Emerging role of galectin 3 in neuroinflammation and neurodegeneration

Neuroinflammation and neurodegeneration are key processes that mediate the development and progression of neurological diseases.However,the mechanisms modulating these processes in different diseases remain incompletely understood.Advances in single cell based multi-omic analyses have helped to identify distinct molecular signatures such as Lgals3 that is associated with neuroinflammation and neurodegeneration in the central nervous system(CNS).Lgals3 encodes galectin-3(Gal3),aβ-galactoside and glycan binding glycoprotein that is frequently upregulated by reactive microglia/macrophages in the CNS during various neurological diseases.While Gal3 has previously been associated with non-CNS inflammatory and fibrotic diseases,recent studies highlight Gal3 as a prominent regulator of inflammation and neuroaxonal damage in the CNS during diseases such as multiple sclerosis,Alzheimer’s disease,and Parkinson’s disease.In this review,we summarize the pleiotropic functions of Gal3 and discuss evidence that demonstrates its detrimental role in neuroinflammation and neurodegeneration during different neurological diseases.We also consider the challenges of translating preclinical observations into targeting Gal3 in the human CNS.

Role of metabolic dysfunction and inflammation along the liver-brain axis in animal models with obesity-induced neurodegeneration

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship.Peripheral lipid accumulation,particularly in the liver,initiates a cascade of inflammatory processes that extend to the brain,influencing critical metabolic regulatory regions.Ceramide and palmitate,key lipid components,along with lipid transporters lipocalin-2 and apolipoprotein E,contribute to neuroinflammation by disrupting blood–brain barrier integrity and promoting gliosis.Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation.Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models.However,translating these findings to clinical practice requires further investigation into human subjects.In conclusion,metabolic dysfunction,peripheral inflammation,and insulin resistance are integral to neuroinflammation and neurodegeneration.Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.

Movement analysis in the diagnosis and management of Parkinson’s disease

Challenges in the diagnosis and treatment of Parkinson’s disease:Parkinson’s disease(PD)is an increasingly prevalent neurodegenerative disease,at first sight primarily characterized by motor symptoms,although non-motor symptoms also constitute a major part of the overall phenotype.Clinically,this disease cannot be diagnosed reliably until a large part of the vulnerable dopaminergic neurons has been irretrievably lost,and the disease progresses inexorably.New biological criteria for PD have been proposed recently and might eventually improve early diagnosis,but they require further validation,and their use will initially be restricted to a research environment(Darweesh et al.,2024).

Low-field, high-gradient NMR shows diffusion contrast consistent with localization or motional averaging of water near surfaces

Nuclear magnetic resonance(NMR)measurements of water diffusion have been extensively used to probe microstructure in porous materials,such as biological tissue,however primarily using pulsed gradient spin echo(PGSE)methods.Low-field single-sided NMR systems have built-in static gradients(SG)much stronger than typical PGSE maximum gradient strengths,which allows for the signal attenuation at extremely high b-values to be explored.Here,we perform SG spin echo(SGSE)and SG stimulated echo(SGSTE)diffusion measurements on biological cells,tissues,and gels.Measurements on fixed and live neonatal mouse spinal cord,lobster ventral nerve cord,and starved yeast cells all show multiexponential signal attenuation on a scale of b with significant signal fractions observed at b×Do>1 with b as high as 400 ms/um2.These persistent signal fractions trend with surface-to-volume ratios for these systems,as expected from porous media theory.An exception found for the case of fixed vs.live spinal cords was attributed to faster exchange or permeability in live spinal cords than in fixed spinal cords on the millisecond timescale.Data suggests the existence of multiple exchange processes in neural tissue,which may be relevant to the modeling of time-dependent diffusion in gray matter.The observed multi-exponential attenuation is from protons on water and not macromolecules because it remains proportional to the normalized signal when a specimen is washed with D20.The signal that persists to b×Do>1 is also drastically reduced after delipidation,indicating that it originates from lipid membranes that restrict water diffusion.The multiexponential or stretched exponential character of the signal attenuation at b×Do>1 appears mono-exponential when viewed on a scale of(b×Do)/3,suggesting it may originate from localization or motional averaging of water near membranes on sub-micron length scales.To try to disambiguate these two contributions,signal attenuation curves were compared at varying temperatures.While the curves align when normalizing them using the localization length scale,they separate on a motional averaging length scale.This supports localization as the source of non-Gaussian displacements,but this interpretation is still provisional due to the possible confounds of heterogeneity,exchange,and relaxation.Measurements on two types of gel phantoms designed to mimic extracellular matrix.one with charged functional groups synthesized from polyacrylic acid(PAC)and another with uncharged functional groups synthesized from polyacrylamide(PAM),both exhibit signal at b×Do>1,potentially due to water interacting with macromolecules.These preliminary finding motivate future research into contrast and attenuation mechanisms in tissue with low-field,high-gradient NMR。

