The phenotype and prediction of long-term physical, mental and cognitive COVID-19 sequelae 20 months after recovery, a community-based cohort study in China.

Long-term sequelae clustering phenotypes are important for precise health care management in COVID-19 survivors. We reported findings for 1000 survivors 20 months after diagnosis of COVID-19 in a community-based cohort in China. Sequelae symptoms were collected from a validated questionnaire covering 27 symptoms involved in five organ systems including self-reported physical condition, dyspnea, cognitive function and mental health. The generalized symptoms were reported with the highest rate (60.7%), followed by the mental (48.3%), cardiopulmonary (39.8%), neurological (37.1%; cognitive impairment, 15.6%), and digestive symptoms (19.1%). Four clusters were identified by latent class analysis: 44.9% no or mild group (cluster 1), 29.2% moderate group with mainly physical impairment (cluster 2), 9.6% moderate group with mainly cognitive and mental health impairment (cluster 3), and 16.3% severe group (cluster 4). Physical comorbidities or history of mental disorders, longer hospitalization periods and severe acute illness predicted severe group. For moderate group, adults less than 60 years, with physical comorbidities and severe acute illness were more likely to have physical symptoms, while adult women with longer hospitalization stays had increased risk of cognitive and mental health impairment. Overall, among more than half of community COVID-19 survivors who presented moderate or severe sequelae 20 months after recovery, three-tenth had physical vulnerability that may require physical therapy aiming to improve functioning, one-tenth mental or cognitive vulnerable cases need psychotherapy and cognitive rehabilitation, and one-sixth severe group needs multidisciplinary clinical management. The remaining half is free to clinical intervention. Our findings introduced an important framework to map numerous symptoms to precise classification of the clinical sequelae phenotype and provide information to guide future stratified recovery interventions.

The miR-29 family members induce glioblastoma cell apoptosis by targeting cell division cycle 42 in a p53-dependent manner.

BACKGROUND: Emerging evidence has shown that miR-29 is a promising biomarker and therapeutic target for malignancies. The roles of miR-29a/b/c in glioma pathogenesis remain need further investigation. METHODS: The expression levels of miR-29a/b/c and CDC42 were systematically analysed, and prognostic significance was evaluated by Kaplan-Meier survival and Cox regression analyses. The roles of miR-29a/b/c in apoptosis and the underlying mechanisms were explored via an alkaline single-cell gel electrophoresis assay, caspase 3/7 activity assays and Western blotting. RESULTS: miR-29a/b/c expression decreased progressively with the elevation of the WHO grade in our 147 human glioma specimens, compared with 20 non-tumour control brain tissues, and decreased miR-29a/b/c expression was associated with more aggressive phenotypes. Kaplan-Meier and Cox regression analyses demonstrated that lower miR-29a/b/c expression was correlated with worse prognosis, which was confirmed by analysis of 198 glioma patients from the CGGA cohort. These all indicate that miR-29a/b/c were independent predictors of prognosis in glioma patients. miR-29a/b/c induced apoptosis in GBM cells by silencing CDC42. Further detailed mechanistic investigation revealed that miR-29a/b/c promoted apoptosis in a p53-dependent manner by suppressing the CDC42/PAK/AKT/MDM2 pathway. CONCLUSIONS: miR-29a/b/c are independent predictors of prognosis in glioma patients. They induce glioblastoma cell apoptosis via silencing of CDC42 and suppression of downstream PAK/AKT/MDM2 signalling in a p53-dependent manner.

miR-135a-5p Functions as a Glioma Proliferation Suppressor by Targeting Tumor Necrosis Factor Receptor-Associated Factor 5 and Predicts Patients' Prognosis.

