Iron-inhibited autophagy via transcription factor ZFP27 in Parkinson's disease.

Parkinson's disease (PD) is a challenge because of the ageing of the population and the disease's complicated pathogenesis. Accumulating evidence showed that iron and autophagy were involved in PD. Nevertheless, the molecular mechanism and role of iron and autophagy in PD are not yet elucidated. In the present study, it was shown that PD mice had significant motor dysfunction, increased iron content, less dopamine neurons and more α-synuclein accumulation in the substantia nigra. Meanwhile, PD mice treated with deferoxamine exhibited less iron content, relieved the dyskinesia and had a significant increase in dopamine neurons and a significant decrease in α-synuclein. Autophagy induced by LC3 was inhibited in PD models with iron treatment. Following verification showed that iron aggregation restrained insulin-like growth factor 2 (IGF2) and transcription factor zinc finger protein 27 (ZFP27) in PD models. In addition, LC3-induced autophagy flux was reduced with ZFP27 knockdown. Furthermore, ZFP27 affected autophagy by regulating LC3 promoter activity. These data suggest that iron deposition inhibits IGF2 and ZFP27 to reduce LC3-induced autophagy, and ultimately decrease dopamine neurons, accelerating PD progression. Our findings provide a novel insight that ZFP27-mediated iron-related autophagy and IGF2 may activate the downstream kinase gene to trigger autophagy in the PD model.

Small G protein RAC-2 regulates forgetting via the JNK-1 signalling pathway in Caenorhabditis elegans.

Although forgetting was once regarded as a passive decline in memory and an occasional source of embarrassment, recent research suggests that it is an active biological process of removing outdated or irrelevant memories via activation of specific genes and signal transduction pathways. Rho family G proteins are known to have a role in synaptic plasticity mediated by the actin cytoskeleton. However, the current study reveals that another Rho guanosine triphosphate enzyme (GTPase), RAC-2, facilitates the occurrence of forgetting in Caenorhabditis elegans independent of actin dynamics. Functioning downstream of RAC-2 in the same signalling pathway, JNK-1 and its phosphorylated protein are required to positively regulate forgetting. The pan-neuronal rescue of RAC-2 or JNK-1, instead of AWC neuron-specific expression, reverses the delayed forgetting caused by the rac-2 mutation, which indicates that the involvement of RAC-2/JNK-1 in more than AWCs must be required. In summary, our work elucidates the action of the Rho GTPase RAC-2 and downstream JNK-1 as a potential novel pathway in forgetting in C. elegans.

A trade-off switch of two immunological memories in Caenorhabditis elegans reinfected by bacterial pathogens.

Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories.

TNIP1-mediated TNF-α/NF-κB signalling cascade sustains glioma cell proliferation.

As a malignant tumour of the central nervous system, glioma exhibits high incidence and poor prognosis. Although TNIP1 and the TNF-α/NF-κB axis play key roles in immune diseases and inflammatory responses, their relationship and role in glioma remain unknown. Here, we revealed high levels of TNIP1 and TNF-α/NF-κB in glioma tissue. Glioma cell proliferation was activated with TNF-α treatment and showed extreme sensitivity to the TNF receptor antagonist. Furthermore, loss of TNIP1 disbanded the A20 complex responsible for IκB degradation and NF-κB nucleus translocation, and consequently erased TNFα-induced glioma cell proliferation. Thus, our investigation uncovered a vital function of the TNIP1-mediated TNF-α/NF-κB axis in glioma cell proliferation and provides novel insight into glioma pathology and diagnosis.

Combined use of murine double minute-2 promoter methylation and serum AFP improves diagnostic efficiency in hepatitis B virus-related hepatocellular carcinoma.

