendritic growth. We identify parameters that yield a good compromise between accuracy and computational efficiency in both needle-based and envelope-based models. We expect that these results will guide further developments and utilization of these models, and ultimately pave the way to a quantitative bridging of the dendrite tip scale with that of entire experiments and solidification processes.

Envelope dynamics of resonant inverter driven electromagnetic levitation melting system with experimental verification

The paper presents a methodology for nonlinear envelope dynamics derivation of a levitation melting type induction heating system, fed by a resonant inverter, based on recently established work piece electro-mechanical model. The work piece under consideration is formed by an aluminum sphere, floated by conical-shaped copper coil. Resonant power converter is used to drive the induction heating system due to the fact that significant impedance of the work piece coil at high operation frequency (several tens of kilohertz) limits the power transferred to the load and therefore needs to be cancelled by corresponding capacitive impedance. Since the application requires levitation of the object being heated up, low-frequency (several hertz) dynamics appears, related to floating body movement. As a result, high-frequency electrical signals become modulated by low-frequency oscillations induced by mechanical side dynamics. It is known that power transfer in sinusoidal excited electrical system is governed by magnitudes and related phases of currents and voltages. Consequently, in order to assess both the low-frequency dynamics of levitated object mechanical motion and the amount of power transferred, information regarding envelope behavior of electrical-side signals is sufficient. Once established, envelope model of the electrical subsystem combined with typical model of the mechanical subsystem describe mechanical side parameters (position, speed and acceleration) exactly as if full electrical model would have been utilized. Moreover, envelope model significantly decreases simulation time and memory requirements of simulation platform. The proposed modeling approach is validated by comparing full and envelope model simulation results, accompanied by results obtained from experimental prototype.

Nanoscale Nuclear Envelope Dynamics and Spatial Organization of the Muscular Dystrophy Protein Emerin

Nanoscale Nuclear Envelope Dynamics and Spatial Organization of the Muscular Dystrophy Protein Emerin