Resident immune responses to spinal cord injury:role of astrocytes and microglia

Spinal cord injury can be traumatic or non-traumatic in origin,with the latter rising in incidence and prevalence with the aging demographics of our society.Moreove r,as the global population ages,individuals with co-existent degenerative spinal pathology comprise a growing number of traumatic spinal cord injury cases,especially involving the cervical spinal cord.This makes recovery and treatment approaches particula rly challenging as age and comorbidities may limit regenerative capacity.For these reasons,it is critical to better understand the complex milieu of spinal cord injury lesion pathobiology and the ensuing inflammatory response.This review discusses microglia-specific purinergic and cytokine signaling pathways,as well as microglial modulation of synaptic stability and plasticity after injury.Further,we evaluate the role of astrocytes in neurotransmission and calcium signaling,as well as their border-forming response to neural lesions.Both the inflammatory and reparative roles of these cells have eluded our complete understanding and remain key therapeutic targets due to their extensive structural and functional roles in the nervous system.Recent advances have shed light on the roles of glia in neurotransmission and reparative injury responses that will change how interventions are directed.Understanding key processes and existing knowledge gaps will allow future research to effectively target these cells and harness their regenerative potential.

A mini review and hypothesis for coronavirus detection using photonics: surface enhanced Raman scattering and fluorescence resonance energy transfer

COVID-19 has devastated numerous nations around the world and has overburdened numerous healthcare systems,which has also caused the loss of livelihoods due to prolonged shutdowns and further led to a cascading effect on the global economy.COVID-19 infections have an incubation period of 2–7 days,but 40 to 45%of cases are asymptomatic or show mild to moderate respiratory symptoms after the period due to subclinical lung abnormalities,making it more likely to spread the pandemic disease.To restrict the spread of the virus,on-site diagnosis methods that are quicker,more precise,and easily accessible are required.Rapid Antigen Detection Tests and Polymerase Chain Reaction tests are currently the primary methods used to determine the presence of COVID-19 viruses.These tests are typically time-consuming,not accurate,and,more importantly,not available to everyone.Hence,in this review and hypothesis,we proposed equipment that employs the properties of photonics to improve the detection of COVID-19 viruses by taking the advantage of typical binding of coronavirus with angiotensin-converting enzyme 2(ACE2)receptors.This hypothetical model would combine Surface-Enhanced Raman Scattering(SERS)and Fluorescence Resonance Energy Transfer(FRET)to provide great flexibility,high sensitivities,and enhanced accessibility.

Neuromodulation and ablation with focused ultrasound-toward the future of noninvasive brain therapy

With an aging patient population and an increased burden of neurological disease,the demand for noninvasive alternatives to open neurosurgical procedures is imperative.Noninvasive or minimally invasive approaches to targeting brain regions include transcranial magnetic stimulation(TMS),transcranial direct current stimulation,temporally interfering electric fields,and focused ultrasound(FUS).Among these modalities,FUS offers a unique combination of target specificity,deep brain penetration,and compatibility with real-time structural and thermal monitoring using magnetic resonance imaging(MRI)and MR thermometry.Depending on the intensity and frequency used,ultrasound can have either modulating or ablative effects on brain tissue.High-intensity MR-guided FUS(MRgFUS)is a noninvasive and effective alternative to conventional deep-brain stimulation and radiofrequency lesioning for essential tremor(ET),and is being investigated for other movement disorders,particularly Parkinson’s disease.Wider clinical implementation of high-intensity ultrasound is challenged by limitations in target selection precision,technical barriers(such as variable penetration and heat deposition)and the possibility of lesion-related adverse effects(Schwartz et al.,2018).Emerging studies,including those from our group(Boutet et al.,2018)are striving to refine targeting of MRgFUS to improve safety and patient clinical outcomes.At the same time,low-intensity FUS(LIFUS)has been found to safely modulate brain activity in rodents,primates,and healthy human subjects(Fomenko et al.,2018).Clinical translation of LIFUS has been hampered however,by a poor understanding of the mechanisms of action,uncertainty over effective sonication parameters and intensities,and conflicting study results due to heterogeneous experimental protocols.In this perspective,the current state of both MRgFUS ablation and LIFUS neuromodulation will be presented.Ongoing technical challenges to delivering ultrasound to the brain,recent innovations in target and parameter selection,and future directions for this emerging nonsurgical alternative are also discussed.

Regulation of Parkin-dependent mitophagy by Bcl-2-associated athanogene(BAG)family members

Mitochondria are essential organelles that play a central role in cellular metabolism and physiology.Their broad range of functions include supplying energy,regulating signaling pathways,and maintaining control of cell proliferation and apoptosis.As defective mitochondria can perturb cellular homeostasis,quality control mechanisms have evolved to preserve mitochondrial fidelity in response to stress and aging(Palikaras et al.,2018).Persistent defects,however,trigger elimination of the entire organelle by an evolutionarily conserved set of cellular processes that specifically remove dysfunctional or surplus mitochondria.This selective degradation of the mitochondria through autophagy,termed mitophagy,is important in fine-tuning mitochondrial number.