Objective: Hepatocellular carcinoma (HCC) accounts for approximately 85% of all cases of liver cancer. In China, chronic hepatitis B virus-related HCC (HBV-related HCC) is the most common type of HCC. However, the majority of HBV-related HCC patients are asymptomatic, and the best opportunities for treating these patients are missed. The precise diagnosis of HBV-related HCC is crucial. The main purpose of this study was to evaluate the diagnostic value of murine double minute-2 (MDM2) promoter methylation in HBV-related HCC patients. Methods: The methylation status of the MDM2 promoter was detected by methylation-specific PCR. The MDM2 expression levels were validated by quantitative real-time PCR. Enzyme-linked immunosorbent assay was used to determine the levels of interleukin-6 (IL-6) and tumor-necrosis factor-α (TNF-α) in plasma. Results: The methylation frequency of the MDM2 promoter was decreased in HBV-related HCC patients. The MDM2 mRNA levels of patients with HBV-related HCC were higher than those of patients with liver cirrhosis and chronic hepatitis B. The plasma levels of IL-6 and TNF-α were significantly higher in HBV-related HCC patients than that in liver cirrhosis and chronic hepatitis B patients. The TNF-α levels were higher in the unmethylated MDM2 promoter group than in the methylated MDM2 promoter group in HBV-related HCC patients. Moreover, the combination of MDM2 promoter methylation and alpha-fetoprotein (AFP) improved the diagnosis of HBV-related HCC. Conclusions: Our study indicates, for the first time, that MDM2 promoter hypomethylation is present in HBV-related HCC patients. The combination of MDM2 promoter methylation and AFP can greatly improve diagnostic efficiency in HBV-related HCC, which might provide a new method for HBV-related HCC diagnosis.

Gastrodin protects dopaminergic neurons via insulin-like pathway in a Parkinson's disease model.

BACKGROUND: Recently, the use of traditional Chinese medicine (TCM) has become more generally accepted, including by the Food and Drug Administration. To expand the use of TCM worldwide, it is important to study the molecular mechanisms by which TCM and its active ingredients produce effects. Gastrodin is an active ingredient from Gastrodia elata Blume. It is reported that gastrodin has neuroprotective function in Parkinson's disease. But its mechanisms of neuroprotection remain not clear in PD. Here, we build two C. elegans PD model using 6-OHDA and transgenic animal to observe the changes of PD worms treated with or without gastrodin to confirm the function of gastrodin, then utilize mutant worms to investigate DAF-2/DAF-16 signaling pathway, and finally verify the mechanism of gastrodin in PD. RESULTS: Gastrodin attenuates the accumulation of α-synuclein and the injury of dopaminergic neurons, improves chemotaxis behavior in Parkinson's disease models, then recovers chemotaxis behavior by insulin-like pathway. DAF-2/DAF-16 is required for neuroprotective effect of dopamine neuron in PD. CONCLUSIONS: Our study demonstrated that gastrodin rescued dopaminergic neurons and reduced accumulation of α-synuclein protein, and the activity of gastrodin against Parkinson's disease depended on the insulin-like DAF-2/DAF-16 signaling pathway. Our findings revealed that this insulin-like pathway mediates neuroprotection of gastrodin in a Parkinson's disease model.

The Signaling Pathway of Caenorhabditis elegans Mediates Chemotaxis Response to the Attractant 2-Heptanone in a Trojan Horse-like Pathogenesis.

The nematode Caenorhabditis elegans exhibits behavioral responses to a wide range of odorants associated with food and pathogens. A previous study described a Trojan Horse-like strategy of pathogenesis whereby the bacterium Bacillus nematocida B16 emits the volatile organic compound 2-heptanone to trap C. elegans for successful infection. Here, we further explored the receptor for 2-heptanone as well as the pathway involved in signal transduction in C. elegans Our experiments showed that 2-heptanone sensing depended on the function of AWC neurons and a GPCR encoded by str-2 Consistent with the above observation, the HEK293 cells expressing STR-2 on their surfaces showed a transient elevation in intracellular Ca2+ levels after 2-heptanone applications. After combining the assays of RNA interference and gene mutants, we also identified the Gα subunits and their downstream components in the olfactory signal cascade that are necessary for responding to 2-heptanone, including Gα subunits of egl-30 and gpa-3, phospholipase C of plc-1and egl-8, and the calcium channel of cmk-1 and cal-1. Our work demonstrates for the first time that an integrated signaling pathway for 2-heptanone response in C. elegans involves recognition by GPCR STR-2, activation by Gα subunits of egl-30/gpa-3 and transfer to the PLC pathway, indicating that a potentially novel olfactory pathway exists in AWC neurons. Meanwhile, since 2-heptanone, a metabolite from the pathogenic bacterium B. nematocida B16, can be sensed by C. elegans and thus strongly attract its host, our current work also suggested coevolution between the pathogenic microorganism and the chemosensory system in C. elegans.

