Emergency department presentations during the COVID-19 pandemic in Queensland (to June 2021): interrupted time series analysis.

OBJECTIVES: To assess emergency department (ED) presentation numbers in Queensland during the coronavirus disease 2019 (COVID-19) pandemic to mid-2021, a period of relatively low COVID-19 case numbers. DESIGN: Interrupted time series analysis. SETTING: All 105 Queensland public hospital EDs. MAIN OUTCOME MEASURES: Numbers of ED presentations during the COVID-19 lockdown period (11 March 2020 - 30 June 2020) and the period of easing restrictions (1 July 2020 - 30 June 2021), compared with pre-pandemic period (1 January 2018 - 10 March 2020), overall (daily numbers) and by Australasian Triage Scale (ATS; daily numbers) and selected diagnostic categories (cardiac, respiratory, mental health, injury-related conditions) and conditions (stroke, sepsis) (weekly numbers). RESULTS: During the lockdown period, the mean number of ED presentations was 19.4% lower (95% confidence interval, -20.9% to -17.9%) than during the pre-pandemic period (predicted mean number: 5935; actual number: 4786 presentations). The magnitudes of the decline and the time to return to predicted levels varied by ATS category and diagnostic group; changes in presentation numbers were least marked for ATS 1 and 2 (most urgent) presentations, and for presentations with cardiac conditions or stroke. Numbers remained below predicted levels during the 12-month post-lockdown period for ATS 5 (least urgent) presentations and presentations with mental health problems, respiratory conditions, or sepsis. CONCLUSIONS: The COVID-19 pandemic and related public restrictions were associated with profound changes in health care use. Pandemic plans should include advice about continuing to seek care for serious health conditions and health emergencies, and support alternative sources of care for less urgent health care needs.

Coexistence of chronic hyperalgesia and multilevel neuroinflammatory responses after experimental SCI: a systematic approach to profiling neuropathic pain.

BACKGROUND: People with spinal cord injury (SCI) frequently develop neuropathic pain (NP) that worsens disability and diminishes rehabilitation efficacy. Chronic NP is presently incurable due to poor understanding of underlying mechanisms. We hypothesized that multilocus neuroinflammation (NIF) might be a driver of SCI NP, and tested it by investigating whether NP coexisted with central NIF, neurotransmission (NTM), neuromodulation (NML) and neuroplasticity (NPL) changes post-SCI. METHODS: Female Sprague-Dawley rats (230-250 g) with T10 compression or laminectomy were evaluated for physical conditions, coordinated hindlimb functions, neurological reflexes, and mechanical/thermal sensitivity thresholds at 1 day post-injury (p.i.) and weekly thereafter. Eight weeks p.i., central nervous system tissues were histochemically and immunohistochemically characterized for parameters/markers of histopathology and NIF/NTM/NML/NPL. Also analyzed was the correlative relationship between levels of selected biomarkers and thermosensitivity thresholds via statistical linear regression. RESULTS: SCI impaired sensorimotor functions, altered reflexes, and produced spontaneous pain signs and hypersensitivity to evoked nociceptive, mechanical, and thermal inputs. Only injured spinal cords exhibited neural lesion, microglia/astrocyte activation, and abnormal expression of proinflammatory cytokines, as well as NIF/NTM/NML/NPL markers. Brains of SCI animals displayed similar pathophysiological signs in the gracile and parabrachial nuclei (GrN and PBN: sensory relay), raphe magnus nucleus and periaqueduct gray (RMN and PAG: pain modulation), basolateral amygdala (BLA: emotional-affective dimension of pain), and hippocampus (HPC: memory/mood/neurogenesis). SCI augmented sensory NTM/NPL (GrN and PBN); increased GAD67 (PAG) level; reduced serotonin (RMN) and fear-off neuronal NTR2 (BLA) expressions; and perturbed neurogenesis (HPC). CONCLUSION: T10 compression caused chronic hyperalgesia that coexisted with NIF/NTM/NML/NPL responses at multilevel neuroaxis centers. The data have provided multidimensional biomarkers as new mechanistic leads to profile SCI NP for therapeutic/therapy development.

