Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. Cytosolic TERC-53 levels respond to mitochondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53 functions downstream of mitochondria as a signal of mitochondrial functions. Here, we show that cytosolic TERC-53 plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53 levels affects cellular senescence and cognition decline in 10 months old mouse hippocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc-/- cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals.

Mycoplasma columbinum is a member of nonglycolytic Mycoplasma species which can hydrolyze arginine. Increasingly research has revealed that M. columbinum is associated with respiratory disease of pigeons and that the respiratory disease symptoms could be eliminated via the use of mycoplasma treatment medicine. Here we report the genome sequence of M. columbinum strain SF7, which is the first genome report for M. columbinum.

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive muscular dystrophy and paralysis; most ALS patients die from respiratory failure within 3 to 5 years, and there is currently no effective treatment. Some studies have indicated sex differences in the incidence of ALS, and evidence suggests a neuroprotective role for estrogen. MATERIAL AND METHODS We used human Cu/Zn superoxide dismutase (hSOD1-G93A) transgenic mice to determine the effects of ovariotomy on the onset of disease and behavior; we also used Western blotting to measure the expression of aromatase and estrogen receptors, as well as the inflammatory cytokines and apoptosis markers, in the lumbar spinal cord to determine the mechanism of estrogen-mediated neuroprotection. RESULTS Ovariectomy advanced the onset of disease, down-regulated aromatase and estrogen receptor alpha (ER-a) expression, and inhibited expression of the anti-inflammatory factors arginase-1 and the anti-apoptotic factor B-cell lymphoma-2 (Bcl-2) in the lumbar spinal cord of hSOD1-G93A transgenic mice. CONCLUSIONS Ovariectomy resulted in earlier disease onset and attenuated the anti-inflammatory and anti-apoptotic actions of estrogen in hSOD1-G93A transgenic mice. Therefore, estrogen may play an important role in protecting spinal cord motor neurons.

Endophytic fungi of medicinal plants have attracted wide attention due to their various active biochemical substances that are similar to those of the host plants and can be easily fermented and cultured. As a traditional medicine and food homologous plant in Xinjiang, Brassica rapa L. has a long history of applications. Recently, it has been shown that B. rapa L. has hypoglycemic, antimicrobial, immunomodulatory, and antioxidant properties. However, there are no studies on the function and diversity of enophytic fungi of B. rapa L. Four endophytic fungus (pr6, pr7, pr8, and pr10) strains were isolated from B. rapa L. in our laboratory. The metabolic extracts from pr10 have significant effects in terms of antitumor activity. In this study, in terms of types and contents, compared with those of the other three endophytic fungi, the dominant metabolites of pr10 were determined by comparative metabolomics analysis. The results of metabolomics analysis indicated that the metabolites of pr10 are rich in amino acids and sugar derivatives such as trehalose, whose ability to inhibit the A549 cell line has been proved. This study provides a theoretical basis for the development and utilization of B. rapa L. and its endophytic fungi to form antitumor agents.

Diabetes is a chronic metabolic disease with a high prevalence worldwide, which typically delays or impairs wound healing, potentially causing death. Low-frequency ultrasound treatment promotes the repair of various injuries and may promote wound healing. The aim of the present study was to determine whether low-frequency ultrasound can accelerate wound healing, as well as investigate its effects on the expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, interleukin (IL)-6 and tumor necrosis factor (TNF)-α in diabetic rats. A total of 45 Wistar rats were intraperitoneally injected with 1% streptozocin following intraperitoneal injection of pentobarbital sodium anesthesia. Subsequently an incision wound was created in the skin of back. The area of the wound was recorded to calculate the rate of wound healing. The expression of VEGF and TGF-β1 was determined via immunohistochemical analysis and their mRNA and protein levels were measured via reverse transcription-quantitative PCR analysis. The results revealed that when compared with the control group, low-frequency ultrasound treatment significantly increased wound healing rate in diabetic rats and markedly increased the mRNA and protein levels of VEGF and TGF-β1. US treatment also reduced the mRNA and protein levels of TNF-α and IL-6. In conclusion, the results of the present study indicated that low-frequency ultrasound promotes the expression of VEGF and TGF-β1, and inhibits the expression of IL-6 and TNF-α, thereby promoting wound healing in diabetic rats.