A novel role for the alcohol sensitive ring/PHD finger protein Asr1p in regulating cell cycle mediated by septin-dependent assembly in yeast.

Septin is a conserved eukaryotic family of GTP-binding filament-forming proteins with functions in cytokinesis and other processes. It has been suggested that the dynamic assembly of septin, including the processes from septin initially localizing to the presumptive bud site to the septin collar finally splitting into two cells, coordinates closely with the checkpoint response of cell cycle. Here, we discovered that over-expression of Alcohol sensitive Ring/PHD finger 1 protein (Asr1p) in Saccharomyces cerevisiae triggered the Swe1p-dependent cell cycle checkpoint for a G2/M transition delay, and this G2/M transition delay was caused by the septin defect. Since it was shown that Asr1p affected actin dynamics through the interaction with Crn1p and crn1 should be epistatic to asr1 in the regulation of actin, the gene knockout of crn1 in the Asr1p over-expression strain restored the defects in septin and cell cycle along with the disordered actin dynamics. Our investigation further showed that the disturbed septin assembly caused by abnormal Asr1p lead to the abnormal localization of the checkpoint proteins such as Gla4/PAK and Cdc5/Polo, and finally triggered the Swe1p-dependent G2/M transition arrest. Additionally, the Ring finger/PHD domains of Asr1p were illustrated to be required but not sufficient for its role in septin. Taken together, our current data suggested a close relationship in the assembly between septin and actin cytoskeleton, which also partially explained how actin cytoskeleton participated in the regulation of the checkpoint of G2/M.

Single-stage correction of severe scoliosis with syringomyelia: performed with traction assistance without prophylactic neurosurgical decompression.

OBJECTIVE: There is still controversy about whether it is necessary to perform prophylactic neurosurgical decompression for severe scoliosis (SS) with syringomyelia (SM) to reduce the risk of neurological complications during subsequent spinal correction. This study aimed to explore the safety and effectiveness of using traction-assisted single-stage spinal correction as a treatment for patients who had SS with SM (SS-SM). METHODS: The patients who had SS-SM without previous neurosurgical intervention and who underwent traction-assisted single-stage posterior spinal correction at a single center were included, and the initial, posttraction, and postoperative clinical data were reviewed. Based on preoperative MRI, the included patients were divided into two categories: those with versus those without Chiari malformation type I (CM-I-related SM [CS] vs idiopathic SM [IS]), and those with a moderate syrinx (MS) versus those with a large syrinx (LS). Different groups' traction and operation contributions were calculated for comparisons (CS vs IS, MS vs LS). RESULTS: A total of 28 patients were included. The initial mean major scoliosis was 101.0° with a mean flexibility of 21.4%. After the operation, the mean total correction rate for scoliosis was 63.9%. The mean traction and operation contributions were 61.5% and 38.5%, respectively. Most of the patients (75%) underwent spinal corrections without 3-column osteotomies, and only 1 patient reported postoperative regional numbness without motor deficits. No differences were found in the mean total correction rates, traction, and operation contributions when comparing CS versus IS and MS versus LS with the comparable initial clinical data (p > 0.05). More than 50% of the total corrections were achieved by preoperative traction in all groups. CONCLUSIONS: Traction-assisted single-stage spinal correction can safely and effectively correct SS-SM without prophylactic neurosurgical decompression under strict patient selection. Additionally, traction can achieve more than half of the final spinal correction, even for patients with varying sizes of SMs.

Valeric acid reduction by chitosan oligosaccharide induces autophagy in a Parkinson's disease mouse model.

Parkinson's disease (PD) is a central nervous system disease with the highest disability and mortality rate worldwide, and it is caused by a variety of factors. The most common medications for PD have side effects with limited therapeutic outcomes. Many studies have reported that chitosan oligosaccharide (COS) crossed blood-brain barrier to achieve a neuroprotective effect in PD. However, the role of COS in PD remains unclear. The present study demonstrated that COS increased dopaminergic neurons in the substantia nigra (SN) and ameliorated dyskinesia in a PD mouse model. Moreover, COS reduced gut microbial diversity and faecal short-chain fatty acids. Valeric acid supplementation enhanced the inflammatory response in the colon and SN, and it reversed COS - suppressed dopamine neurons damage. Autophagy was involved in COS modulating inflammation through valeric acid. These results suggest that COS reduces bacterial metabolites - valeric acid, which diminishes inflammation via activating autophagy, ultimately alleviating PD.

