Recent advances in the role of miRNAs in post-traumatic stress disorder and traumatic brain injury.

Post-traumatic stress disorder (PTSD) is usually considered a psychiatric disorder upon emotional trauma. However, with the rising number of conflicts and traffic accidents around the world, the incidence of PTSD has skyrocketed along with traumatic brain injury (TBI), a complex neuropathological disease due to external physical force and is also the most common concurrent disease of PTSD. Recently, the overlap between PTSD and TBI is increasingly attracting attention, as it has the potential to stimulate the emergence of novel treatments for both conditions. Of note, treatments exploiting the microRNAs (miRNAs), a well-known class of small non-coding RNAs (ncRNAs), have rapidly gained momentum in many nervous system disorders, given the miRNAs' multitudinous and key regulatory role in various biological processes, including neural development and normal functioning of the nervous system. Currently, a wealth of studies has elucidated the similarities of PTSD and TBI in pathophysiology and symptoms; however, there is a dearth of discussion with respect to miRNAs in both PTSD and TBI. In this review, we summarize the recent available studies of miRNAs in PTSD and TBI and discuss and highlight promising miRNAs therapeutics for both conditions in the future.

Dietary ketone body-escalated histone acetylation in megakaryocytes alleviates chemotherapy-induced thrombocytopenia.

Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating ß-hydroxybutyrate (ß-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-ß-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked ß-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.

Protective effects and regulatory pathways of melatonin in traumatic brain injury mice model: Transcriptomics and bioinformatics analysis.

Traumatic brain injury (TBI) is the leading cause of disability and mortality globally. Melatonin (Mel) is a neuroendocrine hormone synthesized from the pineal gland that protects against TBI. Yet, the precise mechanism of action is not fully understood. In this study, we examined the protective effect and regulatory pathways of melatonin in the TBI mice model using transcriptomics and bioinformatics analysis. The expression profiles of mRNA, long non-coding RNA (lncRNA), microRNA (miRNA), and circular RNA (circRNA) were constructed using the whole transcriptomes sequencing technique. In total, 93 differentially expressed (DE) mRNAs (DEmRNAs), 48 lncRNAs (DElncRNAs), 59 miRNAs (DEmiRNAs), and 59 circRNAs (DEcircRNAs) were identified by the TBI mice with Mel treatment compared to the group without drug intervention. The randomly selected coding RNAs and non-coding RNAs (ncRNAs) were identified by quantitative real-time polymerase chain reaction (qRT-PCR). To further detect the biological functions and potential pathways of those differentially expressed RNAs, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were executed. In our research, the regulatory network was constructed to show the relationship of lncRNA-RBPs. The lncRNA-mRNA co-expression network was established based on the Pearson coefficient to indicate the expression correlations. Moreover, the DEcircRNA-DEmiRNA-DEmRNA and DElncRNA-DEmiRNA-DEmRNA regulatory networks were constructed to demonstrate the regulatory relationship between ncRNAs and mRNA. Finally, to further verify our predicted results, cytoHubba was used to find the hub gene in the synaptic vesicle cycle pathway, and the expression level of SNAP-25 and VAMP-2 after melatonin treatment were detected by Western blotting and immunofluorescence. To sum up, these data offer a new insight regarding the molecular effect of melatonin treatment after TBI and suggest that the high-throughput sequencing and analysis of transcriptomes are useful for studying the drug mechanisms in treatment after TBI.

A novel circular RNA, circIgfbp2, links neural plasticity and anxiety through targeting mitochondrial dysfunction and oxidative stress-induced synapse dysfunction after traumatic brain injury.

