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MicroRNAs（miRNAs）are small noncoding RNAs,which play a central role in gene expression regulation and have been considered as excellent biomarker candidates for clinical diagnosis and prognosis.So far,many miRNAs detection methods require polymerase chain reaction（PCR）amplification following reverse transcription of miRNAs.These processes are complicated and time-consuming.In this work,we have developed a simpler method for miRNA detection based on base stacking hybridization happening on the surface of NaYF_4：Yb,Er upconversion nanoparticles.In this method,the fluorescence of NaYF_4：Yb,Er upconversion nanoparticles were functionalized as a reference standard,which can improve the accuracy of miRNA detection.On the basis of these findings,we suggest this novel approach for miRNA detection could be applied as an accurate and specific technique for miRNAs detection.

Chimeric antigen receptor (CAR) technology has revolutionized cancer treatment, particularly in malignant hematological tumors. Currently, the BCMA-targeted second-generation CAR-T cells have showed impressive efficacy in the treatment of refractory/relapsed multiple myeloma (R/R MM), but up to 50% relapse remains to be addressed urgently. Here we constructed the BCMA-targeted fourth-generation CAR-T cells expressing IL-7 and CCL19 (i.e., BCMA-7 × 19 CAR-T cells), and demonstrated that BCMA-7 × 19 CAR-T cells exhibited superior expansion, differentiation, migration and cytotoxicity. Furthermore, we have been carrying out the first-in-human clinical trial for therapy of R/R MM by use of BCMA-7 × 19 CAR-T cells (ClinicalTrials.gov Identifier: NCT03778346), which preliminarily showed promising safety and efficacy in first two enrolled patients. The two patients achieved a CR and VGPR with Grade 1 cytokine release syndrome only 1 month after one dose of CAR-T cell infusion, and the responses lasted more than 12-month. Taken together, BCMA-7 × 19 CAR-T cells were safe and effective against refractory/relapsed multiple myeloma and thus warranted further clinical study.

Mucosal-associated invariant T (MAIT) cells, which are enriched in human blood and express a semi-invariant TCR chain, play important roles in conditions such as infectious diseases and cancer. The influence of age on levels and functional characteristics of circulating MAIT cells have not been fully addressed. Here we have collected blood samples from a large cohort of healthy Chinese individuals from newborn (cord blood) to the elderly and assessed the levels of circulating MAIT cells as well as their phenotype, activation and apoptosis status, and cytokine expression profiles after stimulation. We found that the frequencies of circulating MAIT cells gradually increased in blood from newborns as they progressed into adulthood (20-40 years old) but then decreased during further progression toward old age (>60 years old). The lowered numbers of circulating MAIT cells in the elderly was correlated with a gradual increase of apoptosis. A majority of circulating MAIT cells expressed the chemokine receptors CCR5 and CCR6, and most also expressed CD8 and CD45RO. Few expressed CD69 in cord blood, but the frequency increased with age. Upon activation with PMA plus ionomycin or IL12 plus IL18, fewer MAIT cells isolated from the young adult group expressed IFN-γ, IL17A and Granzyme B then cells from other age groups while the proportion of cells that expressed TNF-α was similar. Taken together, our data provide information for guiding the assessment of normal levels and phenotypes of MAIT cells at different ages in healthy individuals and patients.

Bottleneck stage and reentrance often exist in real-life manufacturing processes; however, the previous research rarely addresses these two processing conditions in a scheduling problem. In this study, a reentrant hybrid flow shop scheduling problem (RHFSP) with a bottleneck stage is considered, and an elite-class teaching-learning-based optimization (ETLBO) algorithm is proposed to minimize maximum completion time. To produce high-quality solutions, teachers are divided into formal ones and substitute ones, and multiple classes are formed. The teacher phase is composed of teacher competition and teacher teaching. The learner phase is replaced with a reinforcement search of the elite class. Adaptive adjustment on teachers and classes is established based on class quality, which is determined by the number of elite solutions in class. Numerous experimental results demonstrate the effectiveness of new strategies, and ETLBO has a significant advantage in solving the considered RHFSP.