Glioblastoma (GBM) is a highly vascularized malignant tumor that depends on new blood vessel formation. Small molecules targeting the angiogenic process may be an effective anti-GBM therapeutic strategy. We previously demonstrated that RhoJ promoted the progression and invasion of GBM. RhoJ has also been shown to be expressed in endothelial cells and plays an important role in regulating endothelial cell migration and tumor angiogenesis. Therefore, we aimed to evaluate the role and mechanism of actions of RhoJ in GBM angiogenesis. We analyzed the expression of RhoJ in different grade gliomas and investigated its role in GBM angiogenesis in vivo and in vitro. Furtherly, RNA sequencing (RNA-seq), Western blotting and immunofluorescence were performed to identify the molecular mechanism of RhoJ in regulating endothelial cell behavior and GBM angiogenesis. Here, we found that silencing RhoJ resulted in inhibition of HUVEC cell migration and blood vessel formation. Overexpression of RhoJ promoted the expression of CD31, EpCAM and moesin, suggesting RhoJ facilitated angiogenesis and the malignant progression of GBM. RNA-seq data showed that VEGF/TNF signaling pathway positively regulated RhoJ. The expression levels of RhoJ was upregulated with the stimulation of VEGF, and reduced by the treatment of JNK inhibitor SP600125. It was also found that the activity of PAK-BRAF-ERK was down-regulated upon RhoJ and JNK knockdown. In conclusion, these results suggested that RhoJ plays an essential role in regulating GBM angiogenesis through the JNK/VEGFR2-PAK-ERK signaling pathway and there might exist a VEGF-JNK/ERK-VEGF circuitry. Thus, RhoJ may be a candidate therapeutic target for anti-angiogenesis treatment in GBM.

Quorum sensing (QS) can regulate the pathogenicity of bacteria and the production of some virulence factors. It is a promising target for screening to find anti-virulence agents in the coming post-antibiotics era. Cyclo (L-Trp-L-Ser), one variety of cyclic dipeptides (CDPs), isolated from a marine bacterium Rheinheimera aquimaris, exhibited anti-QS activity against Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Unlike the CDPs composed of phenylalanine or tyrosine, the anti-QS activity has been widely studied; however, cyclo (L-Trp-L-Ser) and derivatives, containing one tryptophan unit and one non-aromatic amino acid, have not been systematically explored. Herein, the cyclo (L-Trp-L-Ser) and seven derivatives were synthesized and evaluated. All tryptophane-contained CDPs were able to decrease the production of violacein in C.violaceum CV026 and predicted as binding within the same pocket of receptor protein CviR, but in lower binding energy compared with the natural ligand C6HSL. As for P. aeruginosa PAO1, owning more complicated QS systems, these CDPs also exhibited inhibitory effects on pyocyanin production, swimming motility, biofilm formation, and adhesion. These investigations suggested a promising way to keep the tryptophan untouched and make modifications on the non-aromatic unit to increase the anti-QS activity and decrease the cytotoxicity, thus developing a novel CDP-based anti-virulence agent.

The Schroth exercise can train the paraspinal muscles of patients with adolescent idiopathic scoliosis (AIS), however, muscle performance during the training remains unknown. This study applied surface electromyography (sEMG) to investigate the paraspinal muscle activities before, during and after Schroth exercise in nine AIS patients. This study found that after the Schroth exercise, the paraspinal muscle symmetry index (PMSI) was significantly reduced (PMSI = 1.3), while symmetry exercise significantly lowered the PMSI (PMSI = 0.93 and 0.75), and asymmetric exercise significantly increased the PMSI (PMSI = 2.56 and 1.52) compared to relax standing (PMSI = 1.36) in participants (p < 0.05). Among the four exercises, the PMSI of on all fours (exercise 1) and kneeling on one side (exercise 3) was the most and the least close to 1, respectively. The highest root mean square (RMS) of sEMG at the concave and convex side was observed in squatting on the bar (exercise 2) and sitting with side bending (exercise 4), respectively. This study observed that the asymmetric and symmetric exercise induced more sEMG activity on the convex and concave side, respectively, and weight bearing exercise activated more paraspinal muscle contractions on both sides of the scoliotic curve in the included AIS patients. A larger patient sample size needs to be investigated in the future to validate the current observations.

Akt is commonly activated and serves as a valuable target in human cancer. In this study, OTUD1 is identified as an Akt-associated protein and is downregulated upon Akt activation. Ectopic OTUD1 inhibits Akt phosphorylation; however, its deubiquitinase activity contributes only slightly to this effect. A short peptide (OUN-36) located in the OTUD1 N-terminal intrinsically disordered region strongly binds to the Akt PH domain. The residues in the PH domain, which are required for PtdIns(3,4,5)P3 recognition, are also essential for OUN-36 binding. OUN-36 preferentially inhibits Akt-hyperactive tumor cells' proliferation and interferes with Akt cell membrane localization, presumably by disrupting PH domain-PIP3 interaction. Importantly, OUN-36-based therapy efficiently abrogates Akt feedback reactivation in response to MK-2206 treatment and sensitizes cancer cells to chemotherapy and immunotherapy. We therefore show a mechanism by which OTUD1 modulates Akt activity and suggest a potential peptide-based cancer therapeutic strategy implemented by targeting the Akt PH domain.

