Core Nucleus Research Articles

Biomechanics of the intervertebral disc : Consequences of degenerative changes

The intervertebral disc represents the flexible connection between two adjacent vertebral bodies. Intervertebral discs, therefore, give the spine its enormous range of motion. At the same time, intervertebral discs distribute the load evenly over the bony vertebral bodies to ensure load transfer from the upper body to the pelvis, provide sufficient stability, and absorb shocks during everyday movements as well as under extreme loads. The two tissue regions of the intervertebral disc, the central fluid-rich core (nucleus pulposus) and the lamellae of the outer fibrous ring (annulus fibrosus) experience different stresses under load and movement. This article summarizes current knowledge on the biomechanical properties of the intervertebral disc and explains how these are altered by degeneration and which surgical treatment options for degenerated and herniated discs are advisable from abiomechanical perspective.

A Hydrophobic Core Stabilizes the Residual Structure in the RRM2 Intermediate State of the ALS-linked Protein TDP-43

Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.

Developmental emergence of first- and higher-order thalamic neuron molecular identities.

The thalamus is organized into nuclei that have distinct input and output connectivities with the cortex. Whereas first-order (FO) nuclei - also called core nuclei - relay input from sensory organs on the body surface and project to primary cortical sensory areas, higher-order (HO) nuclei - matrix nuclei - instead receive their driver input from the cortex and project to secondary and associative areas within cortico-thalamo-cortical loops. Input-dependent processes have been shown to play a crucial role in the emergence of FO thalamic neuron identity from a ground-state HO neuron identity, yet how this identity emerges during development remains unknown. Here, using single-cell RNA sequencing of the developing mouse embryonic thalamus, we show that, although they are born together, HO neurons start differentiating earlier than FO neurons. Within the FO visual thalamus, postnatal peripheral input is crucial for the maturation of excitatory, but not inhibitory, neurons. Our findings reveal different differentiation tempos and input sensitivities of HO and FO neurons, and highlight neuron type-specific molecular differentiation programs in the developing thalamus.

Luminescent triazolo-fused pyrido[3,4-b]pyrazines as novel fluorophores

A series of organic fluorophores based on novel [1,2,4]triazolo [4′,3':1,2]pyrido [3,4-b]pyrazine architecture were synthesized by a simple two-step protocol. Synthesized organic fluorophores exhibit blue-to-green fluorescence and their UV absorption and fluorescent emission properties were studied. The photophysical properties of synthesized derivatives were tuned by introducing functionalities of varying electronic nature on the core nucleus. The luminescence maxima of the synthesized compounds are found in the range from 427 nm to 503 nm, and the quantum yields ranging from 0.01 to 0.64 were calculated. Among various synthesized molecules, 3-(4-bromophenyl)-8,9-bis(4-methoxyphenyl)-[1,2,4]triazolo [4′,3':1,2]pyrido [3,4-b]pyrazine showed highest quantum yield (ΦF = 0.64), and was further explored for its solvatochromic, acidochromic, aggregation induced fluorescence studies along with theoretical HOMO-LUMO calculations.

Interplay of single-particle and collective modes in the 12C(p,2p) reaction near 100 MeV

The 12C(p,2p)11B reaction at Ep=98.7 MeV proton beam energy is analyzed using a rigorous three-particle scattering formalism extended to include the internal excitation of the nuclear core or residual nucleus. The excitation proceeds via the core interaction with any of the external nucleons. We assume the 11B ground and low-lying excited states [32− (0.0 MeV), 52− (4.45 MeV), 72− (6.74 MeV)] and the excited states [12− (2.12 MeV), 32− (5.02 MeV)] to be members of K=32− and K=12− rotational bands, respectively. The dynamical core excitation results in a significant cross section for the reaction leading to the 52− (4.45 MeV) excited state of 11B that cannot be populated through the single-particle excitation mechanism. The detailed agreement between the theoretical calculations and data depends on the used optical model parametrizations and the kinematical configuration of the detected nucleons.

Motor Control of Distinct Layer 6 Corticothalamic Feedback Circuits.

Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by modulating thalamic excitability. However, the functional role(s) feedback serves during sensory processing is unclear. One hypothesis is that CT feedback is under the control of extra-sensory signals originating from higher-order cortical areas, yet we know nothing about the mechanisms of such control. It is also unclear whether such regulation is specific to CT neurons with distinct thalamic connectivity. Using mice (either sex) combined with in vitro electrophysiology techniques, optogenetics, and retrograde labeling, we describe studies of vibrissal primary motor cortex (vM1) influences on different CT neurons in the vibrissal primary somatosensory cortex (vS1) with distinct intrathalamic axonal projections. We found that vM1 inputs are highly selective, evoking stronger postsynaptic responses in Dual ventral posterior medial nucleus (VPm) and posterior medial nucleus (POm) projecting CT neurons located in lower L6a than VPm-only projecting CT cells in upper L6a. A targeted analysis of the specific cells and synapses involved revealed that the greater responsiveness of Dual CT neurons was due to their distinctive intrinsic membrane properties and synaptic mechanisms. These data demonstrate that vS1 has at least two discrete L6 CT subcircuits distinguished by their thalamic projection patterns, intrinsic physiology, and functional connectivity with vM1. Our results also provide insights into how a distinct CT subcircuit may serve specialized roles specific to contextual modulation of tactile-related sensory signals in the somatosensory thalamus during active vibrissa movements.

Motor Control of Distinct Layer 6 Corticothalamic Feedback Circuits.

Layer 6 corticothalamic (L6 CT) neurons provide massive input to the thalamus, and these feedback connections enable the cortex to influence its own sensory input by modulating thalamic excitability. However, the functional role(s) feedback serves during sensory processing is unclear. One hypothesis is that CT feedback is under the control of extrasensory signals originating from higher-order cortical areas, yet we know nothing about the mechanisms of such control. It is also unclear whether such regulation is specific to CT neurons with distinct thalamic connectivity. Using mice (either sex) combined with in vitro electrophysiology techniques, optogenetics, and retrograde labeling, we describe studies of vibrissal primary motor cortex (vM1) influences on different CT neurons in the vibrissal primary somatosensory cortex (vS1) with distinct intrathalamic axonal projections. We found that vM1 inputs are highly selective, evoking stronger postsynaptic responses in CT neurons projecting to the dual ventral posterior medial nucleus (VPm) and posterior medial nucleus (POm) located in lower L6a than VPm-only-projecting CT cells in upper L6a. A targeted analysis of the specific cells and synapses involved revealed that the greater responsiveness of Dual CT neurons was due to their distinctive intrinsic membrane properties and synaptic mechanisms. These data demonstrate that vS1 has at least two discrete L6 CT subcircuits distinguished by their thalamic projection patterns, intrinsic physiology, and functional connectivity with vM1. Our results also provide insights into how a distinct CT subcircuit may serve specialized roles specific to contextual modulation of tactile-related sensory signals in the somatosensory thalamus during active vibrissa movements.

Lambda motion and cluster states of [formula omitted] predicted via neural networks guided microscopic calculation

We investigate the Λ particle motion and cluster states of BeΛ9−11 using a novel multiple cooling approach guided by the Control Neural Networks method (Ctrl.NN). The numerical results are well reproduced, and the Ctrl.NN method shows rapid convergence concerning the set of the basis states in comparison to traditional generator coordinate method (GCM) calculations. Taking advantage of this merit, we calculate ground state energies and rotational bands of BeΛ9−11 which agree well with experimental observations. By analyzing the density distributions of the main basis, a slight short-range repulsive correlation between Λ particle and α clusters in directions perpendicular to the axis of the Be8 core is revealed. The Λ particle presents a significant broad distribution as a consequence of this correlation, which we call an “analog π-orbit” structure. Furthermore, we prove that this correlation originates from the competition between kinetic energy and Λ-N interaction, as indicated by the energy curves for different configurations of BeΛ9. In the ground states of BeΛ10 and BeΛ11, the Λ particle is confined in a cage-like structure of core nuclei formed by two α clusters and valence neutrons. These structures lead to the development of more compact Λ particle configurations, and the shrinkage of α-α relative distance is also well reproduced.

A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43.

Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.

A survey of isatin hybrids and their biological properties.

The emergence of diverse infections worldwide, which is a serious global threat to human existence, necessitates the urgent development of novel therapeutic candidates that can combat these diseases with efficacy. Molecular hybridization has been established as an efficient technique in designing bioactive molecules capable of fighting infections. Isatin, a core nucleus of an array of compounds with diverse biological properties can be modified at different positions leading to the creation of novel drug targets, is an active area of medicinal chemistry. This review containing published articles from 2005 to 2022 highlights isatin hybrids which have been synthesized and reported in the literature alongside a discussion on their biological properties. The enriched structure-activity relationship studies discussed provides insights for the rational design of novel isatin hybrids with tailored biological properties as effective therapeutic candidates inspired by nature.