ATP and spontaneous calcium oscillations control neural stem cell fate determination in Huntington's disease: a novel approach for cell clock research.

Calcium, the most versatile second messenger, regulates essential biology including crucial cellular events in embryogenesis. We investigated impacts of calcium channels and purinoceptors on neuronal differentiation of normal mouse embryonic stem cells (ESCs), with outcomes being compared to those of in vitro models of Huntington's disease (HD). Intracellular calcium oscillations tracked via real-time fluorescence and luminescence microscopy revealed a significant correlation between calcium transient activity and rhythmic proneuronal transcription factor expression in ESCs stably expressing ASCL-1 or neurogenin-2 promoters fused to luciferase reporter genes. We uncovered that pharmacological manipulation of L-type voltage-gated calcium channels (VGCCs) and purinoceptors induced a two-step process of neuronal differentiation. Specifically, L-type calcium channel-mediated augmentation of spike-like calcium oscillations first promoted stable expression of ASCL-1 in differentiating ESCs, which following P2Y2 purinoceptor activation matured into GABAergic neurons. By contrast, there was neither spike-like calcium oscillations nor responsive P2Y2 receptors in HD-modeling stem cells in vitro. The data shed new light on mechanisms underlying neurogenesis of inhibitory neurons. Moreover, our approach may be tailored to identify pathogenic triggers of other developmental neurological disorders for devising targeted therapies.

Functional multipotency of stem cells: Biological traits gleaned from neural progeny studies.

In this review, a stem cell concept, initially defined by the author more than 10 years ago focusing on neural stem cells, has been systematically refined and updated. Relative to the conventional view which touched principally on the totipotency, pluripotentcy and multipotency of cell lineage differentiation (e.g., the ability of neural stem cells to grow into all three types of neural cells), accumulated data obtained by other researchers and my own team promoted me and my colleagues to propose and establish a new biological concept: Functional Multipotency of Stem Cells. The goal is to recognize the biofunctional multipotency of the stem cell to mediate homeostasis during development and adulthood. Under this academic context, an enriched repertoire of signaling, epigenetic and genetic events has been revealed. Such insight has enabled appreciation of the wide range of molecular tactics the stem cell can use at each developmental or adult stage. The multifunctionality allows stem cells to properly migrate, differentiate, and integrate into as well as prepare, influence, and repair the neighboring cells to steer the micro- and macro-environment towards the formation and self-maintenance of a physiological organ and system. It has been demonstrated that embracing this concept of the stem cell's "functional multipotency" is pivotal for correctly, efficiently, and optimally investigating stem cells to advance fundamental biology and therapeutic translation.

Defining recovery neurobiology of injured spinal cord by synthetic matrix-assisted hMSC implantation.

Mesenchymal stromal stem cells (MSCs) isolated from adult tissues offer tangible potential for regenerative medicine, given their feasibility for autologous transplantation. MSC research shows encouraging results in experimental stroke, amyotrophic lateral sclerosis, and neurotrauma models. However, further translational progress has been hampered by poor MSC graft survival, jeopardizing cellular and molecular bases for neural repair in vivo. We have devised an adult human bone marrow MSC (hMSC) delivery formula by investigating molecular events involving hMSCs incorporated in a uniquely designed poly(lactic-co-glycolic) acid scaffold, a clinically safe polymer, following inflammatory exposures in a dorsal root ganglion organotypic coculture system. Also, in rat T9-T10 hemisection spinal cord injury (SCI), we demonstrated that the tailored scaffolding maintained hMSC stemness, engraftment, and led to robust motosensory improvement, neuropathic pain and tissue damage mitigation, and myelin preservation. The scaffolded nontransdifferentiated hMSCs exerted multimodal effects of neurotrophism, angiogenesis, neurogenesis, antiautoimmunity, and antiinflammation. Hindlimb locomotion was restored by reestablished integrity of submidbrain circuits of serotonergic reticulospinal innervation at lumbar levels, the propriospinal projection network, neuromuscular junction, and central pattern generator, providing a platform for investigating molecular events underlying the repair impact of nondifferentiated hMSCs. Our approach enabled investigation of recovery neurobiology components for injured adult mammalian spinal cord that are different from those involved in normal neural function. The uncovered neural circuits and their molecular and cellular targets offer a biological underpinning for development of clinical rehabilitation therapies to treat disabilities and complications of SCI.

Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis.

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active nonphosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2:CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the "lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways.

Adrenergic activation attenuates astrocyte swelling induced by hypotonicity and neurotrauma.

Edema in the central nervous system can rapidly result in life-threatening complications. Vasogenic edema is clinically manageable, but there is no established medical treatment for cytotoxic edema, which affects astrocytes and is a primary trigger of acute post-traumatic neuronal death. To test the hypothesis that adrenergic receptor agonists, including the stress stimulus epinephrine protects neural parenchyma from damage, we characterized its effects on hypotonicity-induced cellular edema in cortical astrocytes by in vivo and in vitro imaging. After epinephrine administration, hypotonicity-induced swelling of astrocytes was markedly reduced and cytosolic 3'-5'-cyclic adenosine monophosphate (cAMP) was increased, as shown by a fluorescence resonance energy transfer nanosensor. Although, the kinetics of epinephrine-induced cAMP signaling was slowed in primary cortical astrocytes exposed to hypotonicity, the swelling reduction by epinephrine was associated with an attenuated hypotonicity-induced cytosolic Ca(2+) excitability, which may be the key to prevent astrocyte swelling. Furthermore, in a rat model of spinal cord injury, epinephrine applied locally markedly reduced neural edema around the contusion epicenter. These findings reveal new targets for the treatment of cellular edema in the central nervous system.

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A.

Diverse mechanisms including activation of NMDA receptors, microglial activation, reactive astrogliosis, loss of descending inhibition, and spasticity are responsible for ∼40% of cases of intractable neuropathic pain after spinal cord injury (SCI). Because conventional treatments blocking individual mechanisms elicit only short-term effectiveness, a multimodal approach with simultaneous actions against major pain-related pathways may have value for clinical management of chronic pain. We hypothesize that [-]-huperzine A (HUP-A), an alkaloid isolated from the club moss Huperzia serrata, that is a potent reversible inhibitor of acetylcholinesterase and NMDA receptors, could mitigate pain without invoking drug tolerance or dependence by stimulating cholinergic interneurons to impede pain signaling, inhibiting inflammation via microglial cholinergic activation, and blocking NMDA-mediated central hypersensitization. We tested our hypothesis by administering HUP-A i.p. or intrathecally to female Sprague-Dawley rats (200-235 g body weight) after moderate static compression (35 g for 5 min) of T10 spinal cord. Compared with controls, HUP-A treatment demonstrates significant analgesic effects in both regimens. SCI rats manifested no drug tolerance following repeated bolus i.p. or chronic intrathecal HUP-A dosing. The pain-ameliorating effect of HUP-A is cholinergic dependent. Relative to vehicle treatment, HUP-A administration also reduced neural inflammation, retained higher numbers of calcium-impermeable GluR2-containing AMPA receptors, and prevented Homer1a up-regulation in dorsal horn sensory neurons. Therefore, HUP-A may provide safe and effective management for chronic postneurotrauma pain by reestablishing homeostasis of sensory circuits.

Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell.

In the field of induced potency and fate reprogramming, it remains unclear what the best starting cell might be and to what extent a cell need be transported back to a more primitive state for translational purposes. Reprogramming a committed cell back to pluripotence to then instruct it toward a particular specialized cell type is demanding and may increase risks of neoplasia and undesired cell types. Precursor/progenitor cells from the organ of therapeutic concern typically lack only one critical attribute--the capacity for sustained self-renewal. We speculated that this could be induced in a regulatable manner such that cells proliferate only in vitro and differentiate in vivo without the need for promoting pluripotence or specifying lineage identity. As proof-of-concept, we generated and tested the efficiency, safety, engraftability, and therapeutic utility of "induced conditional self-renewing progenitor (ICSP) cells" derived from the human central nervous system (CNS); we conditionally induced self-renewal efficiently within neural progenitors solely by introducing v-myc tightly regulated by a tetracycline (Tet)-on gene expression system. Tet in the culture medium activated myc transcription and translation, allowing efficient expansion of homogeneous, clonal, karyotypically normal human CNS precursors ex vivo; in vivo, where Tet was absent, myc was not expressed, and self-renewal was entirely inactivated (as was tumorigenic potential). Cell proliferation ceased, and differentiation into electrophysiologically active neurons and other CNS cell types in vivo ensued upon transplantation into rats, both during development and after adult injury--with functional improvement and without neoplasia, overgrowth, deformation, emergence of non-neural cell types, phenotypic or genomic instability, or need for immunosuppression. This strategy of inducing self-renewal might be applied to progenitors from other organs and may prove to be a safe, effective, efficient, and practical method for optimizing insights gained from the ability to reprogram cells.