Traumatic brain injury (TBI) can lead to different neurological and psychiatric disorders. Circular RNAs (circRNAs) are highly expressed in the nervous system and enriched in synapses; yet, the underlying role and mechanisms of circRNAs in neurological impairment and dysfunction are still not fully understood. In this study, we investigated the expression of circRNAs and their relation with neurological dysfunction after TBI. RNA-Seq was used to detect differentially expressed circRNAs in injured brain tissue, revealing that circIgfbp2 was significantly increased. Up-regulated hsa_circ_0058195, which was highly homologous to circIgfbp2, was further confirmed in the cerebral cortex specimens and serum samples of patients after TBI. Moreover, correlation analysis showed a positive correlation between hsa_circ_0058195 levels and the Self-Rating Anxiety Scale scores in these subjects. Furthermore, knockdown of circIgfbp2 in mice relieved anxiety-like behaviors and sleep disturbances induced by TBI. Knockdown of circIgfbp2 in H2O2 treated HT22 cells alleviated mitochondrial dysfunction, while its overexpression reversed the process. Mechanistically, we discovered that circIgfbp2 targets miR-370-3p to regulate BACH1, and down-regulating BACH1 alleviated mitochondrial dysfunction and oxidative stress-induced synapse dysfunction. In conclusion, inhibition of circIgfbp2 alleviated mitochondrial dysfunction and oxidative stress-induced synapse dysfunction after TBI through the miR-370-3p/BACH1/HO-1 axis. Thus, circIgfbp2 might be a novel therapeutic target for anxiety and sleep disorders after TBI.

Erratum: Author Correction: Chinese Adolescents' Struggle in Online Compulsory Education during the COVID-19 Pandemic: A Foucauldian Perspective.

[This corrects the article DOI: 10.1007/s10639-021-10688-9.].

CircLphn3 protects the blood-brain barrier in traumatic brain injury.

Circular RNAs (circRNAs) are a new and large group of non-coding RNA molecules that are abundantly expressed in the central nervous system. However, very little is known about their roles in traumatic brain injury. In this study, we firstly screened differentially expressed circRNAs in normal and injured brain tissues of mice after traumatic brain injury. We found that the expression of circLphn3 was substantially decreased in mouse models of traumatic brain injury and in hemin-treated bEnd.3 (mouse brain cell line) cells. After overexpressing circLphn3 in bEnd.3 cells, the expression of the tight junction proteins, ZO-1, ZO-2, and occludin, was upregulated, and the expression of miR-185-5p was decreased. In bEnd.3 cells transfected with miR-185-5p mimics, the expression of ZO-1 was decreased. Dual-luciferase reporter assays showed that circLphn3 bound to miR-185-5p, and that miR-185-5p bound to ZO-1. Additionally, circLphn3 overexpression attenuated the hemin-induced high permeability of the in vitro bEnd.3 cell model of the blood-brain barrier, while miR-185-5p transfection increased the permeability. These findings suggest that circLphn3, as a molecular sponge of miR-185-5p, regulates tight junction proteins' expression after traumatic brain injury, and it thereby improves the permeability of the blood-brain barrier. This study was approved by the Animal Care and Use Committee of Chongqing Medical University of China (approval No. 2021-177) on March 22, 2021.

Chinese Adolescents' Struggle in Online Compulsory Education during the COVID-19 Pandemic: A Foucauldian Perspective.

To tackle the debate surrounding the tension between knowledge and power in online education for adolescents and between freedom and control at large, this study examines how disciplinary power was exercised and resisted in a Chinese setting of online compulsory education during the COVID-19 outbreak in 2020. Overall, 60 participants, including students (from Grade 7 to 12), their parents, and teachers joined in our focus groups or individual interviews in a secondary school in Xi'an, China. By following Foucault's concepts of three techniques of disciplinary power: hierarchical observation, normalizing judgement and examination, we identified four themes based on the data: (1) diminished discipline with the dissolving boundary, (2) reconfigured disciplinary power by teachers, (3) self-discipline as a vital skill, and (4) online compulsory education as a future trend. Interpretations from the Foucauldian perspective were presented, suggesting that most adolescents depend upon more external disciplines from schools and teachers, while only a few may achieve autonomy through self-discipline.

