Case report: Identification of Hepatitis B Virus in the cerebrospinal fluid of neuromyelitis optica spectrum disorders and successful treatment with ofatumumab and inebilizumab.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare demyelinating disease of the central nervous system primarily affecting the optic nerves, spinal cord, and brainstem. Viral infection may trigger NMOSD. Here, we report the case of a 34-year-old female presenting with a range of symptoms including nausea, vomiting, dysphagia, choking, and fatigue with unsteady gait, diplopia, hearing loss, left-sided facial paralysis, breathing difficulties, and hoarseness of voice. Her HBV DNA concentration, as determined by quantitative PCR analysis, exceeded 5×107 IU/ml in serum and 4.48×102 IU/ml in CSF. Next-generation sequencing of CSF revealed 1,528 HBV sequences in DNA analysis and 6 sequences in RNA analysis. Serum aquaporin-4 antibody (AQP4-Ab) titer was 1:10, and the CSF titer was 1:3.2. Brain magnetic resonance imaging showed high signal intensities in the brain stem, medulla oblongata, and left middle cerebellar peduncle with mild restricted-diffusion. The patient received antiviral and hepatoprotective medications before the high-dose methylprednisolone pulse therapy. However, the patient did not respond well to the first-line treatment. Subsequently, the patient received ofatumumab and inebilizumab. Throughout the follow-up period, there was a gradual improvement in her neurological symptoms, with no reactivation of hepatitis B or deterioration of liver function observed. Thereby, to the best of our knowledge, we report the first case of successful treatment with ofatumumab and inebilizumab in a patient with NMOSD concurrent with HBV infection.

Mitochondria-Specific Molecular Crosstalk between Ferroptosis and Apoptosis Revealed by In Situ Raman Spectroscopy.

Ferroptosis and apoptosis are two types of regulated cell death that are closely associated with the pathophysiological processes of many diseases. The significance of ferroptosis-apoptosis crosstalk in cell fate determination has been reported, but the underlying molecular mechanisms are poorly understood. Herein mitochondria-mediated molecular crosstalk is explored. Based on a comprehensive spectroscopic investigation and mass spectrometry, cytochrome c-involved Fenton-like reactions and lipid peroxidation are revealed. More importantly, cytochrome c is found to induce ROS-independent and cardiolipin-specific lipid peroxidation depending on its redox state. In situ Raman spectroscopy unveiled that erastin can interrupt membrane permeability, specifically through cardiolipin, facilitating cytochrome c release from the mitochondria. Details of the erastin-cardiolipin interaction are determined using molecular dynamics simulations. This study provides novel insights into how molecular crosstalk occurs around mitochondrial membranes to trigger ferroptosis and apoptosis, with significant implications for the rational design of mitochondria-targeted cell death reducers in cancer therapy.

In Situ Raman Spectroscopy Reveals Cytochrome c Redox-Controlled Modulation of Mitochondrial Membrane Permeabilization That Triggers Apoptosis.

The selective interaction of cytochrome c (Cyt c) with cardiolipin (CL) is involved in mitochondrial membrane permeabilization, an essential step for the release of apoptosis activators. The structural basis and modulatory mechanism are, however, poorly understood. Here, we report that Cyt c can induce CL peroxidation independent of reactive oxygen species, which is controlled by its redox states. The structural basis of the Cyt c-CL binding was unveiled by comprehensive spectroscopic investigation and mass spectrometry. The Cyt c-induced permeabilization and its effect on membrane collapse, pore formation, and budding are observed by confocal microscopy. Moreover, cytochrome c oxidase dysfunction is found to be associated with the initiation of Cyt c redox-controlled membrane permeabilization. These results verify the significance of a redox-dependent modulation mechanism at the early stage of apoptosis, which can be exploited for the design of cytochrome c oxidase-targeted apoptotic inducers in cancer therapy.

METTL4-mediated N6-methyladenine DNA modification regulates thermotolerance in Arabidopsis thaliana.