miR-135a-5p has been reported as a tumor suppressor in several extracranial tumors. However, its exact roles in gliomagenesis and relevance to the patients' prognoses are largely unknown. Herein, we detected the miR-135a-5p and tumor necrosis factor receptor-associated factor 5 (TRAF5) levels in 120 human glioma specimens and 20 nontumoral brain tissues; we found the miR-135a-5p level decreased, whereas the TRAF5 level increased, with the elevation of glioma grade. Their labeling indexes were inversely correlated with each other and showed strong negative (miR-135a-5p) and positive (TRAF5) correlation with the Ki-67 index. Cox regression demonstrated that both of their expression levels were independent survival predictors, whereas Kaplan-Meier analysis showed that subgrouping the glioma patients according to their levels could perfectly reflect the patients' prognoses regardless of the similarities in pathologic, molecular, and clinical features. In the following in vitro and in vivo studies, it was demonstrated that miR-135a-5p induced G1 arrest and inhibited the proliferation of glioma cells by targeting TRAF5 and subsequently blocking AKT phosphorylation as well as c-Myc and cyclin D1 expression. These effects could be reversed by TRAF5 overexpression and simulated by specific TRAF5 silencing. This study highlights the importance of miR-135a-5p and TRAF5 in gliomagenesis and progression and implies their potential prognostic and therapeutic values in malignant glioma.

Comparative Proteomic Analysis of Posterior Silk Glands of Wild and Domesticated Silkworms Reveals Functional Evolution during Domestication.

The wild silkworm Bombyx mandarina was domesticated to produce silk in China approximately 5000 years ago. Silk production is greatly improved in the domesticated silkworm B. mori, but the molecular basis of the functional evolution of silk gland remains elusive. We performed shotgun proteomics with label-free quantification analysis and identified 1012 and 822 proteins from the posterior silk glands (PSGs) of wild silkworms on the third and fifth days of the fifth instar, respectively, with 128 of these differentially expressed. Bioinformatics analysis revealed that, with the development of the PSG, the up-regulated proteins were mainly involved in the ribosome pathway, similar to what we previously reported for B. mori. Additionally, we screened 50 proteins with differential expression between wild and domesticated silkworms that might be involved in domestication at the two stages. Interestingly, the up-regulated proteins in domesticated compared to wild silkworms were enriched in the ribosome pathway, which is closely related to cell size and translation capacity. Together, these results suggest that functional evolution of the PSG during domestication was driven by reinforcing the advantageous pathways to increase the synthesis efficiency of silk proteins in each cell and thereby improve silk yield.

Effect of distribution of nasal polyps in ostiomeatal complex on long-term outcomes after endoscopic surgery.

The objective of the study was to elucidate the characteristics of spatial distribution of nasal polyps in the ostiomeatal complex (OMC) and the corresponding correlation with long-term quality of life in patients who underwent endoscopic sinus surgery. 107 patients with unilateral or bilateral nasal polyps who had undergone functional endoscopic sinus surgery from September 2009 to June 2010 were enrolled in this study. Distribution of nasal polyps in the study subjects was documented. Long-term quality of life assessment was carried out at 1-year after surgery by SNOT-20 analysis. Observation of a total of 214 sides of rhinal cavities revealed that nasal polyps were distributed inside the OMC at 573 sites out of the total 635 sites (90.2 %), and predominantly distributed at the middle turbinate, the ethmoid sinus, the middle meatus, the uncinate process, the maxillary sinus, and the ethmoid bulla and significantly differed from the nasal polyps which were found outside the OMC (P < 0.01). Statistical analysis indicated that pre-operative Sinonasal Outcome Test 20 (SNOT-20) scores and 1-year post-operative scores were statistically significant (P < 0.05). The score changes of the left maxillary sinus, both sides ethmoid bulla were significant, respectively (P < 0.05). Nasal polyps predominantly distribute in the OMC. The differences among the sites of nasal polyps do not significantly impact the long-term score for quality of life except for the maxillary sinus and ethmoid bulla.

Metabolomics identifies and validates serum androstenedione as novel biomarker for diagnosing primary angle closure glaucoma and predicting the visual field progression.