Prediction of two-neutron halos in the N = 28 isotones 40Mg and 39Na

The ground states of the nuclei Mg40 and Na39 are investigated using the hyperspherical formalism. Since they are located at the edge of the “big island of inversion”, we concentrate on whether we are likely to find two-neutron Borromean halos in these nuclei. A three-body model with effective n-n and Mg38+n interactions is built for Mg40 based on the available data. We also give predictions for the low-lying spectrum of Na38=37Na+n and two-neutron separation energy of the Na39 nucleus. Depending on parameter choice, we report an increase in the matter radii in the range 0.1-0.5 fm relative to those of the core nuclei. The results suggest a two-neutron halo structure in Mg40 for a subset of parameters, reinforcing the prediction of a Borromean halo nucleus. The calculations indicate that a two-neutron halo is even more likely for Na39. As expected, the halo is linked to the disappearance of the shell gap in these nuclei due to the inversion of the 2p3/2 and 1f7/2 orbitals. We study the total cross section for scattering of these nuclei from a carbon target using a Glauber model and show that these provide a clear signal to assess the halo structure.

Quantifying landscape fragmentation and forest carbon dynamics over 35 years in the Brazilian Atlantic Forest

The Brazilian Atlantic Forest (AF) covers 13% of Brazil but retains only 26% of its original forest area. Utilizing a Morphological Spatial Pattern Analysis (MSPA), we generated 30 m spatial resolution fragmentation maps for old-growth and secondary forests across the AF. We quantified landscape fragmentation patterns and carbon (C) dynamics over 35 years using MapBiomas data between the years 1985 and 2020. We found that from 1985 to 2020 the forest suffered continuous fragmentation, losing core (nuclei forest fragments) and bridge (areas that connect different core areas) components of the landscape. About 87.5% (290 468.4 km2) of the remaining forest lacked core areas, with bridges (38.0%) and islets (small, isolated fragments) (35.4%) being predominant. Secondary forests (1986–2020) accounted for 99 450.5 km2 and played a significant role in fragmentation pattern, constituting 44.9% of the areas affected by edge effects (perforation, edge, bridge, and loop), 53.7% of islets, and comprising only 1.4% of core forest. Additionally, regeneration by secondary forests contributed to all fragmentation classes in 2020. Even with the regrowth of forests, the total forested area in the biome did not increase between 1985 and 2020. Deforestation emissions reached 818 Tg CO2, closely paralleled by edge effects emissions at 810 Tg CO2, highlighting a remarkable parity in C emissions between the two processes. Despite slow changes, AF biome continues to lose its C stocks. We estimated that around 1.96 million hectares (19 600 km2) of regenerated forest would be required to offset the historical C emissions over the analysed period. Hence, MSPA can support landscape monitoring, optimizing natural or active forest regeneration to reduce fragmentation and enhance C stocks. Our study’s findings are critical for guiding land-use policies focusing on minimizing emissions, promoting forest regrowth, and monitoring its permanence. This study offers biome scale, spatially explicit information, critical for AF conservation and management.

Cocktail Cell-Reprogrammed Hydrogel Microspheres Achieving Scarless Hair Follicle Regeneration.

The scar repair inevitably causes damage of skin function and loss of skin appendages such as hair follicles (HF). It is of great challenge in wound repair that how to intervene in scar formation while simultaneously remodeling HF niche and inducing in situ HF regeneration. Here, chemical reprogramming techniques are used to identify a clinically chemical cocktail (Tideglusib and Tamibarotene) that can drive fibroblasts toward dermal papilla cell (DPC) fate. Considering the advantage of biomaterials in tissue repair and their regulation in cell behavior that may contributes to cellular reprogramming, the artificial HF seeding (AHFS) hydrogel microspheres, inspired by the natural processes of "seeding and harvest", are constructed via using a combination of liposome nanoparticle drug delivery system, photoresponsive hydrogel shell, positively charged polyamide modification, microfluidic and photocrosslinking techniques. The identified chemical cocktail is as the core nucleus of AHFS. In vitro and in vivo studies show that AHFS can regulate fibroblast fate, induce fibroblast-to-DPC reprogramming by activating the PI3K/AKT pathway, finally promoting wound healing and in situ HF regeneration while inhibiting scar formation in a two-pronged translational approach. In conclusion, AHFS provides a new and effective strategy for functional repair of skin wounds.