DNA N6-methyladenine (6 mA) is an evolutionarily conserved DNA modification in procaryotes and eukaryotes. The DNA 6 mA methylation is tightly controlled by 6 mA regulatory proteins. DNA N6-adenine methyltransferase 1 (DAMT-1) has been identified as a DNA 6 mA methyltransferase in animals. In plants, DNA 6 mA methylation has been found, however, the DNA 6 mA methyltransferases and their function in plants are largely unknown. In our study, we find METTL4 is a DNA 6 mA methyltransferase in Arabidopsis thaliana. Both in vitro and in vivo evidences support the DNA 6 mA methyltransferase activity of METTL4. mettl4 mutant is hypersensitive to heat stress, suggesting DNA 6 mA methylation plays important role in heat stress adaption. RNA-seq and 6 mA IP-qPCR analysis show that METTL4 participates in heat stress tolerance by regulating expression of heat responsive genes. Our study find METTL4 is a plant DNA 6 mA methyltransferase and illustrates its function in regulating heat stress response.

Flexible SERS Biosensor Based on Core-Shell Nanotags for Sensitive and Multiple Detection of T1DM Biomarkers.

Sensitive and multiple detection of the biomarkers of type 1 diabetes mellitus (T1DM) is vital to the early diagnosis and clinical treatment of T1DM. Herein, we developed a SERS-based biosensor using polyvinylidene fluoride (PVDF) membranes as a flexible support for the detection of glutamic acid decarboxylase antibodies (GADA) and insulin autoantibodies (IAA). Two kinds of silver-gold core-shell nanotags embedded with Raman probes and attached with GADA or IAA antibodies were synthesized to capture the targets, enabling highly sensitive and highly selective detection of GADA and IAA. The embedded Raman probes sandwiched between silver and gold layers guaranteed spectral stability and reliability. Moreover, the utilization of two Raman probes enables simultaneous and multiplexing detection of both GADA and IAA, improving the detection accuracy for T1DM. The proposed SERS-based method has been proven feasible for clinical sample detection, demonstrating its great potential in sensitive, reliable, and rapid diagnosis of T1DM.

In Situ and Real-Time Monitoring of Mitochondria-Endoplasmic Reticulum Crosstalk in Apoptosis via Surface-Enhanced Resonance Raman Spectroscopy.

The crosstalk between mitochondria and endoplasmic reticula plays a crucial role in apoptotic pathways in which reactive oxygen species (ROS) produced by microsomal monooxygenase (MMO) are believed to accelerate cytochrome c release. Herein, we successfully demonstrate the potential of surface-enhanced resonance Raman spectroscopy (SERRS) for monitoring MMO-derived ROS formation and ROS-mediated cytochrome c release. Silver nanoparticles coated with nickel shells are used as both Raman signal enhancers and electron donors for cytochrome c. SERRS of cytochrome c is found to be sensitive to ROS, allowing for in situ probing of ROS formation with a cell death inducer. Label-free evaluation of ROS-induced apoptosis is achieved by SERRS-based monitoring of cytochrome c release in living cells. This study verifies the capability of SERRS for label-free, in situ, and real-time monitoring of the mitochondria-endoplasmic reticulum crosstalk in apoptosis and provides a novel strategy for the rational design and screening of ROS-inducing drugs for cancer treatment.

Comparison of effects of multiple adjuvants and immunization routes on the immunogenicity and protection of HSV-2 gD subunit vaccine.

Genital herpes caused by herpes simplex virus type 2 (HSV-2) poses a global health issue. HSV-2 infection increases the risk of acquiring HIV infection. Studies have demonstrated that HSV-2 subunit vaccines have potential benefits, but require adjuvants to induce a balanced Th1/Th2 response. To develop a novel, effective vaccine, in this study, a truncated glycoprotein D (aa 1-285) of HSV-2 was formulated with an Al(OH)3 adjuvant, three squalene adjuvants, zMF59, zAS03, and zAS02, or a mucosal adjuvant, bacterium-like particles (BLPs). The immunogenicity of these subunit vaccines was evaluated in mice. After three immunizations, vaccines formulated with Al(OH)3, zMF59, zAS03, and zAS02 (intramuscularly) induced higher titers of neutralizing antibody than that formulated without adjuvant, and in particular, mice immunized with the vaccine plus zAS02 had the highest neutralizing antibody titers and tended to produce a more balanced immune reaction than others. Intranasal gD2-PA-BLPs also induced excellent IgA levels and a more balanced Th1 and Th2 responses than intranasal gD2. After challenge with a lethal dose of HSV-2, all five adjuvants exhibited a positive effect in improving the survival rate. zAS02 and gD2-PA-BLPs enhanced survival by 50% and 25%, respectively, when compared with the vaccine without adjuvant. zAS02 was the only adjuvant that resulted in complete vaginal virus clearance and genital lesion healing within eight days. These results demonstrate the potential of using zAS02 as a subunit vaccine adjuvant, and BLPs as a mucosal vaccine adjuvant.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Transcriptome-wide profiling of RNA N4-cytidine acetylation in Arabidopsis thaliana and Oryza sativa.