On-chip spectral splitting structures with compact footprints hold tremendous potential for next-generation molecular sensing applications in the mid-infrared region. Here, we propose and theoretically investigate a carefully designed structure comprising a tilt grating and metalenses for dual-band spectral splitting with enhanced bandwidth. The tilt grating serves to separate the wavelength bands, and the metalenses following the grating guarantee a smooth transition of light into single-mode waveguides, giving rise to transmittances of 73.59% at 4 μm and 68.74% at 11 μm. The use of this tandem structure results in a significant footprint reduction and a remarkable 25.8% bandwidth enhancement over conventional approaches. The proposed spectral splitting scheme, with its broad wavelength range applicability, unlocks new pathways for on-chip simultaneous multi-target molecule detection.

Plague is a typical natural focus disease that circulates in different ecology of vectors and reservoir hosts. We conducted genomic population and phylogenetic analyses of the Yersinia pestis collected from the 12 natural plague foci in China with more than 20 kinds of hosts and vectors. Different ecological landscapes with specific hosts, vectors, and habitat which shape various niches for Y. pestis. The phylogeographic diversity of Y. pestis in different kinds plague foci in China showed host niches adaptation. Most natural plague foci strains are region‐and focus‐specific, with one predominant subpopulation; but the isolates from the Qinghai–Tibet plateau harbor a higher genetic diversity than other foci. The Y. pestis from Marmota himalayana plague foci are defined as the ancestors of different populations at the root of the evolutionary tree, suggesting several different evolutionary paths to other foci. It has the largest pan‐genome and widest SNP distances with most accessory genes enriched in mobilome functions (prophages, transposons). Geological barriers play an important role in the maintenance of local Y. pestis species and block the introduction of non‐native strains. This study provides new insights into the control of plague outbreaks and epidemics, deepened the understanding of the evolutionary history of MHPF (M. himalayana plague focus) in China. The population structure and identify clades among different natural foci of China renewed the space cognition of the plague. We conducted genomic population and phylogenetic analyses of the Yersinia pestis collected from 12 natural plague foci in China with more than 20 kinds of hosts and vectors. The evolutionary history and correlation between the genetic groups and plague foci of this study provide new insights into the control of plague outbreaks and epidemics, deepened the understanding of the evolutionary history of plague in China.

Background Little is known about the link between the monocyte to high-density lipoprotein cholesterol ratio (MHR) and frequent premature ventricular complexes (PVCs). This investigation aimed to evaluate the link between the MHR and frequent PVCs in patients, as well as their outcomes, using the axis, burden, coupling interval–ventricular tachycardia (ABC-VT) risk score (ARS). Methods Two hundred patients with frequent PVCs and 70 controls were retrospectively enrolled, and their general data were gathered. The MHR and ARS were calculated. Then, patients developing frequent PVCs were classified into a medium−/high-risk subgroup and a low-risk subgroup according to ARS. The results were evaluated employing comparative statistical analyses, Spearman’s correlation, logistic regression analyses, and receiver operating characteristic (ROC) curves. Results The MHR in the controls was obviously lower than that in the frequent PVC group. In addition, the MHR was the lowest in the control group and highest in the medium−/high-risk subgroup, with that of the low-risk subgroup falling in the middle. Spearman’s correlation analyses showed that the MHR was positively correlated with the ARS ( ρ  = 0.307, P  < 0.001). Ultimately, the MHR was found to be a risk factor for frequent PVCs in the multivariate analysis. In addition, an MHR cutoff point of 254.6 featured 67.50% sensitivity and 67.14% specificity for predicting frequent PVCs, and the area under the curve (AUC) reached 0.694 (95% confidence interval: 0.623–0.766) ( P  < 0.001). Conclusions The MHR is positively and independently correlated with frequent PVCs and can be used as a practical, cost-saving and simple biomarker of inflammation owing to its value in predicting frequent PVCs. In addition, the MHR is crucial to risk stratification and prognosis, which may give it clinical value in the prevention and management of frequent PVCs.