Background: Primary angle closure glaucoma (PACG) is the leading cause of irreversible blindness in Asia, and no reliable, effective diagnostic, and predictive biomarkers are used in clinical routines. A growing body of evidence shows metabolic alterations in patients with glaucoma. We aimed to develop and validate potential metabolite biomarkers to diagnose and predict the visual field progression of PACG. Methods: Here, we used a five-phase (discovery phase, validation phase 1, validation phase 2, supplementary phase, and cohort phase) multicenter (EENT hospital, Shanghai Xuhui Central Hospital), cross-sectional, prospective cohort study designed to perform widely targeted metabolomics and chemiluminescence immunoassay to determine candidate biomarkers. Five machine learning (random forest, support vector machine, lasso, K-nearest neighbor, and GaussianNaive Bayes [NB]) approaches were used to identify an optimal algorithm. The discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC). Calibration was assessed by Hosmer-Lemeshow tests and calibration plots. Results: Studied serum samples were collected from 616 participants, and 1464 metabolites were identified. Machine learning algorithm determines that androstenedione exhibited excellent discrimination and acceptable calibration in discriminating PACG across the discovery phase (discovery set 1, AUCs=1.0 [95% CI, 1.00-1.00]; discovery set 2, AUCs = 0.85 [95% CI, 0.80-0.90]) and validation phases (internal validation, AUCs = 0.86 [95% CI, 0.81-0.91]; external validation, AUCs = 0.87 [95% CI, 0.80-0.95]). Androstenedione also exhibited a higher AUC (0.92-0.98) to discriminate the severity of PACG. In the supplemental phase, serum androstenedione levels were consistent with those in aqueous humor (r=0.82, p=0.038) and significantly (p=0.021) decreased after treatment. Further, cohort phase demonstrates that higher baseline androstenedione levels (hazard ratio = 2.71 [95% CI: 1.199-6.104], p=0.017) were associated with faster visual field progression. Conclusions: Our study identifies serum androstenedione as a potential biomarker for diagnosing PACG and indicating visual field progression. Funding: This work was supported by Youth Medical Talents - Clinical Laboratory Practitioner Program (2022-65), the National Natural Science Foundation of China (82302582), Shanghai Municipal Health Commission Project (20224Y0317), and Higher Education Industry-Academic-Research Innovation Fund of China (2023JQ006).

Brain abnormalities in survivors of COVID-19 after 2-year recovery: a functional MRI study.

Background: A variety of symptoms, particularly cognitive, psychiatric and neurological symptoms, may persist for a long time among individuals recovering from COVID-19. However, the underlying mechanism of these brain abnormalities remains unclear. This study aimed to investigate the long-term neuroimaging effects of COVID-19 infection on brain functional activities using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Fifty-two survivors 27 months after infection (mild-moderate group: 25 participants, severe-critical: 27 participants), from our previous community participants, along with 35 healthy controls, were recruited to undergo fMRI scans and comprehensive cognitive function measurements. Participants were evaluated by subjective assessment of Cognitive Failures Questionnaire-14 (CFQ-14) and Fatigue Scale-14 (FS-14), and objective assessment of Montreal Cognitive Assessment (MoCA), N-back, and Simple Reaction Time (SRT). Each had rs-fMRI at 3T. Measures such as the amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and regional homogeneity (ReHo) were calculated. Findings: Compared with healthy controls, survivors of mild-moderate acute symptoms group and severe-critical group had a significantly higher score of cognitive complains involving cognitive failure and mental fatigue. However, there was no difference of cognitive complaints between two groups of COVID-19 survivors. The performance of three groups was similar on the score of MoCA, N-back and SRT. The rs-fMRI results showed that COVID-19 survivors exhibited significantly increased ALFF values in the left putamen (PUT.L), right inferior temporal gyrus (ITG.R) and right pallidum (PAL.R), while decreased ALFF values were observed in the right superior parietal gyrus (SPG.R) and left superior temporal gyrus (STG.L). Additionally, decreased ReHo values in the right precentral gyrus (PreCG.R), left postcentral gyrus (PoCG.L), left calcarine fissure and surrounding cortex (CAL.L) and left superior temporal gyrus (STG.L). Furthermore, significant negative correlations between the ReHo values in the STG.L, and CFQ-14 and mental fatigue were found. Interpretation: This long-term study suggests that individuals recovering from COVID-19 continue to experience cognitive complaints, psychiatric and neurological symptoms, and brain functional alteration. The rs-fMRI results indicated that the changes in brain function in regions such as the putamen, temporal lobe, and superior parietal gyrus may contribute to cognitive complaints in individuals with long COVID even after 2-year infection. Funding: The National Programs for Brain Science and Brain-like Intelligence Technology of China, the National Natural Science Foundation of China, Natural Science Foundation of Beijing Municipality of China, and the National Key Research and Development Program of China.

