A cascade radical cyclization/sulfenylation or selenylation of β,γ-unsaturated hydrazones and oximes was realized under mild conditions with phenyliodine(iii) diacetate (PIDA) as the sole oxidant, ...leading to the construction of diversely functionalized heteroatom-containing pyrazoline and isoxazoline derivatives. This metal-free radical process is suggested to encompass a sequential C-N/O and C-S/Se bond fomation.
Neurotransmitters and neuromodulators are key neurochemicals that mediate cell–cell communication, maintain the body's homeostasis, and control a wide range of biological processes. Thus, ...dysregulation of neurochemical signaling is associated with a range of psychiatric disorders and neurological diseases. Understanding the physiological and pathophysiological functions of neurochemicals, particularly in complex biological systems in vivo, requires tools that can probe their dynamics with high sensitivity and specificity. Recently, genetically encoded fluorescent sensors for visualizing specific neurochemicals were developed by coupling neurochemical‐sensing G‐protein‐coupled receptors (GPCRs) with a circular‐permutated fluorescent protein. These GPCR‐based sensors can monitor the dynamics of neurochemicals in behaving animals with high spatiotemporal resolution. Here, we review recent progress regarding the development and application of GPCR‐based sensors for imaging neurochemicals, and we discuss future perspectives.
Precisely probing the dynamics of specific neurochemicals in the complex biological system is the key to understand their functions. In this review, we summarized the recent progress on using GPCRs as the scaffold to engineer neurochemical‐specific fluorescent sensors, which could achieve the sensitive and specific detection of neurochemicals with millisecond temporal resolution and sub‐cellular spatial resolution. Taking advantage of these tools, researchers have successfully dissected the dynamics as well as function of neurochemicals in various of animal species performing distinct behaviors. With future optimizations, we anticipate that these GPCR‐based sensors will be powerful tools in studying neurochemical signals.
Hierarchically porous metal–organic frameworks (HP‐MOFs) have attracted great attention owing to their advantages over microporous MOFs in some applications. Despite many attempts, the development of ...a facile approach to generate HP‐MOFs remains a challenge. Herein we develop a new strategy, namely the modulation of cation valence, to create hierarchical porosity in MOFs. Some of the CuII metal nodes in MOFs can be transformed into CuI via reducing vapor treatment (RVT), which partially changes the coordination mode and thus breaks coordination bonds, resulting in the formation of HP‐MOF based on the original microporous MOF. Both the experimental results and the first‐principles calculation show that it is easy to tailor the amount of CuI and subsequent hierarchical porosity by tuning the RVT duration. It is found that the resultant HP‐MOFs perform much better in the capture of aromatic sulfides than the original microporous MOF.
Making the cut: Some of CuII nodes in the metal–organic framework (MOF) HKUST‐1 can be transformed into CuI by a reducing vapor treatment (RVT). This treatment partially changes the coordination mode of the Cu nodes and thus breaks coordination bonds, resulting in the formation of hierarchical pores from the original microporous HKUST‐1.
Background
Elevated thyroid hormone (TH) levels have been suggested to be associated with the pathological progression of Graves' disease (GD). However, direct evidence from clinical studies remains ...unclear.
Methods
Peripheral blood samples were collected from patients with or without the recurrence of Graves' hyperthyroidism (GH) and healthy donors. Thyroid tissue samples were obtained from patients with benign thyroid nodules. To assess the differentiation of autoreactive B cells, the expression of B‐cell‐activating factor (BAFF) and the proportion of CD11c+/–IgG+/− subsets of B cells stimulated by high levels of triiodothyronine (T3) in vivo and in vitro were examined by ELISA, flow cytometry, western blotting, and qRT‐PCR.