There are currently approximately 4,000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide. Universal vaccines with high efficacy and safety urgently need to be developed to prevent SARS-CoV-2 variants pandemic. Here, we described a novel self-assembling universal mRNA vaccine containing a heterologous receptor-binding domain (HRBD)-based dodecamer (HRBDdodecamer) against SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28.1), Delta (B.1.617.2) and Omicron (B.1.1.529). HRBD containing four heterologous RBD (Delta, Beta, Gamma, and Wild-type) can form a stable dodecameric conformation under T4 trimerization tag (Flodon, FD). The HRBDdodecamer -encoding mRNA was then encapsulated into the newly-constructed LNPs consisting of a novel ionizable lipid (4N4T). The obtained universal mRNA vaccine (4N4T-HRBDdodecamer) presented higher efficiency in mRNA transfection and expression than the approved ALC-0315 LNPs, initiating potent immune protection against the immune escape of SARS-CoV-2 caused by evolutionary mutation. These findings demonstrated the first evidence that structure-based antigen design and mRNA delivery carrier optimization may facilitate the development of effective universal mRNA vaccines to tackle SARS-CoV-2 variants pandemic.

Commensal microbes cross talk with their colonized mucosa. We show that microbes and their cell wall components induce an inflammatory response in cultured human mucosal cells derived from the nonmalignant nasopharyngeal epithelium (NNE) cells in vitro. NNE cells show significant induction of NF-κB with nuclear shuttling and inflammatory gene response when exposed to Gram-positive bacteria (streptococci) or peptidoglycan (PGN), a component of the Gram-positive bacterial cell wall. This response is abrogated in nasopharyngeal carcinoma (NPC)-derived cell lines. The inflammatory response induced by NF-κB signaling was blocked at two levels in the tumor-derived cells. We found that NF-κB was largely trapped in lipid droplets (LDs) in the cytoplasm of the NPC-derived cells, while the increased expression of lysine-specific histone demethylase 1 (LSD1, a repressive nuclear factor) reduces the response mediated by remaining NF-κB at the promoters responding to inflammatory stimuli. This refractory response in NPC cells might be a consequence of long-term exposure to microbes in vivo during carcinogenic progression. It may contribute to the decreased antitumor immune responses in NPC, among others despite heavy T-helper cell infiltration, and thus facilitate tumor progression.

The phagocytic receptor CED-1 mediates apoptotic cell recognition by phagocytic cells, enabling cell corpse clearance in Caenorhabditis elegans. Whether appropriate levels of CED-1 are maintained for executing the engulfment function remains unknown. Here, we identified the C. elegans E3 ubiquitin ligase tripartite motif containing-21 (TRIM-21) as a component of the CED-1 pathway for apoptotic cell clearance. When the NPXY motif of CED-1 was bound to the adaptor protein CED-6 or the YXXL motif of CED-1 was phosphorylated by tyrosine kinase SRC-1 and subsequently bound to the adaptor protein NCK-1 containing the SH2 domain, TRIM-21 functioned in conjunction with UBC-21 to catalyze K48-linked poly-ubiquitination on CED-1, targeting it for proteasomal degradation. In the absence of TRIM-21, CED-1 accumulated post-translationally and drove cell corpse degradation defects, as evidenced by direct binding to VHA-10. These findings reveal a unique mechanism for the maintenance of appropriate levels of CED-1 to regulate apoptotic cell clearance.

COVID-19 pandemic has resulted in an unprecedented global public health crisis. It is obvious that SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Since obvious advantages including fast manufacturing speed, potent immunogenicity and good safety profile, six mRNA vaccines have been used to prevent SARS-CoV-2 infections in clinic with lipid nanoparticles (LNP) formulation via intramuscular injection. In this work, we first constructed RBD-encoding mRNA (RBD-mRNA) formulated in liposomes (LPX/RBD-mRNA) and investigated the influence of administration routes on the immunogenicity. LPX/RBD-mRNA can express RBD in vivo and successfully induced SARS-CoV-2 RBD specific antibodies in the vaccinated mice, which efficiently neutralized SARS-CoV-2 pseudotyped virus. Moreover, the administration routes were found to affect the virus neutralizing capacity of sera derived from the immunized mice and the types (Th1-type and Th2-type) of cellular immune responses. This study indicated that liposome-based RBD-mRNA vaccine with optimal administration route might be a potential candidate against SARS-CoV-2 infection with good efficacy and safety.

