Pulsed vapor cell atomic clock with a differential Faraday rotation angle detection.

Laser intensity noise is one of the main limiting factors in pulsed vapor cell clocks. To reduce the contribution of the laser intensity noise to detection signal in the pulsed optically pumped atomic clock, a scheme based on the differential Faraday rotation angle is proposed. Theoretically, the Ramsey fringes, the sensitivity of clock frequency to laser intensity fluctuation and the signal to noise ratio for absorption, differential, and Faraday rotation angle methods are calculated and compared. Using a Wollaston prism rotated 45°relative to the incident polarization, and two photodetectors, Ramsey fringes of three detection methods are obtained simultaneously. In the proposed scheme, the long-term Faraday rotation angle fluctuation is 0.66% at 30000s, which is much smaller than fluctuation of traditional absorption signal 3.9% at 30000s. And the contribution of laser intensity noise to clock instability is also reduced. Using optimized photodetector with high common mode rejection ratio, a better performance should be expected. This proposed scheme is attractive for the development of high performance vapor clock based on pulsed optically pumped.

EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC: From molecular mechanisms to clinical research.

With the development of precision medicine, molecular targeted therapy has been widely used in the field of cancer, especially in non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) is a well-recognized and effective target for NSCLC therapies, targeted EGFR therapy with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) has achieved ideal clinical efficacy in recent years. Unfortunately, resistance to EGFR-TKIs inevitably occurs due to various mechanisms after a period of therapy. EGFR mutations, such as T790M and C797S, are the most common mechanism of EGFR-TKI resistance. Here, we discuss the mechanisms of EGFR-TKIs resistance induced by secondary EGFR mutations, highlight the development of targeted drugs to overcome EGFR mutation-mediated resistance, and predict the promising directions for development of novel candidates.

The Neuroprotective Role of MiR-124-3p in a 6-Hydroxydopamine-Induced Cell Model of Parkinson's Disease via the Regulation of ANAX5.

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by a progressive loss of dopaminergic neurons in the midbrain. Several pathogenetic factors have been involved in the onset and progression of PD, including inflammation, oxidative stress, unfolded protein accumulation, and apoptosis. Ample evidence indicates that miRNAs could regulate post-transcriptional gene expression and neuronal disease. In this study, we evaluated the effects and mechanism of miR-124-3p on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PC12 cells and SH-SY5Y cells. qRT-PCR results showed that the level of miR-124-3p was downregulated in 6-OHDA-treated PC12 and SH-SY5Y cells, and overexpression of miR-124-3p significantly promoted the cell viability of 6-OHDA-treated PC12 and SH-SY5Y cells, whereas miR-124-3p inhibitor reversed these effects. In addition, PC12 or SH-SY5Y cells were treated with miR-124-3p mimics or inhibitors following 6-OHDA administration, which mediated cell apoptosis and downregulation or upregulation of Caspase-3 activity, respectively. A luciferase reporter assay revealed that annexinA5 (ANXA5) is a direct target gene of miR-124-3p, and miR-124-3p overexpression markedly downregulated the level of ANXA5. Strikingly, further analysis showed that miR-124-3p enhanced the viability of 6-OHDA-treated PC12 or SH-SY5Y cells by targeting ANXA5, which was associated with the stimulation of the ERK pathway. This study revealed that miR-124-3p may play a neuroprotective role in PD; this observation may provide new ideas and therapeutic targets for PD. J. Cell. Biochem. 119: 269-277, 2018. © 2017 Wiley Periodicals, Inc.

Effect of lamotrigine on epilepsy-induced cognitive impairment and hippocampal neuronal apoptosis in pentylenetetrazole-kindled animal model.

