Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.

Emerging insights into the function of very long chain fatty acids at cerebellar synapses

Very long chain-saturated and-polyunsaturated fatty acids(VLC-SFA and VLC-PUFA, respectively) are a functionally important class of fatty acids containing 28 carbons or more in their acyl chain. They are synthesized by the elongation of very long fatty acids-4(ELOVL4) enzyme, expressed mainly in the brain, retina, skin, testes, and meibomian gland, where these fatty acids are found(Agbaga et al., 2008). Further, these organs exhibit tissuespecific VLC-PUFA and VLC-SFA biosynthesis and incorporation into complex lipids for specific functions. In the brain, skin, and Meibomian glands, the ELOVL4 mainly makes VLC-SFA, which are incorporated into complex sphingolipids. In the retina, the ELOVL4 makes VLC-PUFA that are incorporated into phosphatidylcholine, that are critical for visual function, while in testes and sperm, the VLC-PUFA are incorporated into sphingolipids that are critical for fertility(Yeboah et al., 2021).

Avoiding the Use of Lagrange Multipliers. II. Constrained Extrema of Functionals and the Evaluation of Constrained Derivatives

A method for determining the extrema of a real-valued and differentiable function for which its dependent variables are subject to constraints and that avoided the use of Lagrange multipliers was previously presented (Corti and Fariello, Op. Res. Forum 2 (2021) 59). The method made use of projection matrices, and a corresponding Gram-Schmidt orthogonalization process, to identify the constrained extrema. Furthermore, information about the second-derivatives of the given function with constraints was generated, from which the nature of the constrained extrema could be determined, again without knowledge of the Lagrange multipliers. Here, the method is extended to the case of functional derivatives with constraints. In addition, constrained first-order and second-order derivatives of the function are generated, in which the derivatives with respect to a given variable are obtained and, concomitantly, the effect of the variations of the remaining chosen set of dependent variables are strictly accounted for. These constrained derivatives are valid not only at the extrema points, and also provide another equivalent route for the determination of the constrained extrema and their nature.

The complex role of protocadherin-19 in brain function:a focus on the oxytocin system

Mutations in the protocadherin-19(PCDH19)gene(Xq22.1)cause the X-linked syndrome known as developmental and epileptic encephalopathy 9(DEE9,OMIM#300088)(Dibbens et al.,2008).DEE9 is characterized by early-onset clustering epilepsy associated with intellectual disability ranging from mild to profound,autism spectrum disorder,and other neuropsychiatric features including schizophrenia,anxiety,attentiondeficit/hyperactivity,and obsessive or aggressive behaviors.While seizures may become less frequent in adolescence,psychiatric comorbidities persist and often worsen with age(Dibbens et al.,2008;Kolc et al.,2020).

Neuropeptide cholecystokinin:a key neuromodulator for hippocampal functions

Spatial memory is crucial for survival within external surroundings and wild environments.The hippocampus,a critical hub for spatial learning and memory formation,has received extensive investigations on how neuromodulators shape its functions(Teixeira et al.,2018;Zhang et al.,2024).However,the landscape of neuromodulations in the hippocampal system remains poorly understood because most studies focus on classical monoamine neuromodulators,such as acetylcholine,serotonin,dopamine,and noradrenaline.The neuropeptides,comprising the most abundant neuromodulators in the central nervous system,play a pivotal role in neural information processing in the hippocampal system.Cholecystokinin(CCK),one of the most abundant neuropeptides,has been implicated in regulating various physiological and neurobiological statuses(Chen et al.,2019).CCK-A receptor(CCK-AR)and CCK-B receptors(CCK-BR)are two key receptors mediating the biological functions of CCK,both of which belong to class-A sevenfold transmembrane G protein-coupled receptors(Nishimura et al.,2015).CCK-AR preferentially reacts to sulfated CCK,whereas CCK-BR binds both CCK and gastrin with similar affinities(Ding et al.,2022).The expression patterns of CCK-AR and CCK-BR are distinct,implying that CCK has various functions in target regions.For instance,CCK-AR is widely expressed in the GI and brain subregions and is hence implicated in the control of digestive function and satiety regulation.Conversely,CCK-BR is abundantly and widely distributed in the central nervous system,which majorly regulates anxiety,learning,and memory(Ding et al.,2022).However,the roles of endogenous CCK and CCK receptors in regulating hippocampal function at electrophysiological and behavioral levels have received less attention.