A lytic Yersinia pestis phage vB_YpP - YepMm (also named YepMm for briefly) was first isolated from the bone marrow of a Marmota himalayana who died of natural causes on the Qinghai-Tibet plateau in China. Based on its morphologic (isometric hexagonal head and short non-contractile conical tail) and genomic features, we classified it as belonging to the Podoviridae family. At the MOI of 10, YepMm reached maximum titers; and the one-step growth curve showed that the incubation period of the phage was about 10 min, the rise phase was about 80 min, and the lysis amount of the phage during the lysis period of 80 min was about 187 PFU/cell. The genome of the bacteriophage YepMm had nucleotide-sequence similarity of 99.99% to that of the Y. pestis bacteriophage Yep-phi characterized previously. Analyses of the biological characters showed that YepMm has a short latent period, strong lysis, and a broader lysis spectrum. It could infect Y. pestis , highly pathogenic bioserotype 1B/O:8 Y. enterocolitica , as well as serotype O:1b Y. pseudotuberculosis —the ancestor of Y. pestis . It could be further developed as an important biocontrol agent in pathogenic Yersinia spp. infection.

The immunity of patients who recover from coronavirus disease 2019 (COVID-19) could be long lasting but persist at a lower level. Thus, recovered patients still need to be vaccinated to prevent reinfection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or its mutated variants. Here, we report that the inactivated COVID-19 vaccine can stimulate immunity in recovered patients to maintain high levels of anti-receptor-binding domain (RBD) and anti-nucleocapsid protein (NP) antibody titers within 9 months, and high neutralizing activity against the prototype, Delta, and Omicron strains was observed. Nevertheless, the antibody response decreased over time, and the Omicron variant exhibited more pronounced resistance to neutralization than the prototype and Delta strains. Moreover, the intensity of the SARS-CoV-2-specific CD4+ T cell response was also increased in recovered patients who received COVID-19 vaccines. Overall, the repeated antigen exposure provided by inactivated COVID-19 vaccination greatly boosted both the potency and breadth of the humoral and cellular immune responses against SARS-CoV-2, effectively protecting recovered individuals from reinfection by circulating SARS-CoV-2 and its variants.

Transcription factors play a significant role during the symptomatic onset and progression of prion diseases. We previously showed the immunomodulatory and nuclear factor of activated T cells’ (NFAT) suppressive effects of an immunosuppressant, FK506, in the symptomatic stage and an antibiotic, minocycline, in the pre-symptomatic stage of prion infection in hamsters. Here we used for the first time, a combinatory FK506+minocycline treatment to test its transcriptional modulating effects in the symptomatic stage of prion infection. Our results indicate that prolonged treatment with FK506+minocycline was effective in alleviating astrogliosis and neuronal death triggered by misfolded prions. Specifically, the combinatory therapy with FK506+minocycline lowered the expression of the astrocytes activation marker GFAP and of the microglial activation marker IBA-1, subsequently reducing the level of pro-inflammatory cytokines interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α), and increasing the levels of anti-inflammatory cytokines IL-10 and IL-27. We further found that FK506+minocycline treatment inhibited mitogen-activated protein kinase (MAPK) p38 phosphorylation, NF-kB nuclear translocation, caspase expression, and enhanced phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated Bcl2-associated death promoter (pBAD) levels to reduce cognitive impairment and apoptosis. Interestingly, FK506+minocycline reduced mitochondrial fragmentation and promoted nuclear factor–erythroid2-related factor-2 (NRF2)-heme oxygenase 1 (HO-1) pathway to enhance survival. Taken together, our results show that a therapeutic cocktail of FK506+minocycline is an attractive candidate for prolonged use in prion diseases and we encourage its further clinical development as a possible treatment for this disease.