Proteome analysis of silkworm, Bombyx mori, larval gonads: characterization of proteins involved in sexual dimorphism and gametogenesis.

Sexual dimorphism is initialed by the components of the sex determination pathway and is most evident in gonads and germ cells. Although striking dimorphic expressions have been detected at the transcriptional level between the silkworm larval testis and the ovary, the sex-dimorphic expressions at the protein level have not yet been well characterized. The proteome of silkworm larval gonads was investigated using a shotgun-based identification. A total of 286 and 205 nonredundant proteins were identified from the silkworm testis and ovary, respectively, with a false discovery rate (FDR) lower than 1%. Only 40 and 16 proteins were previously identified, and 246 and 189 proteins were newly identified in the silkworm testis and the ovary, respectively. The gametogenesis mechanism of silkworm was demonstrated using the protein expression profile and bioinformatics analysis. Cellular retinoic acid binding protein (CRABP) showed to be highly abundant in testis, while tubulins were abundant in ovary. Several homologies of Drosophila essential proteins for gametogenesis were identified in silkworm, such as male meiotic arrest gene product ALY and VISMAY in testis, and maternal mRNA localization protein exuperantia and SQUID in ovary. The gene ontology (GO) annotation and pathway analysis provide system-level insights into the sexual dimorphism and gametogenesis.

An Effective Strategy to Synthesize Well-Designed Activated Carbon Derived from Coal-Based Carbon Dots via Oxidation before Activation with a Low KOH Content as Supercapacitor Electrodes.

The development of coal-based activated carbon for supercapacitors provides a robust and effective approach toward the clean and efficient use of coal, and it also offers high-quality and low-cost raw materials for energy storage devices. However, the one-step activation method for preparing coal-based activated carbon has problems, such as difficulty in introducing surface-functional groups and high KOH dosage. In our work, activated carbon was prepared through an effective strategy of oxidation and KOH activation with a low KOH content by employing coal-based carbon dots as raw material. The influence of temperature during the KOH activation of carbon dots on a specific surface area, pore structure, and various quantities and types of surface-functional groups, as well as on the electrochemical performance of supercapacitors, was systematically studied. The as-prepared sample, with the alkali-carbon ratio of 0.75, processes a large specific surface area (1207 m2 g-1) and abundant surface-functional groups, which may provide enormous active sites and high wettability, thus bringing in high specific capacitance and boosted electrochemical performances. The oxygen and nitrogen content of the activated carbon decreases while the carbon content increases, and the activation temperature also increases. The as-prepared activated carbon reaches the highest specific capacitance of 202.2 F g-1 in a 6 M KOH electrolyte at a current density of 10 A g-1. This study provides new insight into the design of high-performance activated carbon and new avenues for the application of coal-based carbon dots.

Foldable and wearable supercapacitors for powering healthcare monitoring applications with improved performance based on hierarchically co-assembled CoO/NiCo networks.