Acetylation of N4-cytidine (ac4C) has recently been discovered as a novel modification of mRNA. RNA ac4C modification has been shown to be a key regulator of RNA stability, RNA translation, and the thermal stress response. However, its existence in eukaryotic mRNAs is still controversial. In plants, the existence, distribution pattern, and potential function of RNA ac4C modification are largely unknown. Here we report the presence of ac4C in the mRNAs of both Arabidopsis thaliana and rice (Oryza sativa). By comparing two ac4C sequencing methods, we found that RNA immunoprecipitation and sequencing (acRIP-seq), but not ac4C sequencing, was suitable for plant RNA ac4C sequencing. We present transcriptome-wide atlases of RNA ac4C modification in A. thaliana and rice mRNAs obtained by acRIP-seq. Analysis of the distribution of RNA ac4C modifications showed that ac4C is enriched near translation start sites in rice mRNAs and near translation start sites and translation end sites in Arabidopsis mRNAs. The RNA ac4C modification level is positively correlated with RNA half-life and the number of splicing variants. Similar to that in mammals, the translation efficiency of ac4C target genes is significantly higher than that of other genes. Our in vitro translation results confirmed that RNA ac4C modification enhances translation efficiency. We also found that RNA ac4C modification is negatively correlated with RNA structure. These results suggest that ac4C is a conserved mRNA modification in plants that contributes to RNA stability, splicing, translation, and secondary structure formation.

Investigation on marital status of patients with neuromyelitis optica spectrum disorders in China.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) may have a great impact on patients' marriage, and marital status may also affect patients' compliance and prognosis. We investigated the marital status of 494 NMOSD patients in China to explore the mutual influence between them. METHODS: A cross-sectional survey was conducted by the online questionnaires or telephone follow-up. Basic information of all respondents was analyzed from NMOSD-database of West China hospital. All 444 married respondents finished self-assessment of NMOSD's effect on marriage and over 80% of them accepted Marital Cumulative Damage Score (MCDS). RESULTS: The proportion of unmarried male patients is higher than female (23.1% vs. 9.0%), especially in youth stage (44.0% vs. 20.2%). However, the females reported bigger impacts on their marriage among married NMOSD patients (97.5% vs. 70.7%). Compared to married patients, divorced patients costed more in hospital every time (29,857.1 CNY vs. 15,577.2 CNY), received longer education (12.75 years vs. 9.36 years), had longer duration of disease (117.16 vs. 93.62 months), more relapses (5.50 vs. 3.73) and higher EDSS score (3.58 vs. 2.59). EDSS scores are associated with MCDS (R2=0.267, P<0.0001), and divorced patients have higher MCDS (P<0.01). Decreased group activities (84.1%), declined working ability (73.7%) and alienation from friends (72.54%) are the first three factors in MCDS. CONCLUSION: NMOSD exerts cumulative damage for patients' marriage, and the progression of NMOSD is more likely to lead to marital breakdown. Healthy marriage may improve the prognosis of patients by providing the psychological support and improving treatment compliance.

An Adenovirus-Based Recombinant Herpes Simplex Virus 2 (HSV-2) Therapeutic Vaccine Is Highly Protective against Acute and Recurrent HSV-2 Disease in a Guinea Pig Model.