PURPOSE: Lamotrigine (LTG) is a broad-spectrum antiepileptic drug that is widely used in clinic. However, the effect of LTG on cognition and neurodegeneration during epilepsy treatment remains controversial. In this study, we compared the cognitive effects of LTG and sodium valproate in pentylenetetrazole (PTZ)-kindled animal model, and the dose dependency was tested for LTG. METHODS: PTZ-kindled animals were divided into the following treatment groups: control group, treated with 3.5 mL/kg of 0.9% sodium chloride; low-dose LTG group, treated with 12.5 mg/kg of LTG; middle-dose LTG group, treated with 25 mg/kg of LTG; high-dose LTG group, treated with 50 mg/kg of LTG; VPA group, treated with 300 mg/kg of VPA. The Morris Water Maze (MWM) test commenced from the 10th day of treatment. Hippocampal cell apoptosis was determined by TUNEL staining after two weeks of treatment. RESULTS: Compared to the vehicle-treated control group, escape latency was significantly reduced in the middle- and high-dose LTG- and VPA-treated groups on the 3rd and 4th day of the MWM test (p < .05), and spatial probe frequency was significantly improved in the middle- and high-dose LTG- and VPA-treated groups (p < .05). Furthermore, the immunohistochemical score of TUNEL positive cells significantly decreased in the hippocampal CA1 region in the middle- and high-dose LTG- and VPA-treated groups (p < .05). CONCLUSION: Our data suggests that LTG may ameliorate epilepsy-induced cognitive impairment and neuronal cell apoptosis during epilepsy treatment. LTG may ameliorate cognitive impairment and neuronal cell apoptosis during epilepsy treatment.

Sanguinarine induces apoptosis in osteosarcoma by attenuating the binding of STAT3 to the single-stranded DNA-binding protein 1 (SSBP1) promoter region.

BACKGROUND AND PURPOSE: Osteosarcoma, a primary malignant bone tumour prevalent among adolescents and young adults, remains a considerable challenge despite protracted progress made in enhancing patient survival rates over the last 40 years. Consequently, the development of novel therapeutic approaches for osteosarcoma is imperative. Sanguinarine (SNG), a compound with demonstrated potent anticancer properties against various malignancies, presents a promising avenue for exploration. Nevertheless, the intricate molecular mechanisms underpinning SNG's actions in osteosarcoma remain elusive, necessitating further elucidation. EXPERIMENTAL APPROACH: Single-stranded DNA-binding protein 1 (SSBP1) was screened out by differential proteomic analysis. Apoptosis, cell cycle, reactive oxygen species (ROS) and mitochondrial changes were assessed via flow cytometry. Western blotting and quantitative real-time reverse transcription PCR (qRT-PCR) were used to determine protein and gene levels. The antitumour mechanism of SNG was explored at a molecular level using chromatin immunoprecipitation (ChIP) and dual luciferase reporter plasmids. KEY RESULTS: Our investigation revealed that SNG exerted an up-regulated effect on SSBP1, disrupting mitochondrial function and inducing apoptosis. In-depth analysis uncovered a mechanism whereby SNG hindered the JAK/signal transducer and activator of transcription 3 (STAT3) signalling pathway, relieved the inhibitory effect of STAT3 on SSBP1 transcription, and inhibited the downstream PI3K/Akt/mTOR signalling axis, ultimately activating apoptosis. CONCLUSIONS AND IMPLICATIONS: The study delved further into elucidating the anticancer mechanism of SNG in osteosarcoma. Notably, we unravelled the previously undisclosed apoptotic potential of SSBP1 in osteosarcoma cells. This finding holds substantial promise in advancing the development of novel anticancer drugs and identification of therapeutic targets.

Discovery of a potent inhibitor of chaperone-mediated autophagy that targets the HSC70-LAMP2A interaction in non-small cell lung cancer cells.

BACKGROUND AND PURPOSE: Chaperone-mediated autophagy (CMA) is a selective type of autophagy targeting protein degradation and maintains high activity in many malignancies. Inhibition of the combination of HSC70 and LAMP2A can potently block CMA. At present, knockdown of LAMP2A remains the most specific method for inhibiting CMA and chemical inhibitors against CMA have not yet been discovered. EXPERIMENTAL APPROACH: Levels of CMA in non-small cell lung cancer (NSCLC) tissue samples were confirmed by tyramide signal amplification dual immunofluorescence assay. High-content screening was performed based on CMA activity, to identify potential inhibitors of CMA. Inhibitor targets were determined by drug affinity responsive target stability-mass spectrum and confirmed by protein mass spectrometry. CMA was inhibited and activated to elucidate the molecular mechanism of the CMA inhibitor. KEY RESULTS: Suppression of interactions between HSC70 and LAMP2A blocked CMA in NSCLC, restraining tumour growth. Polyphyllin D (PPD) was identified as a targeted CMA small-molecule inhibitor through disrupting HSC70-LAMP2A interactions. The binding sites for PPD were E129 and T278 at the nucleotide-binding domain of HSC70 and C-terminal of LAMP2A, respectively. PPD accelerated unfolded protein generation to induce reactive oxygen species (ROS) accumulation by inhibiting HSC70-LAMP2A-eIF2α signalling axis. Also, PPD prevented regulatory compensation of macroautophagy induced by CMA inhibition via blocking the STX17-SNAP29-VAMP8 signalling axis. CONCLUSIONS AND IMPLICATIONS: PPD is a targeted CMA inhibitor that blocked both HSC70-LAMP2A interactions and LAMP2A homo-multimerization. CMA suppression without increasing the regulatory compensation from macroautophagy is a good strategy for NSCLC therapy.