Small-scale and high-performance energy storage devices have drawn tremendous attention with their portable, lightweight, and multi-functionalized features. Here, we present a foldable supercapacitor with affordable flexibility by adopting a developed design and electrode material system as a way to extend usability. Notably, to resolve the limited energy density of conventional capacitors, we successfully synthesize the CoO/NiCo-layered double hydroxide (LDH) core-shell nanostructure on Ni framework as a cathode material. Further, glucose-based activated carbon (GBAC) is utilized for the anode. The CoO/NiCo-LDH electrodes exhibited a high specific capacitance of âˆ¼284.8 mAh g-1 at 1 A g-1, and GBAC delivers a high specific capacitance of âˆ¼166 F g-1 at 1 A g-1. In the following, the combinatorial integration of these materials enabled the asymmetric supercapacitor (ASC) to increase the energy density by enhancing the capacitance and the voltage window, in which a hydrogel-based electrolyte was facilitated for the foldable and wearable capability. The energy density of the ASC device was âˆ¼24.9 Wh kg-1 at a power density of âˆ¼779.5 W kg-1 with a voltage window of âˆ¼1.6 V. As demonstrated, a self-powered energy source was demonstrated by a serially connected multi-ASC device with a help of a commercial solar cell, which was employed for powering wearable healthcare monitoring devices, including personal alarms for patients and recording the human body's electrical signals. The present work offers a viable approach to preparing potential candidates for high-performance electrodes of supercapacitors with deformable configurations to extend the powering capability of other electronic devices with physical functionalities used in wearable electronics.

Effects of Environmental Concentrations of Total Phosphorus on the Plankton Community Structure and Function in a Microcosm Study.

The excessive nutrients in freshwater have been proven to promote eutrophication and harmful algae blooms, which have become great threats to water quality and human health. To elucidate the responses of the plankton community structure and function to total phosphorus (TP) at environmental concentrations in the freshwater ecosystem, a microcosm study was implemented. The results showed that plankton communities were significantly affected by the TP concentration ≥ 0.1 mg/L treatments. In terms of community structure, TP promoted the growth of Cyanophyta. This effect was transmitted to the zooplankton community, resulting in the promotion of Cladocera growth from day 42. The community diversities of phytoplankton and zooplankton had been continuously inhibited by TP. The principal response curve (PRC) analysis results demonstrated that the species composition of phytoplankton and zooplankton community in TP enrichment treatments significantly (p ≤ 0.05) deviated from the control. For community function, TP resulted in the decline in phytoplankton photosynthesis. The chlorophyll fluorescence parameters were significantly inhibited when TP concentration reached 0.4 mg/L. In TP ≥ 0.1 mg/L treatments, the reductions in total phytoplankton abundances led to a continuous decrease in pH. This study can directly prove that the plankton community changes significantly when TP concentrations are greater than 0.1 mg/L and can help managers to establish specific nutrient management strategies for surface water.

Nutrient potentiate the responses of plankton community structure and metabolites to cadmium: A microcosm study.

Metal pollution is a worldwide concern and may pose risks to aquatic organisms, communities, and ecosystems. The toxic effects of metals at the organism level are relatively clear. However, their impacts at the community level are still poorly understood, especially with concurred eutrophication in surface water. In the present study, the effects of Cd on the plankton community structure and function under varying nutrient conditions were evaluated using a microcosm study. The employed concentrations of Cd and nutrient were based on the values currently measured in the freshwater ecosystem. For the plankton structure, our results showed that the Chl a concentration, the abundances of total phytoplankton, Cyanophyta, and Chlorophyta, and the abundance of Copepoda decreased by Cd consistently. The Cyanophyta Oscillatoria tenuis and Copepoda nauplius were the most sensitive species to Cd in the phytoplankton and zooplankton community, respectively. For the community effects, we found the inhibitory effects of Cd on the photosystem II (PSII) activity of phytoplankton community because of the consistent decrease in the chlorophyll fluorescence parameters (Fv/Fm, Y(Ⅱ), and ETR). Furthermore, the reductions of DOC and pH by Cd were only found in the high nutrient condition, which indicated that the toxic effects of Cd on the community structure and community metabolites were aggravated by the increased nutrient. This study emphasizes the importance of considering nutrient conditions when assessing the metal ecotoxicological effects at environmentally relevant concentrations.

Molecular mechanisms by which targeted muscle reinnervation improves the microenvironment of spinal cord motor neurons and target muscles.