Genital herpes (GH) has become one of the most common sexually transmitted diseases worldwide, and it is spreading rapidly in developing countries. Approximately 90% of GH cases are caused by HSV-2. Therapeutic HSV-2 vaccines are intended for people already infected with HSV-2 with the goal of reducing clinical recurrences and recurrent virus shedding. In our previous work, we evaluated recombinant adenovirus-based vaccines, including rAd-gD2ΔUL25, rAd-ΔUL25, and rAd-gD2, for their potency as prophylactic vaccines. In this study, we evaluated these three vaccines as therapeutic vaccines against acute and recurrent diseases in intravaginal challenged guinea pigs. Compared with the control groups, the recombinant vaccine rAd-gD2ΔUL25 induced a higher titer of the binding antibody, and rAd-gD2 + rAd-ΔUL25 induced a higher titer of the neutralizing antibody. Both rAd-gD2ΔUL25 and rAd-gD2 + rAd-ΔUL25 vaccines significantly enhanced the survival rate by 50% compared to rAd-gD2 and reduced viral replication in the genital tract and recurrent genital skin disease. Our findings provide a new perspective for HSV-2 therapeutic vaccine research and provide a new technique to curtail the increasing spread of HSV-2.

Non-immune system comorbidity in neuromyelitis optica spectrum disorders.

Comorbidities may influence the clinical features, prognosis, and treatment outcomes of neuromyelitis optica spectrum disorders (NMOSD). The aim of this study was to determine the status of non-immune system comorbidities in patients with NMOSD and the effect on treatment response and prognosis. We retrospectively collected data from all patients who met the 2015 NMOSD diagnostic criteria from the NMOSD database established by our center. Patients were divided into positive and negative groups based on the presence of non-immune disease comorbidities. Patient data, clinical characteristics, treatment response, prognosis, and mortality were compared between the two groups. A total of 138 patients with NMOSD plus comorbidities were included, and 404 patients without comorbidities were selected as controls. The average age at onset was older (45 years vs 38 years, P < 0.001), the mean body mass index was higher (23.12 vs 22.04, P = 0.042) and more patients experienced relapse after immunotherapy (68.5 % vs 54.5 %, P = 0.020) in the comorbidity group than in the non-comorbidity group. Multifocal central nervous system lesions as an initial symptom was more common in the comorbidity group than in the non-comorbidity group (30.4 % vs 18.32 %, P = 0.003). Further, more patients experienced severe vision attacks (28.3 % vs 15.8 %, P = 0.003) and severe motor attacks (30.4 % vs 11.9 %, P < 0.001) in the comorbidity group than in the non-comorbidity group. In conclusion, patients with NMOSD with comorbidities tended to be older, less responsive to treatment, and at a higher risk of vision loss and paralysis.

Myocardial Injury in Hospitalized Patients with Myasthenia Gravis.

Objective: To investigate the clinical characteristics and outcome of myocardial injury in patients with myasthenia gravis (MG). Methods: We retrospectively searched medical records to screen hospitalized patients with MG at our hospital. The troponin T (TnT) levels were deemed necessary to be performed based on the patient's clinical symptoms and were used as biomarkers of myocardial injury. The patients' demographic and clinical information were collected. Death was the primary outcome. Results: A total of 336 patients with MG measured TnT levels and were included in the final analysis. The male MG patients with elevated TnT levels had a higher prevalence of infection (56.8% vs. 30.0%, p = 0.001) and myasthenic crisis (37.5% vs. 13.3%, p = 0.001) than those with normal TnT levels. Meanwhile, the female MG patients with elevated TnT levels were older (56.0 (16.6) vs. 49.2 (17.2)) years old, p = 0.007] and had a higher prevalence of infection (65.4% vs. 32.1%, p < 0.001), myasthenic crisis (33.6% vs. 17.9%, p = 0.015), and thymoma (38.5% vs. 16.7%, p = 0.001) than those with normal TnT levels. Older age (coef. = 0.004; p = 0.034), infection (coef. = 0.240; p = 0.001), myasthenic crisis (coef. = 0.312; p < 0.001), thymoma (coef. = 0.228; p = 0.001), and ICI therapy (coef. = 1.220; p < 0.001) were independent risk predictors for increasing log TnT levels. Thirty-seven patients died during hospitalization. High log TnT levels (OR = 8.818; p < 0.001), female sex (OR = 0.346; p = 0.023), thymoma (OR = 5.092; p = 0.002), and infection (OR = 14.597; p < 0.001) were independent risk predictors of death. Conclusions: Our study revealed that the surveillance of myocardial injury biomarkers in MG patients might be beneficial.