Lysozyme can kill bacteria by its enzymatic activity or through a mechanism involving its cationic nature, which can facilitate electrostatic interactions with the viral capsid, the negatively charged parts of nucleic acids, and polymerase, so binding to nucleic acids may be another biological function of lysozyme. Here, PCR was used as a research tool to detect the effects of lysozyme on the replication and transcription of nucleic acids after treatment in different ways. We found that lysozyme and its hydrolysate can enter cells and inhibit PCR to varying degrees in vitro, and degraded lysozyme inhibited nucleic acid replication more effectively than intact lysozyme. The inhibition of lysozyme may be related to polymerase binding, and the sensitivity of different polymerases to lysozyme is inconsistent. Our findings provide a theoretical basis for further explaining the pharmacological effects of lysozyme, such as antibacterial, antiviral, anticancer, and immune regulatory activities, and directions for the development of new pharmacological effects of lysozyme and its metabolites.

Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at the Bact state, an active spliceosome but not catalytically primed, which depends on Smad Nuclear Interacting Protein 1 (SNIP1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and Bact components preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in the cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake to promote spliceosome pausing, and that its misregulation contributes to neurodegeneration.

The deterministic fiber tracking method has the advantage of high computational efficiency and good repeatability, making it suitable for the noninvasive estimation of brain structural connectivity in clinical fields. To address the issue of the current classical deterministic method tending to deviate in the tracking direction in the region of crossing fiber region, in this paper, we propose an adaptive correction-based deterministic white matter fiber tracking method, named FTACTD.

Introduction: During adulthood, the skin microbiota can be relatively stable if environmental conditions are also stable, yet physiological changes of the skin with age may affect the skin microbiome and its function. The microbiome is an important factor to consider in aging since it constitutes most of the genes that are expressed on the human body. However, severity of specific aging signs (one of the parameters used to measure "apparent" age) and skin surface quality (e.g., texture, hydration, pH, sebum, etc.) may not be indicative of chronological age. For example, older individuals can have young looking skin (young apparent age) and young individuals can be of older apparent age. Methods: Here we aim to identify microbial taxa of interest associated to skin quality/aging signs using a multi-study analysis of 13 microbiome datasets consisting of 16S rRNA amplicon sequence data and paired skin clinical data from the face. Results: We show that there is a negative relationship between microbiome diversity and transepidermal water loss, and a positive association between microbiome diversity and age. Aligned with a tight link between age and wrinkles, we report a global positive association between microbiome diversity and Crow's feet wrinkles, but with this relationship varying significantly by sub-study. Finally, we identify taxa potentially associated with wrinkles, TEWL and corneometer measures. Discussion: These findings represent a key step towards understanding the implication of the skin microbiota in skin aging signs.

To investigate the value of quantitative longitudinal relaxation time (T1), transverse relaxation time (T2), and proton density (PD) maps derived from synthetic magnetic resonance imaging (MRI) for evaluating the status of lymphovascular space invasion (LVSI) in cervical squamous cell carcinoma (CSCC) without lymph node metastasis (LNM).

Intertemporal decision-making refers to the process whereby an individual evaluates and selects among competing alternatives based on the cost and benefit over time. While most previous studies on temporal discounting focused their attention on the gain context, only a few explored the loss context. In the present study, both the event-related potentials (ERPs) and the graph theory analysis were employed to investigate the differences in intertemporal decision-making between the gain and loss frameworks. Our results suggested that participants preferred the short latency/small amount (SS) alternatives and exhibited a smaller discount rate in a loss context compared to a gain framework. Furthermore, our ERP data indicated that the P200 component could constitute a preliminary assessment of the decision-making, related to gain and loss. In contrast, the N2 component was associated with negative emotions and showed significantly bigger amplitudes in the loss context, when compared to the gain framework. Further analyses of brain networks suggested the loss decision-making brain network to have a larger small-worldness index given individuals' loss aversion. Taken together, intertemploral decision-making in a loss context was accompanied by a greater brain response due to the negative emotions linked to loss aversion.

Retinoblastoma (RB) is a highly malignant eye tumor with a low survival rate and a high metastatic rate. The current work was designed to investigate the potential roles of microRNA-144 (miR-144) in the diagnosis and prognosis of RB.