The Clinical Strategies Implementation Scale Revised(CSI-R).Fidelity Assessment of Resource Group Assertive Community Treatment

The Clinical Strategies Implementation scale (CSI) was originally designed to be used by external reviewers in order to measure the extent to which evidence-based strategies had been implemented in the treatment of persons with schizophrenia spectrum disorders according to Resource-group Assertive Community Treatment (RACT). The present investigation had two aims: 1) to conduct a revision of CSI and to examine the revised instrument (CSI-R) in terms of interrater reliability (Study I);2) to compare assessments of CSI-R made by experienced assessors with assessments made by students in case management (Study II) in order to determine whether the instrument has validity even when more inexperienced persons are using it. In Study I six raters, who took part in 12 to 15 cases from three outpatient community mental health teams, participated. Results indicated that internal consistency of the CSI-R was strong (alpha = 0.89) as well as correlations between individual raters’ (r between 0.80-0.98). In Study II 91 newly trained RACT praxis trainees participated. Each of them followed one case for eighteen months, i.e., the client which they had been assigned during training (n = 91). The five external auditors in the education program then independently assessed the 91 cases with the CSI-R. Results showed significant correlations between experts and trainees (rho = 0.68,

Stair climbing,genetic predisposition,and the risk of incident type 2 diabetes:A large population-based prospective cohort study

Background:Cross-sectional evidence and small-scale trials suggest positive effects of stair climbing on cardiometabolic disease and glucose regulation.However,few studies have examined the long-term association between stair climbing and the incidence of type 2 diabetes(T2D).We aimed to prospectively evaluate the association of stair climbing with T2D and assess modifications by genetic predisposition to T2D.Methods:We included 451,699 adults(mean age=56.3±8.1 years,mean±SD;55.2%females)without T2D at baseline in the UK Biobank and followed up to March 31,2021.Stair climbing information was collected through the touchscreen questionnaire.Genetic risk score for T2D consisted of 424 single nucleotide polymorphisms.Results:During a median follow up of 12.1 years,14,896 T2D cases were documented.Compared with participants who reported no stair climbing,those who climbed stairs regularly had a lower risk of incident T2D(10-50 steps/day:hazard ratio(HR)=0.95,95%confidence interval(95%CI):0.89-1.00;60-100 steps/day:HR=0.92,95%CI:0.87-0.98;110-150 steps/day:HR=0.86,95%CI:0.80-0.91;>150 steps/day:HR=0.93,95%CI:0.87-0.99,p for trend=0.0007).We observed a significant interaction between stair climbing and genetic risk score on the subsequent T2D risk(p for interaction=0.0004),where the risk of T2D showed a downward trend in subjects with low genetic risk and those who reported stair climbing activity of 110-150 steps/day appeared to have the lowest overall T2D risk among those with intermediate to high genetic risk.Conclusion:A higher number of stairs climbed at home was associated with lower T2D incidence risk,especially among individuals with a low genetic predisposition to T2D.These findings highlight that stair climbing,as incidental physical activity,offers a simple and low-cost complement to public health interventions for T2D prevention.

Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer’s disease

Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.

Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

Small molecular decoys in Alzheimer's disease

Recent progress in the treatment of Alzheimer’s disease(AD)using antibodies against amyloid sustains amyloid generation as a key process in AD.Amyloid formation starts with two amyloidbeta(Aβ)molecules interacting(dimer formation)followed by an accelerating build-up of socalled protofibrils,which turn into fibrils,which accumulate in the characteristic plaques.

Glycolysis and glucose metabolism as a target for bioenergetic and neuronal protection in glaucoma

Vision is arguably our most valued sense,yet approximately 340 million people globally suffer blindness or moderate visual impairment,highlighting the need to further develop and advance treatments for ophthalmic diseases.Glaucoma refers to a group of ocular disorders united by a clinically characteristic optic neuropathy with associated retinal ganglion cell loss.