Label-Free Surface-Enhanced Raman Spectroscopic Analysis of Proteins: Advances and Applications.

Surface-enhanced Raman spectroscopy (SERS) is powerful for structural characterization of biomolecules under physiological condition. Owing to its high sensitivity and selectivity, SERS is useful for probing intrinsic structural information of proteins and is attracting increasing attention in biophysics, bioanalytical chemistry, and biomedicine. This review starts with a brief introduction of SERS theories and SERS methodology of protein structural characterization. SERS-active materials, related synthetic approaches, and strategies for protein-material assemblies are outlined and discussed, followed by detailed discussion of SERS spectroscopy of proteins with and without cofactors. Recent applications and advances of protein SERS in biomarker detection, cell analysis, and pathogen discrimination are then highlighted, and the spectral reproducibility and limitations are critically discussed. The review ends with a conclusion and a discussion of current challenges and perspectives of promising directions.

Neuromyelitis optica spectrum disorder in Western China impacts employment and increases financial burden in women.

Background: Neuromyelitis optica spectrum disorder (NMOSD) often leads to disability and exerts a heavy toll on the work and life of affected female patients. This study aimed to analyze the current employment situation and economic burden as well as the risk factors for unemployment in female patients with NMSOD. Methods: We compared the following unemployment- and employment-related aspects in with NSMOD, which were investigated using questionnaires: the specific impact of NMOSD on work, medical expenses, and factors affecting unemployment. Results: We enrolled 351 female patients with NMOSD. More than half (54.1%, 190/351) of participants reported that the disease led to unemployment. The unemployment group was significantly older (46.9 ± 12.1 years vs. 39.3 ± 9.4 years, P = 0.000), had a higher annual recurrence rate (ARR) (0.6 [inter quartile range [IQR]:0.4-0.9] vs. 0.5 [IQR: 0.3-0.8], P = 0.141), and a higher severe disability rate (44.2% vs. 11.2%, P = 0.000) than the employment group. Moreover, unemployed patients had lower education levels. The factors influencing unemployment included low education (junior middle-school or below), age, higher ARR, and severe disability (odds ratio [OR] = 6.943, P = 0.000; OR = 1.034, P = 0.010; OR = 1.778, P = 0.038; and OR = 4.972, P = 0.000, respectively). Medication and hospitalization costs constituted the principal economic burdens. Conclusion: The heavy financial burden, employment difficulties, and high unemployment rate are the most prominent concerns of female patients with NMOSD who require more social support and concern.

Brain structural and functional connectivity alterations are associated with fatigue in neuromyelitis optica spectrum disorder.

BACKGROUND: Many patients with neurological disorders experience chronic fatigue, but the neural mechanisms involved are unclear. OBJECTIVE: Here we investigated whether the brain structural and functional connectivity alterations were involved in fatigue related to neuromyelitis optica spectrum disorder (NMOSD). METHODS: This prospective pilot study used structural and resting-state functional brain magnetic resonance imaging to compare total cortical thickness, cortical surface area, deep gray matter volume and functional connectivity (FC) between 33 patients with NMOSD and 20 healthy controls (HCs). Patients were subgrouped as low fatigue (LF) and high fatigue (HF). RESULTS: HF patients scored higher on the Hamilton Anxiety Rating Scale and Hamilton Rating Scale for Depression than LF patients and HCs. The two patient subgroups and HC group did not differ significantly in cortical thickness, cortical surface area and volumes of the bilateral caudate nucleus, bilateral putamen, bilateral amygdala, bilateral hippocampus, bilateral thalamus proper or right nucleus accumbens (p > 0.05). However, after correcting for age, sex, years of education, anxiety and depression, HF patients showed larger left pallidum than HCs (0.1573 ± 0.0214 vs 0.1372 ± 0.0145, p = 0.009). Meanwhile, both LF patients (0.0377 ± 0.0052 vs 0.0417 ± 0.0052, p = 0.009) and HF patients (0.0361 ± 0.0071 vs 0.0417 ± 0.0052, p = 0.013) showed smaller left nucleus accumbens than HCs.. Compared with LF patients, HF patients showed significantly decreased FC between the left pallidum and bilateral cerebellar posterior lobes. CONCLUSIONS: This was the first evidence linking structural and functional alterations in the brain to fatigue in NMOSD, and in the future, long term follow-up was necessary.