The impact of COVID-19 on emergency department presentations for mental health disorders in Queensland, Australia: A time series analysis.

BACKGROUND: The COVID-19 pandemic has been associated with detrimental effects on mental health and psychological well-being. Although multiple studies have shown decreases in mental health-related Emergency Department (ED) presentations early in the COVID-19 pandemic, the medium-term effects on mental health-related ED presentations have remained less clear. This study aimed to evaluate the effect of the pandemic on mental health ED presentations by comparing observed presentation numbers to predictions from pre-pandemic data. METHODS: This retrospective cohort study tallied weekly ED presentations associated with mental health disorders from a state-wide minimum dataset. Three time periods were identified: Pre-Pandemic (January 1, 2018-March 8, 2020), Statewide Lockdown (March 9, 2020-June 28, 2020), and Restrictions Easing (June 29, 2020-June 27, 2021). Time series analysis was used to generate weekly presentation forecasts using pre-pandemic data. Observed presentation numbers were compared to these forecasts. RESULTS: Weekly presentation numbers were lower than predicted in 11 out of 16 weeks in the Statewide Lockdown period and 52 out of 52 weeks in the Restrictions Easing period. The largest decrease was seen for anxiety disorders (Statewide Lockdown: 76.8% of forecast; Restrictions Easing: 36.4% of forecast), while an increase was seen in presentations for eating disorders (Statewide Lockdown: 139.5% of forecast; Restrictions Easing: 194.4% of forecast). CONCLUSIONS: Overall weekly mental health-related presentations across Queensland public EDs were lower than expected for the first 16 months of the COVID-19 pandemic. These findings underline the limitations of emergency department provision of mental health care and the importance of alternate care modalities in the pandemic context.

Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host.

How grafted neural stem cells (NSCs) and their progeny integrate into recipient brain tissue and functionally interact with host cells is as yet unanswered. We report that, in organotypic slice cultures analyzed by ratiometric time-lapse calcium imaging, current-clamp recordings, and dye-coupling methods, an early and essential way in which grafted murine or human NSCs integrate functionally into host neural circuitry and affect host cells is via gap-junctional coupling, even before electrophysiologically mature neuronal differentiation. The gap junctions, which are established rapidly, permit exogenous NSCs to influence directly host network activity, including synchronized calcium transients with host cells in fluctuating networks. The exogenous NSCs also protect host neurons from death and reduce such signs of secondary injury as reactive astrogliosis. To determine whether gap junctions between NSCs and host cells may also mediate neuroprotection in vivo, we examined NSC transplantation in two murine models characterized by degeneration of the same cell type (Purkinje neurons) from different etiologies, namely, the nervous and SCA1 mutants. In both, gap junctions (containing connexin 43) formed between NSCs and host cells at risk, and were associated with rescue of neurons and behavior (when implantation was performed before overt neuron loss). Both in vitro and in vivo beneficial NSC effects were abrogated when gap junction formation or function was suppressed by pharmacologic and/or RNA-inhibition strategies, supporting the pivotal mediation by gap-junctional coupling of some modulatory, homeostatic, and protective actions on host systems as well as establishing a template for the subsequent development of electrochemical synaptic intercellular communication.

Association of VKORC1-1639G>A polymorphism with susceptibility to ossification of the posterior longitudinal ligament of the spine: a Korean study.