Targeted muscle reinnervation is a clinically valuable nerve transfers technology used to reconstruct the information sources reconstruct the motor nerve information sources lost because of nerve injury. This study aimed to investigate the effects and underlying molecular mechanisms of hind limb TMR on motor neurons and target muscles in rats after tibial nerve transection (TNT). Immunohistochemistry was performed to detect acetylcholinesterase expression in the target muscles and myelin basic protein, neuregulin-1 (NRG1), and ErbB2 expression in the tibial nerve of rats. Masson's trichrome staining was performed to observe fibrillar collagen expression in the target muscles. Western blot analysis was used to detect the protein expression of NRG1 and its receptor, ErbB2, in the target muscles. TMR significantly enhanced NRG1, ErbB2, and myelin basic protein expression in nerve fibers compared with those in the TNT group and exerted a protective effect on the maintenance of a large number of nerve fibers and myelin sheath thickness. The above results indicated that TMR can regulate NRG1 and ErbB2 expression in residual nerve fibers and protect the integrity of the myelin sheath, thus improving the functional status of the target muscles, which is beneficial for restoring hind limb motor function after TNT.

Effects of targeted muscle reinnervation on spinal cord motor neurons in rats following tibial nerve transection.

Targeted muscle reinnervation (TMR) is a surgical procedure used to transfer residual peripheral nerves from amputated limbs to targeted muscles, which allows the target muscles to become sources of motor control information for function reconstruction. However, the effect of TMR on injured motor neurons is still unclear. In this study, we aimed to explore the effect of hind limb TMR surgery on injured motor neurons in the spinal cord of rats after tibial nerve transection. We found that the reduction in hind limb motor function and atrophy in mice caused by tibial nerve transection improved after TMR. TMR enhanced nerve regeneration by increasing the number of axons and myelin sheath thickness in the tibial nerve, increasing the number of anterior horn motor neurons, and increasing the number of choline acetyltransferase-positive cells and immunofluorescence intensity of synaptophysin in rat spinal cord. Our findings suggest that TMR may enable the reconnection of residual nerve fibers to target muscles, thus restoring hind limb motor function on the injured side.

Efficacy of Biological and Physical Enhancement on Targeted Muscle Reinnervation.

Targeted muscle reinnervation (TMR) is a microsurgical repair technique to reconstruct the anatomical structure between the distal nerve and the muscle stump to provide more myoelectric information to the artificially intelligent prosthesis. Postoperative functional electrical stimulation treatment of the patient's denervated muscle or proximal nerve stump as well as nerve growth factor injection is effective in promoting nerve regeneration and muscle function recovery. In this experiment, we successfully established a TMR rat model and divided Sprague-Dawley (SD) adult male rats into TMR group, TMR + FES group, and TMR + NGF group according to TMR and whether they received FES treatment or NGF injection after surgery, and the recovery effect of rat neuromuscular function was assessed by analyzing EMG signals. Through the experiments, we confirmed that growth factor supplementation and low-frequency electrical stimulation can effectively promote the regeneration of the transplanted nerve as well as significantly enhance the motor function of the target muscle and have a positive effect on the regeneration of the transplanted nerve.

Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFß/SMAD signalling during gliomagenesis.

Synergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFß/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFß/SMAD signalling. Intriguingly, we found that Pontin amplified TGFßR2 gene transcription by recruiting LEF1, thereby activating TGFß/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFßR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFßR2 gene transcription, which could be exploited to target TGFß/SMAD signalling for anti-glioma therapy.

Changes in the cognitive function of Chinese college students with a clinical high risk of psychosis.

The purpose of our study was to explore the value of measuring cognitive functions for predicting the conversion to psychosis in Chinese college students with a clinical high risk (CHR). A total of 115 CHR students and 99 healthy controls were enrolled. All included participants were recruited from colleges in Wuhan, China. The MATRICS Consensus Cognitive Battery was used to evaluate cognitive function. CHR individuals were followed for 2 years, and the cognitive function of CHR individuals who later converted to psychosis (CHR-C) was compared to CHR individuals who did not convert (CHR-NC). Of the 107 CHR individuals that completed the 2- year follow-up, 29 (27.1%) developed a psychotic disorder. CHR individuals demonstrated poorer performance on all cognitive function tests compared to controls. CHR-C participants exhibited poorer performance on all cognitive tests except the Trail Making Test A and Continuous Performance Test-Identical Pairs compared to CHR-NC participants. The most significant differences displayed between CHR-C and CHR-NC groups were in visual learning, working memory, and reasoning and problem solving. The degree of cognitive impairment in visual learning and working memory may be a predictive marker for individuals who are at risk of developing psychosis.