Immunogenicity of Varicella Zoster Virus DNA Vaccines Encoding Glycoprotein E and Immediate Early Protein 63 in Mice.

Herpes zoster (HZ) is caused by the reactivation of latent varicella-zoster virus (VZV) from the sensory ganglia due to aging or immunosuppression. Glycoprotein E (gE) is a widely used vaccine antigen for specific humoral and cellular immune responses. Immediate early protein 63 (IE63) is expressed during latency, suggesting that it is a potential antigen against HZ reactivation. In this study, HZ DNA vaccines encoding gE, IE63, IE63-2A-gE (where 2A is a self-cleaving sequence), or IE63-linker-gE were developed and investigated for immunogenicity in mice. The results showed that each HZ DNA vaccine induced VZV-specific antibody production. The neutralizing antibody titer elicited by IE63-2A-gE was comparable to that elicited by gE or live attenuated HZ vaccine (LAV). IE63-2A-gE-induced gE or IE63-specific INF-γ+ T cell frequencies in splenocytes were comparable to those of LAV. Furthermore, IE63-2A-gE, gE, or IE63 led to a significant increase in IFN-γ (IE63 stimulation) and IL-2 (gE stimulation) secretion compared to LAV, showing a Th1-biased immune response. Moreover, IE63-2A-gE and gE induced cytotoxic activity of CD8+ T cells compared to that of LAV. This study elucidates that the IE63-2A-gE DNA vaccine can induce both humoral and cell-mediated immune responses, which provides a candidate for the development of an HZ vaccine.

Electron transfer between cytochrome c and microsomal monooxygenase generates reactive oxygen species that accelerates apoptosis.

Generation of reactive oxygen species (ROS) are possibly induced by the crosstalk between mitochondria and endoplasmic reticula, which is physiologically important in apoptosis. Cytochrome c (Cyt c) is believed to play a crucial role in such signaling pathway by interrupting the coupling within microsomal monooxygenase (MMO). In this study, the correlation of ROS production with the electron transfer between Cyt c and the MMO system is investigated by resonance Raman (RR) spectroscopy. Binding of Cyt c to MMO is found to induce the production of ROS, which is quantitatively determined by the in-situ RR spectroscopy reflecting the interactions of Cyt c with generated ROS. The amount of ROS that is produced from isolated endoplasmic reticulum depends on the redox state of the Cyt c, indicating the important role of oxidized Cyt c in accelerating apoptosis. The role of electron transfer from MMO to Cyt c in the apoptotic mitochondria-endoplasmic reticulum pathway is accordingly proposed. This study is of significance for a deeper understanding of how Cyt c regulates apoptotic pathways through the endoplasmic reticulum, and thus may provide a rational basis for the design of antitumor drugs for cancer therapy.

The meningeal lymphatic vessels and the glymphatic system: Potential therapeutic targets in neurological disorders.

The recent discovery of the meningeal lymphatic vessels (mLVs) and glymphatic pathways has challenged the long-lasting dogma that the central nervous system (CNS) lacks a lymphatic system and therefore does not interact with peripheral immunity. This discovery has reshaped our understanding of mechanisms underlying CNS drainage. Under normal conditions, a close connection between mLVs and the glymphatic system enables metabolic waste removal, immune cell trafficking, and CNS immune surveillance. Dysfunction of the glymphatic-mLV system can lead to toxic protein accumulation in the brain, and it contributes to the development of a series of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. The identification of precise cerebral transport routes is based mainly on indirect, invasive imaging of animals, and the results cannot always be applied to humans. Here we review the functions of the glymphatic-mLV system and evidence for its involvement in some CNS diseases. We focus on emerging noninvasive imaging techniques to evaluate the human glymphatic-mLV system and their potential for preclinical diagnosis and prevention of neurodegenerative diseases. Potential strategies that target the glymphatic-mLV system in order to treat and prevent neurological disorders are also discussed.