Identification of One O-Methyltransferase Gene Involved in Methylated Flavonoid Biosynthesis Related to the UV-B Irradiation Response in Euphorbia lathyris.

Flavonoids are ubiquitous polyphenolic compounds that play a vital role in plants' defense response and medicinal efficacy. UV-B radiation is a vital environmental regulator governing flavonoid biosynthesis in plants. Many plants rapidly biosynthesize flavonoids as a response to UV-B stress conditions. Here, we investigated the effects of flavonoid biosynthesis via UV-B irradiation in Euphorbia lathyris. We found that exposure of the E. lathyris callus to UV-B radiation sharply increased the level of one O-methyltransferase (ElOMT1) transcript and led to the biosynthesis of several methylated flavonoids. The methyltransferase ElOMT1 was expressed heterologously in E. coli, and we tested the catalytic activity of recombinant ElOMT1 with possible substrates, including caffeic acid, baicalin, and luteolin, in vitro. ElOMT1 could efficiently methylate when the hydroxyl groups were contained in the core nucleus of the flavonoid. This molecular characterization identifies a methyltransferase responsible for the chemical modification of the core flavonoid structure through methylation and helps reveal the mechanism of methylated flavonoid biosynthesis in Euphorbiaceae. This study identifies the O-methyltransferase that responds to UV-B irradiation and helps shed light on the mechanism of flavonoid biosynthesis in Euphorbia lathyris.

Alpha-like correlations in 20Ne: Comparison of quartetting wave function and THSR approaches

20Ne can be considered as a double-magic 16O core nucleus surrounded by four nucleons, the constituents of an α-like quartet. Similar to other nuclei (212Po, 104Ti, etc.) with a quartet on top of a double-magic core nucleus, significant α-like correlations are expected. The quartetting wave function (QWF) approach predicts a large α-like cluster contribution near the surface of the nuclei. The Tohsaki-Horiuchi-Schuck-Röpke (THSR) approach describes α-like clustering in nuclear systems. The results of the QWF approach in the Thomas-Fermi and shell-model approximation are compared with THSR calculations for the container model.

Pathways to selective vulnerability in neuromodulatory subcortical structures during the early pathogenic stages of Alzheimer’s disease

AbstractBackgroundThe two main catecholaminergic members of the isodendritic core nuclei are the substantia nigra (SN) and the locus coeruleus (LC). Despite cytoarchitectural and neurochemical similarities between the two nuclei, the LC is significantly more vulnerable to early degenerative changes in tauopathies like Alzheimer’s disease (AD) as compared to the SN. Here, we seek to use the gradient of vulnerability in these catecholaminergic nuclei to identify pathways associated with vulnerability in early AD pathological stages.MethodThis cohort includes individuals with no neuropathologic entities and Alzheimer’s disease proteinopathic stages. Individuals with TDP‐43, Lewy Body, or Chronic Traumatic Encephalopathy pathologic entities were excluded. The LC and SN was dissected from frozen human brainstem tissue using macroscopic anatomic features. To compare the LC and SN, only cases below Braak III with sufficient RNA from both nuclei were included. The Nanostring nCounter platform was used to probe specific pathways related to neurodegenerative processes. DBH and SLC6A3 served as confirmatory readouts of accurate anatomic sampling of the LC and SN. Differential gene expression analysis was used to evaluate patterns of gene expression that differentiate the two nuclei. Annotated gene sets were evaluated using global significance scores (GSS), a representation of cumulative t‐statistics for relevant genes.ResultThe LC and SN were collected from 26 cases (Figure 1) eligible for this analysis. Accurate dissections were confirmed by differential expression of DBH (p = 1.38e‐9) and SLC6A3 (p = 4.5e‐16). Among the differentially expressed genes (Figure 2), genes associated with microglia activation (GSS = 2.35), oxidative stress (GSS = 2.17), and lipid metabolism (GSS = 2.00) significantly differentiated the LC and SN.ConclusionThe LC and SN serve as examples of differentially vulnerable nuclei at the earliest neuropathologic stages of AD. Cell intrinsic factors, physiological demands, vascular contributions, and exposure to extrinsic factors like toxins are thought to contribute to the LC’s early vulnerability. Here, we show that neuroinflammation and oxidative stress pathways are likely central to differential vulnerability at the earliest stages of Alzheimer’s disease and may represent targets for intervention in prodromal stages.