Chitosan alleviates symptoms of Parkinson's disease by reducing acetate levels, which decreases inflammation and promotes repair of the intestinal barrier and blood-brain barrier.

ABSTRACT: Studies have shown that chitosan protects against neurodegenerative diseases. However, the precise mechanism remains poorly understood. In this study, we administered chitosan intragastrically to an MPTP-induced mouse model of Parkinson's disease and found that it effectively reduced dopamine neuron injury, neurotransmitter dopamine release, and motor symptoms. These neuroprotective effects of chitosan were related to bacterial metabolites, specifically short-chain fatty acids, and chitosan administration altered intestinal microbial diversity and decreased short-chain fatty acid production in the gut. Furthermore, chitosan effectively reduced damage to the intestinal barrier and the blood-brain barrier. Finally, we demonstrated that chitosan improved intestinal barrier function and alleviated inflammation in both the peripheral nervous system and the central nervous system by reducing acetate levels. Based on these findings, we suggest a molecular mechanism by which chitosan decreases inflammation through reducing acetate levels and repairing the intestinal and blood-brain barriers, thereby alleviating symptoms of Parkinson's disease.

Intergenerational epigenetic inheritance mediated by MYS-2/MOF in the pathogenesis of Alzheimer's disease.

Although autosomal-dominant inheritance is believed an important cause of familial clustering Alzheimer's disease (FAD), it covers only a small proportion of FAD incidence, and so we investigated epigenetic memory as an alternative mechanism to contribute for intergenerational AD pathogenesis. Our data in vivo showed that mys-2 of Caenorhabditis elegans that encodes a putative MYST acetyltransferase responsible for H4K16 acetylation modulated AD occurrence. The phenotypic improvements in the parent generation caused by mys-2 disfunction were passed to their progeny due to epigenetic memory, which resulted in similar H4K16ac levels among the candidate target genes of MYS-2 and similar gene expression patterns of the AD-related pathways. Furthermore, the ROS/CDK-5/ATM pathway functioned as an upstream activator of MYS-2. Our study indicated that MYS-2/MOF could be inherited intergenerationally via epigenetic mechanisms in C. elegans and mammalian cell of AD model, providing a new insight into our understanding of the etiology and inheritance of FAD.

PD-Like Pathogenesis in Caenorhabditis elegans Intestinally Infected with Nocardia farcinica and the Underlying Molecular Mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the abnormal aggregation of α-synuclein (α-syn) and the loss of dopaminergic neurons. Although microbial infection has been implicated in the pathogenesis of PD, the associated virulence factors and the underlying molecular mechanisms require further elucidation. Here, we found that intestinal infection with Nocardia farcinica induced a series of PD-like symptoms in Caenorhabditis elegans, such as the accelerated degeneration of dopaminergic neurons, impaired locomotion capacity, and enhanced α-syn aggregation, through the disturbance of mitochondrial functions. To identify the potential virulence factors involved in these effects, we knocked out the nbtB/C and nbtS genes in N. farcinica, which are localized in the gene clusters responsible for nocobactin biosynthesis. The deletion of either gene partially rescued the degenerative effects of wild-type N. farcinica on dopaminergic neurons by attenuating mitochondrial dysfunction. LC-MS analysis further identified a decrease in the abundance of several siderophores in the two mutants, including nocobactin NA-a, nocobactin NA-b, and nocardimicin B. Collectively, our results demonstrated that intestinal N. farcinica infection in C. elegans facilitates PD-like pathogenesis and provides novel evidence for the involvement of pathogenic bacteria in neurodegenerative diseases via non-neuroinvasive mechanisms.

[An approach for the measurement of the surface area of scalp flap over the cranial defect after decompressive craniectomy].

OBJECTIVE: To introduce a simple, fast and universal measuring method used in measurement of the surface area of scalp flap over the cranial defect after decompressive craniectomy. METHODS: The first step: CT images of the patient with craniocerebral trauma after decompressive craniectomy were obtained and imported into Mimics. The second step: based on the defined threshold, the 3D geometric models of brain and skull were reconstructed after the original Dicom format pictures three-dimensional processed by Mimics. The third step: based on the two builded 3D models, utilizing the segmentation and measurement tools of Mimics to conduct cutting, splitting and measuring operations for the 3D model of brain. The forth step: estimating the surface area of scalp flap over the removed bone flap by using mathematical computation methods. RESULTS: The application of the introduced method estimated the surface area of scalp flap over the cranial defect of different people with different position of craniocerebral trauma. CONCLUSIONS: This paper introduces a simple, fast and universal new measuring method. We can conveniently estimate the surface area of scalp flap by using the introduced method.

