One of the basic questions in the aging field is whether there is a fundamental difference between the aging of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-aging Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at an early age was observed, indicating its involvement in normal aging of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal aging. adeno-associated virus delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan. These findings demonstrate the complexity of aging in mammals and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.
Animals ; Mice ; RNA, Untranslated/metabolism* ; Aging/genetics* ; Mice, Transgenic ; Telomerase/metabolism* ; RNA/genetics* ; Hippocampus/metabolism* ; Humans ; Mice, Inbred C57BL

Objective:To analyze the clinical characteristics and prognosis of patients with infant acute lymphoblastic leukemia (IALL).Methods:A retrospective cohort study.Clinical data, treatment and prognosis of 28 cases of IALL who have been treated at Beijing Children′s Hospital, Capital Medical University and Baoding Children′s Hospital from October 2013 to May 2023 were analyzed retrospectively. Based on the results of fluorescence in situ hybridization (FISH), all patients were divided into KMT2A gene rearrangement (KMT2A-R) positive group and KMT2A-R negative group. The prognosis of two groups were compared. Kaplan-Meier method and Log-Rank test were used to analyze the survival of the patients.Results:Among 28 cases of IALL, there were 10 males and 18 females, with the onset age of 10.9 (9.4,11.8) months. In terms of immune classification, 25 cases were B-ALL (89%), while the remaining 3 cases were T-ALL (11%). Most infant B-ALL showed pro-B lymphocyte phenotype (16/25,64%). A total of 22 cases (79%) obtained chromosome karyotype results, of which 7 were normal karyotypes, no complex karyotypes and 15 were abnormal karyotypes were found. Among abnormal karyotypes, there were 4 cases of t (9; 11), 2 cases of t (4; 11), 2 cases of t (11; 19), 1 case of t (1; 11) and 6 cases of other abnormal karyotypes. A total of 19 cases (68%) were positive for KMT2A-R detected by FISH. The KMT2A fusion gene was detected by real-time PCR in 16 cases (57%). A total of 24 patients completed standardized induction chemotherapy and were able to undergo efficacy evaluation, 23 cases (96%) achieved complete remission through induction chemotherapy, 4 cases (17%) died of relapse. The 5-year event free survival rate (EFS) was (46±13)%, and the 5-year overall survival rate (OS) was (73±10)%.The survival time was 31.3 (3.3, 62.5) months. There was no significant statistical difference in 5-year EFS ((46±14)% vs. (61±18)%) and 5-year OS ((64±13)% vs. (86±13)%) between the KMT2A-R positive group (15 cases) and the KMT2A-R negative group (9 cases) ( χ2=1.88, 1.47, P=0.170, 0.224). Conclusions:Most IALL patients were accompanied by KMT2A-R. They had poor tolerance to traditional chemotherapy, the relapse rate during treatment was high and the prognosis was poor.

The development of broad-spectrum antivirals against human coronaviruses (HCoVs) is critical to combat the current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants, as well as future outbreaks of emerging CoVs. We have previously identified a polyethylene glycol-conjugated (PEGylated) lipopeptide, EK1C4, with potent pan-CoV fusion inhibitory activity. However, PEG linkers in peptide or protein drugs may reduce stability or induce anti-PEG antibodies in vivo. Therefore, we herein report the design and synthesis of a series of dePEGylated lipopeptide-based pan-CoV fusion inhibitors featuring the replacement of the PEG linker with amino acids in the heptad repeat 2 C-terminal fragment (HR2-CF) of HCoV-OC43. Among these lipopeptides, EKL1C showed the most potent inhibitory activity against infection by SARS-CoV-2 and its spike (S) mutants, as well as other HCoVs and some bat SARS-related coronaviruses (SARSr-CoVs) tested. The dePEGylated lipopeptide EKL1C exhibited significantly stronger resistance to proteolytic enzymes, better metabolic stability in mouse serum, higher thermostability than the PEGylated lipopeptide EK1C4, suggesting that EKL1C could be further developed as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases.

Objective To observe the effects of mesenchymal stem cells (BMSCs) on the expression of Bcl2 and Bax in atrophied muscles.Methods Immature rats (80～ 100 g) were anesthetized to collect marrow from their femurs and tibias.BMSCs were isolated from the marrow,cultured and purified using the whole bone marrow adherence method.Their right hindlimbs were immobilized fiom the thigh to the paw with the knee in extension and the ankle in plantar flexion.After the modeling,24 of the male rats were divided into a sham-operation group,a BMSC group and a phosphate buffer solution (PBS) group,each of 8.The BMSC and PBS groups were injected with either approximately 106 BMSCs or an equal volume of PBS into the belly of the soleus muscle after they had been immobilized for 48 hours,while the control group did not undergo any treatment except for the injection of PBS.All of the rats were sacrificed for analysis after 14 days.Results The BMSCs were mainly spindle cells,showing radial colony arrangement.They grew vigorously and could passage in a continuous and stable manner over 10 passages.At the 4th passage the BMSCs were positive for CD44 (95.84％) and CD90 (96.00％),but negative for CD34 and CD45.Western blotting assay demonstrated that the expression of Bax protein as measured in grey-scale value (0.41±0.08)in the BMSC group was significantly lower than in the PBS group (0.63±0.10),but significantly higher than in the control group (0.14±0.11) on average.The expression of Bcl-2 (0.47±0.14) was also significantly higher in the BMSC group than in the PBS group (0.22-± 0.13),but significantly lower than in the control group (0.81 ± 0.06).Conclusion Bone marrow mesenchymal stem cells can upregulate the expression of anti-apoptotic Bcl-2 protein and downregulate that of the apoptotic Bax protein when injected early into the belly of a muscle in an immobilized limb.

Objective To observe the effects of treadmill training at different intensities on the expression of p-AKT in rats' gastrocnemius muscles after focal cerebral ischemia,and to investigate whether intensive training is beneficial for the recovery of motor function.Methods Left middle cerebral artery occlusion (MCAO) was induced in 120 male Wistar rats using the intraluminal thread method,and they were divided into an MCAO group (no training),a normal training group (treadmill training once a day for 30 min) and an intensive training group (treadmill training twice a day for 60 min),each of 30 rats.There was also a sham control group with 30 members not given MCAO or training.The four groups were further divided into 3 day,7 day and 14 day subgroups.Five rats randomly selected from each subgroup were sacrificed for hematoxylin-eosin staining after 4％ paraformaldehyde treatment.Neurological function was evaluated using Zausinger scores,and the expression of p-Akt was detected by western blotting.Results No significant differences in Zausinger scores were observed between the intensive training group and the normal training group after 1,3 or 7 days of training.However the average Zausinger score in the intensive training group was significantly higher than in the normal training group after 14 d of treadmill training.After 7 d and 14 d of treadmill training the average cross-sectional area of the gastrocnemius muscles in the sham group was significantly higher than in the other three groups.The average area of the intensive training group was significantly larger than that of the normal training group.The expression of p-Akt in the gastrocnemius was significantly increased in the intensive training group compared with the normal training group in the 7 day and 14 day subgroups.Conclusion Treadmill training can improve the expression of p-Akt in atrophied gastrocnemius muscles caused by MCAO.Intensive training is more effective for the recovery of muscle function.