Characterization and engineering of cephalosporin C acylases to produce 7-Aminocephalosporanic acid

7-Aminocephalosporanic acid (7-ACA) is the core nuclei for the synthesis of β-lactam antibiotics. Cephalosporin C acylases (CCAs) are a class of enzymes that enable the hydrolysis of cephalosporin C (CPC) to 7-ACA. In this study, we identified, characterized and engineered new CCAs to prepare 7-ACA. The best mutant A14 (L159S/A419V) was obtained after several rounds of semi-rational enzyme design using the combinatorial active-site saturation testing (CAST) and iterative evolution. A 2.8-fold increase in specific enzymatic activity (6.1 U/mg) was obtained compared to the wild-type enzyme. The engineered variant also enabled the hydrolysis of a variety of β-lactam antibiotics including Penicillin G and phenylacetyl-7-aminodeacetoxycephalosporanic acid (G-7-ADCA). Overall, this study discovered new CCAs from distinct bacterial origins and enabled the synthesis of various core β-lactam antibiotics nuclei.

Ʌ-Hypernuclear States as Dihadronic Molecules

The study of exotic hypernuclei attracts a great deal of interest in nuclear physics. The reality of heavy hyperon hypernuclei is the subject of intense concern among theoreticians and experimenters in recent years. The core-hyperon model uses to explain abnormal nuclei spectra, recent observations of new exotic heavy hyperon hypernuclei cannot be explained or predicted by ordinary heavy core nuclei. These exotic hypernuclei states are a two-cluster bound states. We calculate the mass spectrum and constituent mass of particles in hypernuclei using the relativistic Schrödinger equation with molecular pseudoharmonic-type potential between particles inside the core and hyperon. Such calculations represent the interaction between the hyperon and the nuclei core. I review recent theoretical studies on the ground states and the excited states of hypernuclei bound states. Finally, we present explicit predictions of the exotic bound states based on the interactions obtained from quantum field theory and the projective unitary representation model. Studies have shown that by increasing the mass number of hyperon-core states, the value of the constituent mass and energy eigenvalue of Ʌ-hypernucleus increases. Also, by growing and increasing the proton number in the (Ʌ-N) states the value of the constituent mass of Ʌ-hyperon increases.

Experience-dependent information routing through the basolateral amygdala.

The basolateral amygdala (BLA) is an emotional processing hub and is well-established to influence both positive and negative valence processing. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in valence processing. However, how this process is impacted by previous experiences which influence valence processing is unknown. Here we demonstrate that previous positive (EE) or negative (chronic unpredictable stress) experiences differentially influence the activity of specific populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Using chemogenetic manipulation of these projection-specific neurons we can mimic or occlude the effects of chronic unpredictable stress or enriched environment on valence processing to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to govern valence processing.

Progress in the Design and Development of Phosphoinositide-3-Kinase (PI3Kα) Inhibitors

Background: The phosphatidylinositol 3-kinase (PI3Kα) has been spotlighted as a potential oncogene and therapeutic target for anticancer drug design.
 Objective: Target compounds were designed employing ligand- and structure-based drug design approaches to address the effect of the compounds’ backbones and functionalities on their biological activity.
 Methods: Synthesis of the targeted compounds, biological evaluation tests against human cancer cell lines, and molecular docking studies.
 Results: Fortunately, 20 novel series of diverse scaffolds were prepared and characterized by means of FT-IR, 1H and 13C NMR, HRMS, and elemental analysis. In addition, the identity of one core nucleus was successfully interpreted with the aid of X-ray crystallography. Biological activity of prepared compounds was investigated in vitro against human cancer cell lines. Results that these compounds inhibit cell proliferation and induce apoptosis through an increase in caspase-3 activity and a decrease in DNA cellular content. Furthermore, ligand-based pharmacophore modeling showed that the newly synthesized analogues match PI3Kα inhibitors fingerprint and the molecular docking studies against PI3Kα revealed that the analogues fit PI3Kα kinase catalytic domain and form H-bonding with key binding residues.
 Conclusion: The harvested series exhibited a potential PI3Kα inhibitory activity in human cancer cell lines.