Does an Individual’s Living Accommodation Impact their Ability to Cope with the Pandemic?A Hypothesis for Designing Infrastructure to Eliminate Mental Health Problems during COVID-19

The coronavirus(COVID-19)pandemic has caused severe medical emergencies,economic depression,inflation,social distress,and research burden worldwide.Despite the severity of the spreading COVID-19,individual governments and the World Health Organization have mandated several safety protocols including quarantine,physical distancing,advanced research in decoding the disease mechanism to build an effective vaccine,and promoting mental health to achieve the aim of coping through this infectious pandemic.Around the globe,mental health research emphasizes how social isolation impacts anxiety and depression,however,the cause of mental health depletion due to the type of individual's living accommodation(apartment and house)during a pandemic remains unexplored.The apartments have high elevation and high population density while the houses have low elevation and low population density as they are more spaced apart.This paper presents a novel hypothesis to maintain/enhance individuals’mental health during the pandemic,known as“Modi’s Pandemic Infrastructure Hypothesis”,which suggests that individuals residing in varying living accommodations(i.e.apartment or house)would exhibit a significant difference in the experienced pandemic(i.e.COVID-19)anxiety due to varying amount of experienced“silent stress”.Hence,any type of infrastructure(medical,residential,educational,or corporate)should be designed following the public survey of that geographic area based on hypotheses laid in this paper,to minimize the magnitude of“silent stress”.“Silent stress”can be defined as the stress that is unknowingly experienced in the assimilated living accommodation,which is responsible for depleting individuals’mental health and affecting the ability to cope with the pandemic.In support of this novel hypothesis,previous research has demonstrated that the number of coronavirus per unit area has a positive association with elevation above the ground level while a negative association with the population density.Although the scientific data supports the idea that there would be an equal trade-off in the quantity of coronavirus around an individual in both types of accommodation,however,psychologically the public would perceive it differently.Along with the two key variables(i.e.elevation and population density),other influencing factors would be taken into account while determining the magnitude of silent stress,pandemic anxiety,and the best type of infrastructure.In conclusion,this promising hypothesis will not only help the government to build anxiety-free infrastructure for pandemic times but also increase the effectiveness of medical treatments as mental health and strength is the best medicine to defeat severe diseases.

Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success

Osteoarthritis(OA)is a degenerative multifactorial disease with concomitant structural,inflammatory,and metabolic changes that fluctuate in a temporal and patient-specific manner.This complexity has contributed to refractory responses to various treatments.MsCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression.Here,we evaluated 15 randomized controlled clinical trials(RCTs)and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA,and we found net positive effects of MSCs on mitigating pain and symptoms(improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints)and on cartilage protection and/or repair(18/21 clinical studies).We examined MsC dose,tissue of origin,and autologous vs.allogeneic origins as well as patient clinical phenotype,endotype,age,sex and level of OA severity as key parameters in parsing MSC clinical effectiveness.The relatively small sample size of 610 patients limited the drawing of definitive conclusions.Nonetheless,we noted trends toward moderate to higher doses of MsCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation.Evidence from preclinical studies is supportive of MsC anti-inflammatory and immunomodulatory effects,but additional investigations on immunomodulatory,chondroprotective and other clinical mechanisms of action are needed.We hypothesize that MsC basal immunomodulatory"fitness"correlates with OA treatment efficacy,but this hypothesis needs to be validated in future studies.We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory"ft"or engineered-to-be-fit-for-OA MsCs in well-designed,data-intensive clinical trials to advance the field.

震颤的电生理评估

震颤作为最常见的运动障碍表型之一,是指全身任意部位呈现一定频率和振幅的节律性、无意识性肌肉收缩。按发作起源,其可分为生理性震颤和病理性震颤;按发作时体位,其可分为静止性、运动性和姿势性震颤;按发作频率,其又可分为低频、中频和高频率震颤。无论是患者,还是正常人,每个人一生可能都会经历震颤。

Update on Molecular Imaging in Parkinson's Disease

Advances in radionuclide tracers have allowed for more accurate imaging that reflects the actions of numerous neurotransmitters, energy metabolism utilization, inflammation, and pathological protein accumulation. All of these achievements in molecular brain imaging have broadened our understanding of brain function in Parkinson’s disease(PD).The implementation of molecular imaging has supported more accurate PD diagnosis as well as assessment of therapeutic outcome and disease progression. Moreover, molecular imaging is well suited for the detection of preclinical or prodromal PD cases. Despite these advances, future frontiers of research in this area will focus on using multi-modalities combining positron emission tomography and magnetic resonance imaging along with causal modeling with complex algorithms.

Alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy

Background: Multiple system atrophy (MSA) is a neurodegenerative condition characterized by variable combinations of parkinsonism, autonomic failure, cerebellar ataxia and pyramidal features. Although the distribution of synucleinopathy correlates with the predominant clinical features, the burden of pathology does not fully explain observed differences in clinical presentation and rate of disease progression. We hypothesized that the clinical heterogeneity in MSA is a consequence of variability in the seeding activity of α-synuclein both between different patients and between different brain regions. Methods: The reliable detection of α-synuclein seeding activity derived from MSA using cell-free amplification assays remains challenging. Therefore, we conducted a systematic evaluation of 168 different reaction buffers, using an array of pH and salts, seeded with fully characterized brain homogenates from one MSA and one PD patient. We then validated the two conditions that conferred the optimal ability to discriminate between PD- and MSA-derived samples in a larger cohort of 40 neuropathologically confirmed cases, including 15 MSA. Finally, in a subset of brains, we conducted the first multi-region analysis of seeding behaviour in MSA. Results: Using our novel buffer conditions, we show that the physicochemical factors that govern the in vitro amplification of α-synuclein can be tailored to generate strain-specific reaction buffers that can be used to reliably study the seeding capacity from MSA-derived α-synuclein. Using this novel approach, we were able to sub-categorize the 15 MSA brains into 3 groups: high, intermediate and low seeders. To further demonstrate heterogeneity in α-synuclein seeding in MSA, we conducted a comprehensive multi-regional evaluation of α-synuclein seeding in 13 different regions from 2 high seeders, 2 intermediate seeders and 2 low seeders. Conclusions: We have identified unexpected differences in seed-competent α-synuclein across a cohort of neuropathologically comparable MSA brains. Furthermore, our work has revealed a substantial heterogeneity in seeding activity, driven by the PBS-soluble α-synuclein, between different brain regions of a given individual that goes beyond immunohistochemical observations. Our observations pave the way for future subclassification of MSA, which exceeds conventional clinical and neuropathological phenotyping and considers the structural and biochemical heterogeneity of α-synuclein present. Finally, our methods provide an experimental framework for the development of vitally needed, rapid and sensitive diagnostic assays for MSA.

Reasons for delayed spinal cord decompression in individuals with traumatic spinal cord injuries in Iran:A qualitative study from the perspective of neurosurgeons

Purpose:The median time from the event leading to the spinal cord injury(SCI)to the time of decompressive surgery is estimated to be 6.9 days in Iran,which is much longer than the proposed ideal time(less than 24 h)in published guidelines.The current qualitative study aimed to determine the reasons for the observed decompression surgery delay in Iran from the perspective of neurosurgeons.Methods:This qualitative study is designed to perform content analysis on the gathered data from face-to-face semi-structured interviews with 12 Iranian neurosurgeons.Results:The findings of the current study suggest that patient-related factors constitute more than half of the codes extracted from the interviews.Overall,the type of injury,presence of polytrauma,and surgeons’’wrong attitude are the main factors causing delayed spinal cord decompression in Iranian patients from the perspective of neurosurgeons.Other notable factors include delay in transferring patients to the trauma center,delay in availability of necessary equipment,and scarce medical personnel.Conclusion:In the perspective of neurosurgeons,the type of injury,presence of polytrauma,and surgeons’’wrong attitude are the leading reasons for delayed decompressive surgery of individuals with SCI in Iran.

HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model

The hallmarks of spondyloarthritis(SpA)are type 3 immunity-driven inflammation and new bone formation(NBF).Macrophage migration inhibitory factor(MIF)was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity,yet MIF-interacting molecules and networks remain elusive.Herein,we identified hypoxia-inducible factor-1 alpha(HIF1A)as an interacting partner molecule of MIF that drives SpA pathologies,including inflammation and NBF.HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG(curdlan-SKG)mice compared to the respective controls.Under hypoxic conditions in which HIF1A was stabilized,human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23,an upstream type 3 immunity-related cytokine.Similar to MIF,systemic overexpression of IL-23 induced SpA pathology in SKG mice,while the injection of a HIF1A-selective inhibitor(PX-478)into curdlan-SKG mice prevented or attenuated SpA pathology,as indicated by a marked reduction in the expression of MIF and IL-23.Furthermore,genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF,despite the presence of psoriasis-like dermatitis and blepharitis.We also found that MIF-and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice.These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification.Together,these results provide supporting evidence for an MIF/HIF1A regulatory network,and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.