The ATPase Pontin is a key cell cycle regulator by amplifying E2F1 transcription response in glioma.

Pontin (RUVBL1) is a highly conserved ATPase of the AAA + (ATPases Associated with various cellular Activities) superfamily and is implicated in various biological processes crucial for oncogenesis. Its overexpression is observed in multiple human cancers, whereas the relevance of Pontin to gliomagenesis remains obscure. To gain insights into Pontin involvement in glioma, we performed bioinformatics analyses of Pontin co-expressed genes, Pontin-affected genes, and carried out experimental studies. The results verified that Pontin was upregulated in gliomas. Its higher levels might predict the worse prognosis of glioma patients. The Pontin co-expressed genes were functionally enriched in cell cycle progression and RNA processing. In the nucleus, Pontin promoted cell growth via facilitating cell cycle progression. Using RNA-seq, we found that Pontin knockdown resulted in altered expression of multiple genes, among which the E2F1 targets accounted for a large proportion. Mechanistic studies found that Pontin interacted with E2F1 and markedly amplified the E2F1 transcription response in an ATPase domain-dependent manner. By analyzing the RNA-seq data, we also found that Pontin could impact on the alternative splicing (AS). Both differential expressed genes and AS events affected by Pontin were associated with cell cycle regulation. Taken together, our findings provide novel insights of the importance of Pontin in gliomagenesis by regulating cell cycle and AS, and shed light on the possible application of Pontin as an antineoplastic target in glioma.

Improved Antiglioblastoma Activity and BBB Permeability by Conjugation of Paclitaxel to a Cell-Penetrative MMP-2-Cleavable Peptide.

In order to solve the problems of receptor promiscuity and poor blood-brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual-functional nanocomplex drug delivery system is developed based on the strategy of peptide-drug conjugates. In this study, SynB3-PVGLIG-PTX is designed and screened out by matrix metalloproteinase-2 (MMP-2), to which it exhibits the best affinity. The MMP-2-sensitive peptide (PVGLIG) and a cell-penetration peptide (SynB3) are combined to form a dual-functional peptide. Moreover, as a drug-peptide nanocomplex, SynB3-PVGLIG-PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP-2. From a functional perspective, it is found that SynB3-PVGLIG-PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP-2, in contrast to that observed in MMP-2 siRNA transfected cells. Further investigation in vivo shows that SynB3-PVGLIG-PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3-PVGLIG-PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3-PVGLIG-PTX can be used as a novel drug-loading delivery system to treat GBM due to its specificity and BBB permeability.

Eucalyptal A inhibits glioma by rectifying oncogenic splicing of MYO1B mRNA via suppressing SRSF1 expression.

Glioma is the most common primary intracranial tumor, in which glioblastoma (GBM) is the most malignant and lethal. However, the current chemotherapy drugs are still unsatisfactory for GBM therapy. As the natural products mainly extracted from Eucalyptus species, phloroglucinol-terpene adducts have the potential to be anti-cancer lead compounds that attracted increasing attention. In order to discover the new lead compounds with the anti-GBM ability, we isolated Eucalyptal A with a phloroglucinol-terpene skeleton from the fruit of E. globulus and investigated its anti-GBM activity in vitro and in vivo. Functionally, we verified that Eucalyptal A could inhibit the proliferation, growth and invasiveness of GBM cells in vitro. Moreover, Eucalyptal A had the same anti-GBM activity in tumor-bearing mice as in vitro and prolonged the overall survival time by maintaining mice body weight. Further mechanism research revealed that Eucalyptal A downregulated SRSF1 expression and rectified SRSF1-guided abnormal alternative splicing of MYO1B mRNA, which led to anti-GBM activity through the PDK1/AKT/c-Myc and PAK/Cofilin axes. Taken together, we identified Eucalyptal A as an important anti-GBM lead compound, which represents a novel direction for glioma therapy.