Corrigendum: MicroRNA-502-3p regulates GABAergic synapse function in hippocampal neurons

There is an error in the name of the cell line in the abstract of the published paper“MicroRNA-502-3p regulates GABAergic synapse function in hippocampal neurons”published on pages 2698-2707,Issue 12,Volume 19 of Neural Regeneration Research(Sharma et al.,2024),because of oversight during final proof checking.The correct description should be“human-GABA receptor A-α1/β2/γ2L human embryonic kidney(HEK)recombinant cell line.”The authors apologize for any inconvenience this correction may cause for readers and editors of Neural Regeneration Research.

Chondroitinase ABC combined with Schwann cell transplantation enhances restoration of neural connection and functional recovery following acute and chronic spinal cord injury

Schwann cell transplantation is considered one of the most promising cell-based therapy to repair injured spinal cord due to its unique growth-promoting and myelin-forming properties.A the Food and Drug Administration-approved Phase I clinical trial has been conducted to evaluate the safety of transplanted human autologous Schwann cells to treat patients with spinal cord injury.A major challenge for Schwann cell transplantation is that grafted Schwann cells are confined within the lesion cavity,and they do not migrate into the host environment due to the inhibitory barrier formed by injury-induced glial scar,thus limiting axonal reentry into the host spinal cord.Here we introduce a combinatorial strategy by suppressing the inhibitory extracellular environment with injection of lentivirus-mediated transfection of chondroitinase ABC gene at the rostral and caudal borders of the lesion site and simultaneously leveraging the repair capacity of transplanted Schwann cells in adult rats following a mid-thoracic contusive spinal cord injury.We report that when the glial scar was degraded by chondroitinase ABC at the rostral and caudal lesion borders,Schwann cells migrated for considerable distances in both rostral and caudal directions.Such Schwann cell migration led to enhanced axonal regrowth,including the serotonergic and dopaminergic axons originating from supraspinal regions,and promoted recovery of locomotor and urinary bladder functions.Importantly,the Schwann cell survival and axonal regrowth persisted up to 6 months after the injury,even when treatment was delayed for 3 months to mimic chronic spinal cord injury.These findings collectively show promising evidence for a combinatorial strategy with chondroitinase ABC and Schwann cells in promoting remodeling and recovery of function following spinal cord injury.

Emerging role of A-kinase anchoring protein 5 signaling in reward circuit function

There is a strong evidence supporting the hypothesis of synaptic dysfunction as a major contributor to neural circuit and network disruption underlying emotional and mood dysregulation in psychiatric disorders(Simmons et al.,2024).Diverse sets of distinct molecular signaling pathways converge on the synapse to regulate synaptogenesis,synaptic function,and synaptic plasticity in brain regions and circuits through complex interactions organized by numerous multivalent protein scaffolds,including the family of proteins known as A-kinase anchoring proteins(AKAPs).

Resting-state brain network remodeling after different nerve reconstruction surgeries:a functional magnetic resonance imaging study in brachial plexus injury rats

Distinct brain remodeling has been found after different nerve reconstruction strategies,including motor representation of the affected limb.However,differences among reconstruction strategies at the brain network level have not been elucidated.This study aimed to explore intranetwork changes related to altered peripheral neural pathways after different nerve reconstruction surgeries,including nerve repair,endto-end nerve transfer,and end-to-side nerve transfer.Sprague–Dawley rats underwent complete left brachial plexus transection and were divided into four equal groups of eight:no nerve repair,grafted nerve repair,phrenic nerve end-to-end transfer,and end-to-side transfer with a graft sutured to the anterior upper trunk.Resting-state brain functional magnetic resonance imaging was obtained 7 months after surgery.The independent component analysis algorithm was utilized to identify group-level network components of interest and extract resting-state functional connectivity values of each voxel within the component.Alterations in intra-network resting-state functional connectivity were compared among the groups.Target muscle reinnervation was assessed by behavioral observation(elbow flexion)and electromyography.The results showed that alterations in the sensorimotor and interoception networks were mostly related to changes in the peripheral neural pathway.Nerve repair was related to enhanced connectivity within the sensorimotor network,while end-to-side nerve transfer might be more beneficial for restoring control over the affected limb by the original motor representation.The thalamic-cortical pathway was enhanced within the interoception network after nerve repair and end-to-end nerve transfer.Brain areas related to cognition and emotion were enhanced after end-to-side nerve transfer.Our study revealed important brain networks related to different nerve reconstructions.These networks may be potential targets for enhancing motor recovery.