Single-cell sequencing reveals the landscape of the tumor microenvironment in a skeletal undifferentiated pleomorphic sarcoma patient.

Skeletal undifferentiated pleomorphic sarcoma (SUPS) is an invasive pleomorphic soft tissue sarcoma with a high degree of malignancy and poor prognosis. It is prone to recur and metastasize. The tumor microenvironment (TME) and the pathophysiology of SUPS are barely described. Single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect the landscape of human diseases at an unprecedented resolution, particularly in diseases lacking animal models, such as SUPS. We performed scRNA-seq to analyze tumor tissues and paracancer tissues from a SUPS patient. We identified the cell types and the corresponding marker genes in this SUPS case. We further showed that CD8+ exhausted T cells and Tregs highly expressed PDCD1, CTLA4 and TIGIT. Thus, PDCD1, CTLA4 and TIGIT were identified as potential targets in this case. We applied copy number karyotyping of aneuploid tumors (CopyKAT) to distinguish malignant cells from normal cells in fibroblasts. Our study identified eight malignant fibroblast subsets in SUPS with distinct gene expression profiles. C1-malignant Fibroblast and C6-malignant Fibroblast in the TME play crucial roles in tumor growth, angiogenesis, metastasis and immune response. Hence, targeting malignant fibroblasts could represent a potential strategy for this SUPS therapy. Intervention via tirelizumab enabled disease control, and immune checkpoint inhibitors (ICIs) of PD-1 may be considered as the first-line option in patients with SUPS. Taken together, scRNA-seq analyses provided a powerful basis for this SUPS treatment, improved our understanding of complex human diseases, and may afforded an alternative approach for personalized medicine in the future.

Polyphyllin I promotes cell death via suppressing UPR-mediated CHOP ubiquitination and degradation in non-small cell lung cancer.

Polyphyllin I (PPI) purified from Polyphyllarhizomes displays puissant cytotoxicity in many kinds of cancers. Several researches investigated its anti-cancer activity. But novel mechanisms are still worth investigation. This study aimed to explore PPI-induced endoplasmic reticulum (ER) stress as well as the underlying mechanism in non-small cell lung cancer (NSCLC). Cell viability or colony-forming was detected by MTT or crystal violet respectively. Cell cycle, apoptosis, reactive oxygen species (ROS) and mitochondrial membrane potential were assessed by flow cytometry. Gene and protein levels were evaluated by qRT-PCR and immunoblotting respectively. Protein interaction was determined by immunoprecipitation or immunofluorescence assay. Gene overexpression or silencing was carried out by transient transfection with plasmids or small interfering RNAs. The Cancer Genome Atlas (TCGA) database was used for Gene Set Enrichment Analysis (GSEA), survival analysis, gene expression statistics or pathway enrichment assay. PPI inhibited the propagation of NSCLC cells, increased non-viable apoptotic cells, arrested cell cycle at G2/M phase, induced ROS levels but failed to decrease mitochondrial membrane potential. High levels of GRP78 indicates poor prognosis in NSCLC patients. PPI selectively suppressed unfolded protein response (UPR)-induced GRP78 expression, subsequently protected CHOP from GRP78-mediated ubiquitination and degradation. We demonstrated that the natural product PPI, obtained from traditional herbal medicine, deserves for further study as a valuable candidate for lead compound in the chemotherapy of NSCLC.

MicroRNA and long noncoding RNA involvement in gout and prospects for treatment.

MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are both types of noncoding RNA. They have been demonstrated to be involved in the regulation of various human inflammatory diseases and can be used as biomarkers for disease diagnosis and prognosis, and even be developed into new drugs. Gout is an arthritic disease caused by the deposition of monosodium urate crystal (MSU) in the joints, which can lead to acute inflammation and damage adjacent tissue. Recent studies have shown that miRNAs and lncRNAs mediate the progress of gout. Based on the pathogenesis of gout, including hyperuricemia, MSU deposition, acute gouty arthritis and gouty bone erosion, this paper reviewed the role of miRNAs and lncRNAs in the processes and the possible therapeutic targets of miRNAs and lncRNAs in gout.

Neuroprotective effect of FMS-like tyrosine kinase-3 silence on cerebral ischemia/reperfusion injury in a SH-SY5Y cell line.

Neuron damage contributes to ischemic brain injury. Although FMS-like tyrosine kinase-3 (FLT3) plays a critical role in neuron survival, its function and molecular mechanism in cerebral ischemia/reperfusion injury is unclear. In the present study, we exposed SH-SY5Y cells to oxygen and glucose deprivation/reoxygenation (OGD/R) to mimic ischemia/reperfusion injury. We found that FLT3 and MAPK14/p38α expression increased in OGD/R-treated cells. FLT3 silence significantly increased OGD/R-induced SH-SY5Y cell survival, inhibited reactive oxygen species production. Also, we observed that FLT3 silence suppressed OGD/R-induced SH-SY5Y cell apoptosis, apoptosis related protein Bax level and caspase-3 activity was decreased and Bcl-2 expression was increased in FLT3 silence SH-SY5Y cell treated with OGD/R. Furthermore, FLT3 depletion induced MAPK14/p38α inhibition in SH-SY5Y cultures after OGD/R exposure. These findings suggest that MAPK14/p38α overexpression reverses the action of FLT3 silence in OGD/R-induced SH-SY5Y cells. They also provide the first evidence that FLT3 silence has a neuroprotective role in OGD/R-induced SH-SY5Y cell damage. These data provide insight about potential neuroprotective molecular for ischemia/reperfusion injury.

Exotic vortex lattices in a rotating binary dipolar Bose-Einstein condensate.

In the last decade, considerable advances have been made in the investigation of dipolar quantum gases. Previous theoretical investigations of a rotating binary dipolar Bose-Einstein condensate, where only one component possesses dipole moment, were mainly focused on two special orientations of the dipoles: perpendicular or parallel to the plane of motion. Here we study the ground-state and rotational properties of such a system for an arbitrary orientation of the dipoles. We demonstrate the ground-state vortex structures depend strongly on the relative strength between dipolar and contact interactions and the rotation frequency, as well as on the orientation of the dipoles. In the absence of rotation, the tunable dipolar interaction can be used to induce the squeezing or expansion of the cloud, and to derive the phase transition between phase coexistence and separation. Under finite rotation, the system is found to exhibit exotic ground-state vortex configurations, such as kernel-shell, vortex necklace, and compensating stripe vortex structures. We also check the validity of the Feynman relation, and find no significant deviations from it. The obtained results open up alternate ways for the quantum control of dipolar quantum gases.

Two-component dipolar Bose-Einstein condensate in concentrically coupled annular traps.

Dipolar Bosonic atoms confined in external potentials open up new avenues for quantum-state manipulation and will contribute to the design and exploration of novel functional materials. Here we investigate the ground-state and rotational properties of a rotating two-component dipolar Bose-Einstein condensate, which consists of both dipolar bosonic atoms with magnetic dipole moments aligned vertically to the condensate and one without dipole moments, confined in concentrically coupled annular traps. For the nonrotational case, it is found that the tunable dipolar interaction can be used to control the location of each component between the inner and outer rings, and to induce the desired ground-state phase. Under finite rotation, it is shown that there exists a critical value of rotational frequency for the nondipolar case, above which vortex state can form at the trap center, and the related vortex structures depend strongly on the rotational frequency. For the dipolar case, it is found that various ground-state phases and the related vortex structures, such as polygonal vortex clusters and vortex necklaces, can be obtained via a proper choice of the dipolar interaction and rotational frequency. Finally, we also study and discuss the formation process of such vortex structures.