BACKGROUND: Abnormalities of bone metabolism may be involved in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL) of the spine. Besides its hemostatic effect, vitamin K epoxide reductase complex subunit 1 (VKORC1) plays a pivotal role in bone mineralization. The aim of this study is to investigate whether single nucleotide polymorphisms (SNPs) of the VKORC1 gene are associated with the occurrence of OPLL in a Korean population. METHOD: A total of 98 patients with OPLL and 200 controls were genotyped for the VKORC1-1639G>A SNP (rs9923231) by polymerase chain reaction and restriction fragment length polymorphism analysis. All the patients (n = 98) in this study underwent surgery (60, posterior-only approach; 36, anterior-only approach; 2, combined anterior and posterior approach) during their admission. We analyzed this association separately according to the gender and OPLL subgroup: OPLL continuous group (continuous type plus mixed type) and OPLL segmental group (segmental and localized type). RESULTS: We found that the genotype VKORC1-1639G>A frequency was significantly associated with the occurrence of the OPLL in the female group (adjusted odds ratio = 5.22, 95 % confidence interval: 1.675 to 16.269, p = 0.004). However, there was no overall association between the OPLL susceptibility and VKORC1-1639G>A polymorphism. A subgroup analysis did not show any significant correlation between VKORC1-1639G>A polymorphism and subgroup of OPLL either. CONCLUSION: Our results suggest that the VKORC1-1639G>A SNP may increase susceptibility to OPLL in women. However, there was only a statistical association in the female group despite a number of stratified analyses. Therefore, the findings should be interpreted with caution, and further genetic study is needed to improve our understanding of the role of VKORC1 polymorphisms in determining the risk of OPLL occurrence.

Intra-amniotic delivery of amniotic-derived neural stem cells in a syngeneic model of spina bifida.

OBJECTIVE: Neural stem cells (NSCs) may promote spinal cord repair in fetuses with experimental spina bifida. We sought to determine the fate of amniotic-derived NSCs (aNSCs) after simple intra-amniotic injection in a syngeneic model of spina bifida. METHODS: Fetal neural tube defects were induced on 20 pregnant Lewis dams by prenatal administration of retinoic acid. Ten dams served as amniotic fluid donors for epigenetic isolation of aNSCs, which were expanded and labeled with 5-bromo-2'-deoxyuridine. The remaining 10 dams received intra-amniotic injections of the processed aNSCs, blindly in all their fetuses (n = 37) on gestational day 17 (term = E21-22). Fetuses with spina bifida underwent screening for the presence of donor aNSCs in the spinal cord at term. RESULTS: Donor cells were identified in 93.3% of the animals with spina bifida, selectively populating the neural placode, typically in clusters, retaining an undifferentiated morphology, and predominantly on exposed neural surfaces, though some were detected deeper in neighboring neural tissue. CONCLUSIONS: The amniotic cavity can serve as a route of administration of NSCs in experimental spina bifida. Simple intra-amniotic delivery of NSCs may be a practical adjuvant to regenerative strategies for the treatment of spina bifida.

Direct Cell Reprogramming and Phenotypic Conversion: An Analysis of Experimental Attempts to Transform Astrocytes into Neurons in Adult Animals.

Central nervous system (CNS) repair after injury or disease remains an unresolved problem in neurobiology research and an unmet medical need. Directly reprogramming or converting astrocytes to neurons (AtN) in adult animals has been investigated as a potential strategy to facilitate brain and spinal cord recovery and advance fundamental biology. Conceptually, AtN strategies rely on forced expression or repression of lineage-specific transcription factors to make endogenous astrocytes become "induced neurons" (iNs), presumably without re-entering any pluripotent or multipotent states. The AtN-derived cells have been reported to manifest certain neuronal functions in vivo. However, this approach has raised many new questions and alternative explanations regarding the biological features of the end products (e.g., iNs versus neuron-like cells, neural functional changes, etc.), developmental biology underpinnings, and neurobiological essentials. For this paper per se, we proposed to draw an unconventional distinction between direct cell conversion and direct cell reprogramming, relative to somatic nuclear transfer, based on the experimental methods utilized to initiate the transformation process, aiming to promote a more in-depth mechanistic exploration. Moreover, we have summarized the current tactics employed for AtN induction, comparisons between the bench endeavors concerning outcome tangibility, and discussion of the issues of published AtN protocols. Lastly, the urgency to clearly define/devise the theoretical frameworks, cell biological bases, and bench specifics to experimentally validate primary data of AtN studies was highlighted.