A novel mechanism linking ferroptosis and endoplasmic reticulum stress via the circPtpn14/miR-351-5p/5-LOX signaling in melatonin-mediated treatment of traumatic brain injury.

Traumatic brain injury (TBI) can lead to disability or devastating consequences with few established treatments. Although ferroptosis has been shown to be involved in TBI, the underlying mechanism was rarely known. Melatonin has been indicated to exhibit neuroprotective activities. However, the anti-ferroptotic effects of melatonin on TBI have not yet to be elucidated. We aimed to investigate whether ferroptosis was induced in humans after TBI and whether ferroptosis inhibition by melatonin could protect against blood-brain barrier (BBB) damage after TBI in vivo and in vitro. Circular RNAs (circRNAs) are highly expressed in the brain. For the first time, differentially expressed circRNA after melatonin treatment for TBI were detected by RNA sequencing. We found that lipid peroxidation was induced in humans after TBI, while melatonin significantly improved brain function of mice after TBI and alleviated ferroptosis and endoplasmic reticulum (ER) stress in vivo and in vitro. A total of 1826 differentially expressed circRNAs were found (fold change >2, Q < 0.01), including 921 down-regulated and 905 up-regulated circRNAs in the injured brain tissues of TBI mice receiving melatonin treatment. Mechanistically, melatonin administration reduced the level of circPtpn14 (mmu_circ_0000130), which functioned by acting as a miR-351-5p sponge to positively regulate the expression of the ferroptosis-related 5-lipoxygenase (5-LOX). Moreover, circPtpn14 overexpression partly abolished the inhibitory effects of melatonin on ferroptosis. Collectively, our findings provide the first evidence that melatonin could exert anti-ferroptotic and anti-ER stress effects in brain injury by alleviating lipid peroxidation via the circPtpn14/miR-351-5p/5-LOX signaling.

Megakaryocytes Mediate Hyperglycemia-Induced Tumor Metastasis.

High blood glucose has long been established as a risk factor for tumor metastasis, yet the molecular mechanisms underlying this association have not been elucidated. Here we describe that hyperglycemia promotes tumor metastasis via increased platelet activity. Administration of glucose, but not fructose, reprogrammed the metabolism of megakaryocytes to indirectly prime platelets into a prometastatic phenotype with increased adherence to tumor cells. In megakaryocytes, a glucose metabolism-related gene array identified the mitochondrial molecular chaperone glucose-regulated protein 75 (GRP75) as a trigger for platelet activation and aggregation by stimulating the Ca2+-PKCα pathway. Genetic depletion of Glut1 in megakaryocytes blocked MYC-induced GRP75 expression. Pharmacologic blockade of platelet GRP75 compromised tumor-induced platelet activation and reduced metastasis. Moreover, in a pilot clinical study, drinking a 5% glucose solution elevated platelet GRP75 expression and activated platelets in healthy volunteers. Platelets from these volunteers promoted tumor metastasis in a platelet-adoptive transfer mouse model. Together, under hyperglycemic conditions, MYC-induced upregulation of GRP75 in megakaryocytes increases platelet activation via the Ca2+-PKCα pathway to promote cancer metastasis, providing a potential new therapeutic target for preventing metastasis. SIGNIFICANCE: This study provides mechanistic insights into a glucose-megakaryocyte-platelet axis that promotes metastasis and proposes an antimetastatic therapeutic approach by targeting the mitochondrial protein GRP75.

Metabolomics analysis of TiO2 nanoparticles induced toxicological effects on rice (Oryza sativa L.).