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 acts as a protein kinase to regulate glioblastoma progression by activating the AKT/forkhead box O1 pathway.

Abnormal expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) is closely related to the occurrence and development of tumors, and PFKFB4 has been shown to function as a protein kinase. However, the molecular mechanisms through which PFKFB4 functions in glioblastoma (GBM) remain poorly understood. Accordingly, in this study, we assessed the roles of PFKFB4 in GBM. Compared to in adjacent tissues, PFKFB4 was highly expressed in GBM, and its expression level was negatively correlated with the overall survival time. In addition, knockdown of PFKFB4 inhibited the proliferation and invasion of GBM cells and promoted apoptosis. In a xenograft tumor model, tumor growth was inhibited by knockdown of PFKFB4 using short hairpin RNA. Further studies demonstrated that PFKFB4 is involved in regulating the AKT signaling pathway. Thus, PFKFB4 acts as a protein kinase to regulate GBM progression by activating the AKT/forkhead box O1 pathway, which may be a potential therapeutic target in GBM.

Protective Effects of Polysaccharides in Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are characterized by progressive degeneration and necrosis of neurons, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease and others. There are no existing therapies that correct the progression of these diseases, and current therapies provide merely symptomatic relief. The use of polysaccharides has received significant attention due to extensive biological activities and application prospects. Previous studies suggest that the polysaccharides as a candidate participate in neuronal protection and protect against NDs. In this review, we demonstrate that various polysaccharides mediate NDs, and share several common mechanisms characterized by autophagy, apoptosis, neuroinflammation, oxidative stress, mitochondrial dysfunction in PD and AD. Furthermore, this review reveals potential role of polysaccharides in vitro and in vivo models of NDs, and highlights the contributions of polysaccharides and prospects of their mechanism studies for the treatment of NDs. Finally, we suggest some remaining questions for the field and areas for new development.

Comprehensive analysis of m6A/m5C/m1A-related gene expression, immune infiltration, and sensitivity of antineoplastic drugs in glioma.

This research aims to develop a prognostic glioma marker based on m6A/m5C/m1A genes and investigate the potential role in the tumor immune microenvironment. Data for patients with glioma were downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA). The expression of genes related to m6A/m5C/m1A was compared for normal and glioma groups. Gene Ontology and Kyoto Encyclopedia of Genes and Gene enrichment analysis of differentially expressed genes were conducted. Consistent clustering analysis was performed to obtain glioma subtypes and complete the survival analysis and immune analysis. Based on TCGA, Lasso regression analysis was used to obtain a prognostic model, and the CGGA database was used to validate the model. The model-based risk scores and the hub genes with the immune microenvironment, clinical features, and antitumor drug susceptibility were investigated. The clinical glioma tissues were collected to verify the expression of hub genes via immunohistochemistry. Twenty genes were differentially expressed, Consensus cluster analysis identified two molecular clusters. Overall survival was significantly higher in cluster 2 than in cluster 1. Immunological analysis revealed statistically significant differences in 26 immune cells and 17 immune functions between the two clusters. Enrichment analysis detected multiple meaningful pathways. We constructed a prognostic model that consists of WTAP, TRMT6, DNMT1, and DNMT3B. The high-risk and low-risk groups affected the survival prognosis and immune infiltration, which were related to grade, gender, age, and survival status. The prognostic value of the model was validated using another independent cohort CGGA. Clinical correlation and immune analysis revealed that four hub genes were associated with tumor grade, immune cells, and antitumor drug sensitivity, and WTAP was significantly associated with microsatellite instability(MSI). Immunohistochemistry confirmed the high expression of WTAP, DNMT1, and DNMT3B in tumor tissue, but the low expression of TRMT6. This study established a strong prognostic marker based on m6A/m5C/m1A methylation regulators, which can accurately predict the prognosis of patients with gliomas. m6A/m5C/m1A modification mode plays an important role in the tumor microenvironment, can provide valuable information for anti-tumor immunotherapy, and have a profound impact on the clinical characteristics.