T12-L3 Nerve Transfer-Induced Locomotor Recovery in Rats with Thoracolumbar Contusion: Essential Roles of Sensory Input Rerouting and Central Neuroplasticity.

Locomotor recovery after spinal cord injury (SCI) remains an unmet challenge. Nerve transfer (NT), the connection of a functional/expendable peripheral nerve to a paralyzed nerve root, has long been clinically applied, aiming to restore motor control. However, outcomes have been inconsistent, suggesting that NT-induced neurological reinstatement may require activation of mechanisms beyond motor axon reinnervation (our hypothesis). We previously reported that to enhance rat locomotion following T13-L1 hemisection, T12-L3 NT must be performed within timeframes optimal for sensory nerve regrowth. Here, T12-L3 NT was performed for adult female rats with subacute (7-9 days) or chronic (8 weeks) mild (SCImi: 10 g × 12.5 mm) or moderate (SCImo: 10 g × 25 mm) T13-L1 thoracolumbar contusion. For chronic injuries, T11-12 implantation of adult hMSCs (1-week before NT), post-NT intramuscular delivery of FGF2, and environmentally enriched/enlarged (EEE) housing were provided. NT, not control procedures, qualitatively improved locomotion in both SCImi groups and animals with subacute SCImo. However, delayed NT did not produce neurological scale upgrading conversion for SCImo rats. Ablation of the T12 ventral/motor or dorsal/sensory root determined that the T12-L3 sensory input played a key role in hindlimb reanimation. Pharmacological, electrophysiological, and trans-synaptic tracing assays revealed that NT strengthened integrity of the propriospinal network, serotonergic neuromodulation, and the neuromuscular junction. Besides key outcomes of thoracolumbar contusion modeling, the data provides the first evidence that mixed NT-induced locomotor efficacy may rely pivotally on sensory rerouting and pro-repair neuroplasticity to reactivate neurocircuits/central pattern generators. The finding describes a novel neurobiology mechanism underlying NT, which can be targeted for development of innovative neurotization therapies.

Medical Gas Therapy for Tissue, Organ, and CNS Protection: A Systematic Review of Effects, Mechanisms, and Challenges.

Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable "biological gas" (CO, H2 , H2 S, NO, O2 , O3 , and N2 O) or "noble gas" (He, Ar, and Xe) treatment may preserve cells against common pathologies by regulating oxidative, inflammatory, apoptotic, survival, and/or repair processes. Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO-CO, HIF-1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF-1α/ERK activation. Primary findings also reveal that the need to utilize cutting-edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad-spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.

Effects of Magnetite Nanoparticles and Static Magnetic Field on Neural Differentiation of Pluripotent Stem Cells.

Neurodevelopmental processes of pluripotent cells, such as proliferation and differentiation, are influenced by external natural forces. Despite the presence of biogenic magnetite nanoparticles in the central nervous system and constant exposure to the Earth's magnetic fields and other sources, there is scant knowledge regarding the role of electromagnetic stimuli in neurogenesis. Moreover, emerging applications of electrical and magnetic stimulation to treat neurological disorders emphasize the relevance of understanding the impact and mechanisms behind these stimuli. Here, the effects of magnetic nanoparticles (MNPs) in polymeric coatings and the static external magnetic field (EMF) were investigated on neural induction of murine embryonic stem cells (mESCs) and human induced pluripotent stem cells (hiPSCs). The results show that the presence of 0.5% MNPs in collagen-based coatings facilitates the migration and neuronal maturation of mESCs and hiPSCs in vitro. Furthermore, the application of 0.4 Tesla EMF perpendicularly to the cell culture plane, discernibly stimulates proliferation and guide fate decisions of the pluripotent stem cells, depending on the origin of stem cells and their developmental stage. Mechanistic analysis reveals that modulation of ionic homeostasis and the expression of proteins involved in cytostructural, liposomal and cell cycle checkpoint functions provide a principal underpinning for the impact of electromagnetic stimuli on neural lineage specification and proliferation. These findings not only explore the potential of the magnetic stimuli as neural differentiation and function modulator but also highlight the risks that immoderate magnetic stimulation may affect more susceptible neurons, such as dopaminergic neurons.