Enhancement of motor functional recovery in thoracic spinal cord injury: voluntary wheel running versus forced treadmill exercise

Spinal cord injury necessitates effective rehabilitation strategies, with exercise therapies showing promise in promoting recovery. This study investigated the impact of rehabilitation exercise on functional recovery and morphological changes following thoracic contusive spinal cord injury. After a 7-day recovery period after spinal cord injury, mice were assigned to either a trained group(10 weeks of voluntary running wheel or forced treadmill exercise) or an untrained group. Bi-weekly assessments revealed that the exercise-trained group, particularly the voluntary wheel exercise subgroup, displayed significantly improved locomotor recovery, more plasticity of dopaminergic and serotonin modulation compared with the untrained group. Additionally, exercise interventions led to gait pattern restoration and enhanced transcranial magnetic motor-evoked potentials. Despite consistent injury areas across groups, exercise training promoted terminal innervation of descending axons. In summary, voluntary wheel exercise shows promise for enhancing outcomes after thoracic contusive spinal cord injury, emphasizing the role of exercise modality in promoting recovery and morphological changes in spinal cord injuries. Our findings will influence future strategies for rehabilitation exercises, restoring functional movement after spinal cord injury.

Pharmacological targeting cGAS/STING/NF-κB axis by tryptanthrin induces microglia polarization toward M2 phenotype and promotes functional recovery in a mouse model of spinal cord injury

The M1/M2 phenotypic shift of microglia after spinal cord injury plays an important role in the regulation of neuroinflammation during the secondary injury phase of spinal cord injury.Regulation of shifting microglia polarization from M1(neurotoxic and proinflammatory type)to M2(neuroprotective and anti-inflammatory type)after spinal cord injury appears to be crucial.Tryptanthrin possesses an anti-inflammatory biological function.However,its roles and the underlying molecular mechanisms in spinal cord injury remain unknown.In this study,we found that tryptanthrin inhibited microglia-derived inflammation by promoting polarization to the M2 phenotype in vitro.Tryptanthrin promoted M2 polarization through inactivating the cGAS/STING/NF-κB pathway.Additionally,we found that targeting the cGAS/STING/NF-κB pathway with tryptanthrin shifted microglia from the M1 to M2 phenotype after spinal cord injury,inhibited neuronal loss,and promoted tissue repair and functional recovery in a mouse model of spinal cord injury.Finally,using a conditional co-culture system,we found that microglia treated with tryptanthrin suppressed endoplasmic reticulum stress-related neuronal apoptosis.Taken together,these results suggest that by targeting the cGAS/STING/NF-κB axis,tryptanthrin attenuates microglia-derived neuroinflammation and promotes functional recovery after spinal cord injury through shifting microglia polarization to the M2 phenotype.

Activation of adult endogenous neurogenesis by a hyaluronic acid collagen gel containing basic fibroblast growth factor promotes remodeling and functional recovery of the injured cerebral cortex

The presence of endogenous neural stem/progenitor cells in the adult mammalian brain suggests that the central nervous system can be repaired and regenerated after injury.However,whether it is possible to stimulate neurogenesis and reconstruct cortical layers II to VI in non-neurogenic regions,such as the cortex,remains unknown.In this study,we implanted a hyaluronic acid collagen gel loaded with basic fibroblast growth factor into the motor cortex immediately following traumatic injury.Our findings reveal that this gel effectively stimulated the proliferation and migration of endogenous neural stem/progenitor cells,as well as their differentiation into mature and functionally integrated neurons.Importantly,these new neurons reconstructed the architecture of cortical layers II to VI,integrated into the existing neural circuitry,and ultimately led to improved brain function.These findings offer novel insight into potential clinical treatments for traumatic cerebral cortex injuries.

PARTIAL REGULARITY FOR MINIMIZERS OF HIGHER ORDER QUASICONVEX FUNCTIONALS

We consider the following quasiconvex functional I(u)=∫ Gf(x,δu,D mu) d x where u is a vector valued function in W m,p (G),m>1 and p>2. The partial C m,a —regularity is proved for minimizers of I(u) under weaker conditions.

The Similarity Transformation of Regularizing Functionals and Simularity Property of Their Fourier Transformations

Let and denote respectively the functionswhere λ≥1, The author discusses the similarity transformation of the regularizing functionals of these functions and the similar property of their Fourier transformation.