Psychiatric comorbidities in epilepsy:population co-occurrence,genetic correlations and causal effects

Background Psychiatric comorbidities are common in patients with epilepsy.Reasons for the co-occurrence of psychiatric conditions and epilepsy remain poorly understood.Aim We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these conditions.Methods Using nationwide Swedish health registries,we quantified the lifetime prevalence of psychiatric disorders in patients with epilepsy.We then used summarydata from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score regression.Finally,we assessed the potential bidirectional relationships using two-sample Mendelian randomisation.Results In a cohort of 7628495 individuals,we found that almost half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime(adjusted lifetime prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric conditions.For example,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,p<0.001)—a correlation that was more pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,p<0.001).Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric conditions.Conclusions Psychiatric comorbidities are common in patients with epilepsy.Genetic correlations may partially explain some comorbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric conditions.These findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psychiatric comorbidities in epilepsy.

Association of comorbidities with increasing severity of peripheral neuropathy in diabetes mellitus

AIM: To analyze a large population of patients with diabetes and peripheral neuropathy(PN) to determine other meaningful comorbid etiologies for PN.METHODS: Peripheral Neuropathy is a common complication of type 1 and 2 diabetes mellitus;however,other potential causes for PN may be co-existing in patients with diabetes.A prospective cohort study was performed to assess patients with diabetes and PN.We compared patients having PN due solely to diabetes with patients possessing co-existing comorbidities,performing clinical(Toronto Clinical Scoring System and the Utah Early Neuropathy Scale),laboratory and electrophysiological assessments in all patients.RESULTS: Patients with either type 1 or 2 diabetes mellitus and co-existing comorbidities did not have more severe clinical or electrophysiological PN phenotypes overall.However,in patients with type 1 diabetes,presence of a lipid disorder was associated with greater PN severity.In type 2 diabetes patients,both a lipid disorder and cobalamin deficiency were associated with greater PN severity.There was no additive effect upon PN severity with presence of three or more comorbid etiologies.CONCLUSION: The presence of specific,and not general,comorbidities in patients with type 1 or 2 diabetes corresponds with greater PN severity.

Standards of care and novel approaches in the management of glioblastoma multiforme

Glioblastoma multiforme(GBM) is the most common malignant primary brain tumor in adults. Standard therapeutic approaches provide modest improvement in the progression-free and overall survival, necessitating the investigation of novel therapies. We review the standard treatment options for GBM and evaluate the results obtained in clinical trials for promising novel approaches, including the inhibition of angiogenesis, targeted approaches against molecular pathways, immunotherapies, and local treatment with low voltage electric fields.

Multiplexed Profiling of Extracellular Vesicles for Biomarker Development

Extracellular vesicles(EVs)are cell-derived membranous particles that play a crucial role in molecular trafficking,intercellular transport and the egress of unwanted proteins.They have been implicated in many diseases including cancer and neurodegeneration.EVs are detected in all bodily fluids,and their protein and nucleic acid content offers a means of assessing the status of the cells from which they originated.As such,they provide opportunities in biomarker discovery for diagnosis,prognosis or the stratification of diseases as well as an objective monitoring of therapies.The simultaneous assaying of multiple EV-derived markers will be required for an impactful practical application,and multiplexing platforms have evolved with the potential to achieve this.Herein,we provide a comprehensive overview of the currently available multiplexing platforms for EV analysis,with a primary focus on miniaturized and integrated devices that offer potential step changes in analytical power,throughput and consistency.

Vascular and Morphogenetic Abnormalities Associated with Exposure of Cigarette Smoke Condensate during Chicken and Murine Embryogenesis

Objective Embryonic movements （EM） and angiogenesis pathways are evolutionarily conserved mechanisms which are essential for proper embryonic development. Deviations in these processes by exposure to cigarette smoke condensate （CSC） may cause vascular and morphogenetic disorders. Methods Using chicken and mouse embryos, we have demonstrated the in vivo effects of CSC on EM, vascular development, and organogenesis. Results Examination of the CSC exposed chicken embryos revealed a significant reduction in EM, stunted growth, deviated pattern of blood vessels, hemorrhages, and localized necrosis. Likewise, mouse embryos that were exposed to CSC at E8.5 and E9.5 died between E11.5 and E12.5, respectively. These mouse embryos showed defects in morphogenesis and remodeling of the embryonic vasculature, while littermate controls showed normal development. Conclusion Cigarette smoking during pregnancy is fatal for growing embryos. CSC may induce the remodeling of embryonic vasculature, leading to various pathologies.