Prelude to the special issue on novel neurocircuit, cellular and molecular targets for developing functional rehabilitation therapies of neurotrauma.

The poor endogenous recovery capacity and other impediments to reinstating sensorimotor or autonomic function after adult neurotrauma have perplexed modern neuroscientists, bioengineers, and physicians for over a century. However, despite limited improvement in options to mitigate acute pathophysiological sequalae, the past 20 years have witnessed marked progresses in developing efficacious rehabilitation strategies for chronic spinal cord and brain injuries. The achievement is mainly attributable to research advancements in elucidating neuroplastic mechanisms for the potential to enhance clinical prognosis. Innovative cross-disciplinary studies have established novel therapeutic targets, theoretical frameworks, and regiments to attain treatment efficacy. This Special Issue contained eight papers that described experimental and human data along with literature reviews regarding the essential roles of the conventionally undervalued factors in neural repair: systemic inflammation, neural-respiratory inflammasome axis, modulation of glutamatergic and monoaminergic neurotransmission, neurogenesis, nerve transfer, recovery neurobiology components, and the spinal cord learning, respiration and central pattern generator neurocircuits. The focus of this work was on how to induce functional recovery from manipulating these underpinnings through their interactions with secondary injury events, peripheral and supraspinal inputs, neuromusculoskeletal network, and interventions (i.e., activity training, pharmacological adjuncts, electrical stimulation, and multimodal neuromechanical, brain-computer interface [BCI] and robotic assistance [RA] devices). The evidence suggested that if key neurocircuits are therapeutically reactivated, rebuilt, and/or modulated under proper sensory feedback, neurological function (e.g., cognition, respiration, limb movement, locomotion, etc.) will likely be reanimated after neurotrauma. The efficacy can be optimized by individualizing multimodal rehabilitation treatments via BCI/RA-integrated drug administration and neuromechanical protheses.

Non-invasive approaches to functional recovery after spinal cord injury: Therapeutic targets and multimodal device interventions.

This paper is an interdisciplinary narrative review of efficacious non-invasive therapies that are increasingly used to restore function in people with chronic spinal cord injuries (SCI). First presented are the secondary injury cascade set in motion by the primary lesion and highlights in therapeutic development for mitigating the acute pathophysiologic process. Then summarized are current pharmacological strategies for modulation of noradrenergic, serotonergic, and dopaminergic neurotransmission to enhance recovery in bench and clinical studies of subacute and chronic SCI. Last examined is how neuromechanical devices (i.e., electrical stimulation, robotic assistance, brain-computer interface, and augmented sensory feedback) could be comprehensively engineered to engage efferent and afferent motosensory pathways to induce neuroplasticity-based neural pattern generation. Emerging evidence shows that computational models of the human neuromusculoskeletal system (i.e., human digital twins) can serve as functionalized anchors to integrate different neuromechanical and pharmacological interventions into a single multimodal prothesis. The system, if appropriately built, may cybernetically optimize treatment outcomes via coordination of heterogeneous biosensory, system output, and control signals. Overall, these rehabilitation protocols involved neuromodulation to evoke beneficial adaptive changes within spared supraspinal, intracord, and peripheral neuromuscular circuits to elicit neurological improvement. Therefore, qualitatively advancing the theoretical understanding of spinal cord neurobiology and neuromechanics is pivotal to designing new ways to reinstate locomotion after SCI. Future research efforts should concentrate on personalizing combination therapies consisting of pharmacological adjuncts, targeted neurobiological and neuromuscular repairs, and brain-computer interfaces, which follow multimodal neuromechanical principles.