Markov process functionals in finance and insurance

The Markov property of Markov process functionals which are frequently used in economy, finance, engineering and statistic analysis is studied. The conditions to judge Markov property of some important Markov process functionals are presented, the following conclusions are obtained： the multidimensional process with independent increments is a multidimensional Markov process; the functional in the form of path integral of process with independent increments is a Markov process; the surplus process with the doubly stochastic Poisson process is a vector Markov process. The conditions for linear transformation of vector Markov process being still a Markov process are given.

On the Variational Problems of the Functionals with Derivatives of Higher Orders and Undetermined Boundary

According to the necessary condition of the functional taking the extremum, that is its first variation is equal to zero, the variational problems of the functionals for the undetermined boundary in the calculus of variations are researched, the functionals depend on single argument, arbitrary unknown functions and their derivatives of higher orders. A new view point is posed and demonstrated, i.e. when the first variation of the functional is equal to zero, all the variational terms are not independent to each other, and at least one of them is equal to zero. Some theorems and corollaries of the variational problems of the functionals are obtained.

Observer-Based Adaptive Fuzzy Tracking Control Using Integral Barrier Lyapunov Functionals for A Nonlinear System With Full State Constraints

A new fuzzy adaptive control method is proposed for a class of strict feedback nonlinear systems with immeasurable states and full constraints.The fuzzy logic system is used to design the approximator,which deals with uncertain and continuous functions in the process of backstepping design.The use of an integral barrier Lyapunov function not only ensures that all states are within the bounds of the constraint,but also mixes the states and errors to directly constrain the state,reducing the conservativeness of the constraint satisfaction condition.Considering that the states in most nonlinear systems are immeasurable,a fuzzy adaptive states observer is constructed to estimate the unknown states.Combined with adaptive backstepping technique,an adaptive fuzzy output feedback control method is proposed.The proposed control method ensures that all signals in the closed-loop system are bounded,and that the tracking error converges to a bounded tight set without violating the full state constraint.The simulation results prove the effectiveness of the proposed control scheme.

Assessing Density Functionals for Describing Methane Dissociative Chemisorption on Pt(110)-(2×1)Surface

In this work,we explore the suitability of several density functionals with the generalized gradient approximation(GGA)and beyond for describing the dissociative chemisorption of methane on the reconstructed Pt(110)-(2×1)surface.The bulk and surface structures of the metal,methane adsorption energy,and dissociation barrier are used to assess the functionals.A van der Waals corrected GGA functional(optPBE-vdW)and a metaGGA functional with van der Waals correction(MS PBEl-rVV10)are selected for ab initio molecular dynamics calculations of the sticking probability.Our results suggest that the use of these two functionals may lead to a better agreement with existing experimental results,thus serving as a good starting point for future development of reliable machine-learned potential energy surfaces for the dissociation of methane on the Pt(110)-(2×1)surface.

Combining stochastic density functional theory with deep potential molecular dynamics to study warm dense matter

In traditional finite-temperature Kohn–Sham density functional theory(KSDFT),the partial occupation of a large number of high-energy KS eigenstates restricts the use of first-principles molecular dynamics methods at extremely high temperatures.However,stochastic density functional theory(SDFT)can overcome this limitation.Recently,SDFT and the related mixed stochastic–deterministic density functional theory,based on a plane-wave basis set,have been implemented in the first-principles electronic structure software ABACUS[Q.Liu and M.Chen,Phys.Rev.B 106,125132(2022)].In this study,we combine SDFT with the Born–Oppenheimer molecular dynamics method to investigate systems with temperatures ranging from a few tens of eV to 1000 eV.Importantly,we train machine-learning-based interatomic models using the SDFT data and employ these deep potential models to simulate large-scale systems with long trajectories.Subsequently,we compute and analyze the structural properties,dynamic properties,and transport coefficients of warm dense matter.

Morphological Characterization of Graphene Flake Networks Using Minkowski Functionals

Two Minkowski functionals were tested in the capacity of morphological descriptors to quantitatively compare the arrays of vertically-aligned graphene flakes grown on smooth and nanoporous alumina and silica surfaces. Specifically, the Euler-Poincaré characteristic and fractal dimension graphs were used to characterize the degree of connectivity and order in the systems, i.e. in the graphene flake patterns of petal-like and tree-like morphologies on solid substrates, and meshlike patterns (networks) grown on nanoporous alumina treated in low-temperature inductivelycoupled plasma. It was found that the Minkowski functionals return higher connectivity and fractal dimension numbers for the graphene flakepatterns with more complex morphologies, and indeed can be used as morphological descriptors to differentiate among various configurations of vertically-aligned graphene flakes grown on surfaces.