The wide occurrence and high environmental concentration of titanium dioxide nanoparticles (nano-TiO2) have raised concerns about their potential toxic effects on crops. In this study, we employed a GC-MS-based metabolomic approach to investigate the potential toxicity of nano-TiO2 on hydroponically-cultured rice (Oryza sativa L.) after exposed to 0, 100, 250 or 500 mg/L of nano-TiO2 for fourteen days. Results showed that the biomass of rice was significantly decreased and the antioxidant defense system was significantly disturbed after exposure to nano-TiO2. One hundred and five identified metabolites showed significant difference compared to the control, among which the concentrations of glucose-6-phosphate, glucose-1-phosphate, succinic and isocitric acid were increased most, while the concentrations of sucrose, isomaltulose, and glyoxylic acid were decreased most. Basic energy-generating ways including tricarboxylic acid cycle and the pentose phosphate pathway, were elevated significantly while the carbohydrate synthesis metabolism including starch and sucrose metabolism, and glyoxylate and dicarboxylate metabolism were inhibited. However, the biosynthetic formation of most of the identified fatty acids, amino acids and secondary metabolites which correlated to crop quality, were increased. The results suggest that the metabolism of rice plants is distinctly disturbed after exposure to nano-TiO2, and nano-TiO2 would have a mixed effect on the yield and quality of rice.

Application for MEDPOR Surgical Implant in Modified Penile Elongation: Review of 19 Cases.

OBJECTIVE: To investigate the application of MEDPOR surgical implant in modified penile elongation. METHODS: The suspensory ligaments were divided, and cavernous bodies of crus were partially mobilized, so as to release part of the cavernous bodies from inferior ramus of pubis. Then, the penis was elongated sufficiently. MEDPOR surgical implants (MEDPOR; high-density porous polyethylene, Howmedica Osteonics Corp. Newnan, Ga) were inserted between the cavernous bodies and pubic symphysis. Local fat flap was transposed to fill the front space of pubis to make sure of the effective elongation of penis and improve the appearance of mons pubis. RESULTS: Nineteen cases of micropenis were treated. The average length of the penis was 5.23 cm in the static state and 7.83 cm in erectile state before operation. After the operation, it increased to 8.63 cm in the static state and 11.36 cm in erectile state. CONCLUSIONS: Application for MEDPOR surgical implant in modified penile elongation can make sure of the effective elongation of penis and improve the appearance of mons pubis.

Modification of the Koyanagi Technique for the Single-Stage Repair of Proximal Hypospadias.

We describe a modification of the Koyanagi technique for hypospadias in an attempt to reduce complications and improve results. Between January 2005 and July 2012, 21 patients underwent treatment of proximal hypospadias using a modified hypospadias repair. The procedure involved making a U-incision similar to that in a Thiersch-Duplay repair to preserve the blood supply to the tubular neourethra. The neourethra was reconstructed by island penile skin. An M-incision was made in the glans, and the meatus was attached to tip of glans. Flaps were harvested from both sides of the penis preventing postoperative penile turn. Cosmetic and functional, long-term (mean, 12 months) recovery was excellent. Complications consisted of 3 cases of urethrocutaneous fistula (14.2%), which were corrected surgically, and 2 cases of penile skin necrosis. There were no instances of meatal stenosis, diverticulum, or urethral stricture. Bifid scrotum was present in 6 patients, and associated penoscrotal transposition was present in 15 patients. Both of these associated defects were corrected at the time of surgery. The modified technique permits 1-stage repair of proximal hypospadias with a low complication rate, the satisfactory recovery.

Strained cyclooctyne as a molecular platform for construction of multimodal imaging probes.

Small-molecule-based multimodal and multifunctional imaging probes play prominent roles in biomedical research and have high clinical translation ability. A novel multimodal imaging platform using base-catalyzed double addition of thiols to a strained internal alkyne such as bicyclo[6.1.0]nonyne has been established in this study, thus allowing highly selective assembly of various functional units in a protecting-group-free manner. Using this molecular platform, novel dual-modality (PET and NIRF) uPAR-targeted imaging probe: (64)Cu-CHS1 was prepared and evaluated in U87MG cells and tumor-bearing mice models. The excellent PET/NIRF imaging characteristics such as good tumor uptake (3.69%ID/g at 2 h post-injection), high tumor contrast, and specificity were achieved in the small-animal models. These attractive imaging properties make (64)Cu-CHS1 a promising probe for clinical use.