An Intracranial Tuberculoma with Discharging Scalp Sinus.

Our report highlights a case of intracranial tuberculoma in an elderly woman with chronic discharging sinus. A 77-year-old woman had a mass lesion extending to the scalp through a chronic discharging sinus for 2 years with an intermittent, non-radiating, dull, low-grade headache. Based on our survey of central nervous system tuberculosis, this case is a rare event of documented intracranial tuberculoma with concomitant discharge of the scalp sinus similar to the periodic geyser eruptions in developing countries.

PD-1 Involvement in Peripheral Blood CD8+ T Lymphocyte Dysfunction in Patients with Acute-on-chronic Liver Failure.

BACKGROUND AND AIMS: Programmed cell death-1 (PD-1) plays an important role in downregulating T lymphocytes but the mechanisms are still poorly understood. This study aimed to explore the role of PD-1 in CD8+ T lymphocyte dysfunction in hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). METHODS: Thirty patients with HBV-ACLF and 30 healthy controls (HCs) were recruited. The differences in the numbers and functions of CD8+ T lymphocytes, PD-1 and glucose transporter-1 (Glut1) expression from the peripheral blood of patients with HBV-ACLF and HCs were analyzed. In vitro, the CD8+ T lymphocytes from HCs were cultured (HC group) and the CD8+ T lymphocytes from ACLF patients were cultured with PD-L1-IgG (ACLF+PD-1 group) or IgG (ACLF group). The numbers and functions of CD8+ T lymphocytes, PD-1 expression, glycogen uptake capacity, and Glut1, hexokinase-2 (HK2), and pyruvate kinase (PKM2) expression were analyzed among the HC group, ACLF group and ACLF+ PD-1group. RESULTS: The absolute numbers of CD8+ T lymphocytes in the peripheral blood from patients with HBV-ACLF were lower than in the HCs (p<0.001). The expression of PD-1 in peripheral blood CD8+ T lymphocytes was lower in HCs than in patients with HBV-ACLF (p=0.021). Compared with HCs, PD-1 expression was increased (p=0.021) and Glut1 expression was decreased (p=0.016) in CD8+ T lymphocytes from the HBV-ACLF group. In vitro, glycogen uptake and functions of ACLF CD8+ T lymphocytes were significantly lower than that in HCs (p=0.017; all p<0.001). When PD-1/PD-L1 was activated, the glycogen uptake rate and expression levels of Glut1, HK2, and PKM2 showed a decreasing trend (ACLF+PD-1 group compared to ACLF group , all p<0.05). The functions of CD8+ T lymphocytes in the ACLF+PD-1 group [using biomarkers of Ki67, CD69, IL-2, interferon-gamma, and tumor necrosis factor-alpha- were lower than in the ACLF group (all p<0.05). CONCLUSIONS: CD8+ T lymphocyte dysfunction is observed in patients with HBV-ACLF. PD-1-induced T lymphocyte dysfunction might involve glycolysis inhibition.

Multiple olfactory pathways contribute to the lure process of Caenorhabditis elegans by pathogenic bacteria.

Chemosensation is indispensable for the survival of Caenorhabditis elegans to discriminate food and pathogenic bacteria in their living environment. Food-like odors emitted by the pathogen Bacillus nematocida B16 for trapping its hosts and an olfactory signaling pathway responsible to sense the attractant 2-heptanone were identified in our previous study. Here, we further explore how the worms recognize the attractive molecules indole and 2-ethyl hexanol, which have different chemical properties and modest nematode-luring ability. We show that the chemotaxis toward indole and 2-ethyl hexanol requires the G protein-coupled receptors encoded by str-193 on AWC and str-7 on AWA. In a further genetic screen for downstream effectors in olfactory signaling cascades, the Gα subunit GSA-1, guanylyl cyclase ODR-1 and DAF-11 and the cGMP-gated channel TAX-2/TAX-4 were found to be necessary for indole sensation, whereas the TRPV channels OSM-9/OCR-2 and the PLC pathway activated by GPA-6 are responsible for the detection of 2-ethyl hexanol. Altogether, our current work further clarifies the distinct olfactory signaling pathways through which C. elegans senses different chemicals and is lured by B. nematocida B16, improving our comprehensive understanding of the mechanisms by which bacterial pathogens effectively infect their hosts.