The neuroimaging of neurodegenerative and vascular disease in the secondary prevention of cognitive decline

Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer's disease(amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.

Symposia Report Immunoglobulin G for the Treatment of Chronic Pain：Report of an Expert Workshop

背景:慢性疼痛的治疗效果仍不理想。尽管现在治疗慢性疼痛的药物种类较多,但许多患者对疗效仍不满意或诉药物的副作用太大。越来越多的证据表明,免疫系统参与了伤害性和神经病理性慢性疼痛的病理过程。设计:在英国利物浦的专题会议上,专家们出示了免疫系统参与慢性疼痛的证据。近来的研究表明,静脉(IVIg)或皮下(SCIg)注射免疫调节药物——多价免疫球蛋白(Ig G)可缓解外周神经病理性疼痛和其他疼痛性疾病。专题会议讨论了IVIg和SCIg治疗的适应证、效价比及其副作用。结果:Ig G可缓解某些伤害性和神经病理性慢性疼痛,如糖尿病、干燥综合征、纤维肌痛症、复杂性区域疼痛综合征、小儿麻痹后遗症和继发于病理性自身抗体的疼痛。结论:Ig G对某些慢性疼痛具有一定的治疗前景。Ig G是一种相对安全的治疗方法,副作用少而轻,但价格较贵。今后有必要对Ig G治疗顽固性疼痛进行随机对照研究和预测性临床试验。

Classical Electromagnetic Fields of Moving Charges as a Vehicle to Probe the Connection between the Elementary Charge and Heisenberg’s Uncertainty Principle

The radiation fields generated when a charged particle is incident on or moving away from a perfectly conducting plane are obtained. These fields are known in the literature as transition radiation. The field equations derived thus are used to evaluate the energy, momentum and the action associated with the radiation. The results show that for a charged particle moving with speed ν, the longitudinal momentum associated with the transition radiation is approximately equal to ΔU/c for values of ?1- ν/c smaller than about 10-3 where ΔU is the total radiated energy dissipated during the interaction and cis the speed of light in free space. The action of the radiation, defined as the product of the total energy dissipated and the duration of the emission, increases as 1- ν/c decreases and, for an electron, it becomes equal to h/4π when ν = c - νm where νm is the speed pertinent to the lowest possible momentum associated with a particle confined inside the universe and?h is the Planck constant. Combining these results with Heisenberg’s uncertainty principle, an expression that predicts the value of the elementary charge is derived.

The role of DJ-1 complexes and catecholamine metabolism： relevance for familial and idiopathic Parkinson＇s disease

Autosomal recessive mutations in the PARK7 gene,which encodes for the protein DJ-1,result in a loss of function and are a cause of familial Parkinson’s disease（PD）,while increased wild-type DJ-1protein levels are associated with some forms of cancer.Several functions of DJ-1 have been described,with the greatest evidence indicating that DJ-1 is a redox-sensitive protein involved in the regulation of oxidative stress and cell survival.

Dementia in military and veteran populations:a review of risk factors—traumatic brain injury,post-traumatic stress disorder,deployment,and sleep

The military population face a unique set of risk factors that may increase the risk of being diagnosed with dementia.Traumatic brain injury(TBI)and post-traumatic stress disorder(PTSD)have a higher prevalence in this group in comparison to the civilian population.By delving into the individual relationships between TBI and dementia,and PTSD and dementia,we are able to better explore dementia in the military and veteran populations.While there are some inconsistencies in results,the TBI-dementia association has become more widely accepted.Moderate-tosevere TBI has been found to increase the risk of being diagnosed with Alzheimer’s disease.A correlation between PTSD and dementia has been established,however,whether or not it is a causal relationship remains unclear.Factors such as blast,combat and chemical exposure may occur during a deployment,along with TBI and/or PTSD diagnosis,and can impact the risk of dementia.However,there is a lack of literature exploring the direct effects of deployment on dementia risk.Sleep problems have been observed to occur in those following TBI,PTSD and deployment.Poor sleep has been associated with possible dementia risk.Although limited studies have focused on the link between sleep and dementia in military and veteran populations,sleep is a valuable factor to study due to its association and interconnection with other military/veteran factors.This review aims to inform of various risk factors to the cognitive health of military members and veterans:TBI,PTSD,deployment,and sleep.