Results
Serum BAFF levels in patients with GD were significantly and positively correlated with FT3, FT4, and TRAb levels. Furthermore, the ratio of abnormally differentiated CD11c+ autoreactive B cells positively correlated with BAFF and TRAb. High levels of triiodothyronine (T3) induced BAFF overexpression in thyroid follicular cells and mononuclear cells of the normal thyroid in vitro, thereby promoting the differentiation of CD11c+IgG+ autoreactive secretory B cells (ASCs). However, the precise knockdown of BAFF expression significantly inhibited the abnormal differentiation of ASCs.
Conclusion
The pathological progression of GD was prolonged and exacerbated by autoimmune positive feedback modulation caused by high TH levels. BAFF could be considered a potential target for localized thyroid immunosuppressive treatment of Graves' hyperthyroidism recurrence.
In the present study, we found that the pathological progression of GD was prolonged and exacerbated by positive feedback regulation of abnormal differentiation of local autoimmune secretory B cells (ASCs) in the thyroid induced by high TH levels, in which BAFF plays a key bridging role and can be considered as a potential target for local thyroid immunosuppression in the treatment of Graves' hyperthyroidism relapse.
Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this ...study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.
Activated B cells contribute to heart diseases, and inhibition of B‐cell activating factor (BAFF) expression is an effective therapeutic target for heart diseases. Whether activated B cells ...participate in the development and progression of hyperthyroid heart disease, and what induces B cells activation in hyperthyroidism are unknown. The present study aimed to determine the roles of BAFF overexpression induced by high concentrations of triiodothyronine (T3) in the pathogenesis of hyperthyroid heart disease. Female C57BL/6J mice were subcutaneously injected with T3 for 6 weeks, and BAFF expression was inhibited using shRNA. Protein and mRNA expression of BAFF in mouse heart tissues evaluated via immunohistochemistry, western blotting and polymerase chain reaction (PCR). Proportions of B cells in mouse cardiac tissue lymphocytes were quantified via flow cytometry. Morphology and left ventricle function were assessed using pathological sections and echocardiography, respectively. Here, we demonstrate that compared with the control group, the proportion of myocardial B cells was larger in the T3 group; immunohistochemistry, western blotting and PCR analyses revealed increased protein and mRNA expression levels of TNF‐α and BAFF in heart tissues of the T3 group. Compared with the normal controls group, in the T3 group, the diameter of myocardial cells and some echocardiographic values significantly increased and hypertrophy and structural disorder were noticeable. Our results revealed that elevated levels of circulating T3 can promote the expression of BAFF in myocardial cells and can lead to B‐cell activation, an elevated inflammatory response and ventricular remodelling.
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•Genetically-encoded fluorescent sensors are essential for studying neurotransmission.•Today's sensors are limited in certain aspects, especially for in vivo applications.•GPCR is a ...versatile platform for engineering next-generation fluorescent sensors.
Measuring the precise dynamics of specific neurotransmitters and neuromodulators in the brain is essential for understanding how information is transmitted and processed. Thanks to the development and optimization of various genetically encoded sensors, we are approaching the stage in which a few key neurotransmitters/neuromodulators can be imaged with high cell specificity and good signal-to-noise ratio. Here, we summarize recent progress regarding these sensors, focusing on their design principles, properties, potential applications, and current limitations. We also highlight the G protein-coupled receptor (GPCR) scaffold as a promising platform that may enable the scalable development of the next generation of sensors, enabling the rapid, sensitive, and specific detection of a large repertoire of neurotransmitters/neuromodulators in vivo at cellular or even subcellular resolution.
Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National ...Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma.
In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18–60 years with previously untreated, non-keratinising stage III–IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1–5 and 22–26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68–70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62–68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30–32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed.
From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9–81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7–80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio HR 0·98, 95% CI 0·69–1·39; log-rank p=0·92), with a difference of 0·5% (95% CI −7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (−6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3–4 adverse events were mucositis (102 41% of 252 in the lobaplatin-based group vs 99 40% of 249 in the cisplatin-based group), leucopenia (39 16% vs 56 23%), and neutropenia (25 10% vs 59 24%). No treatment-related deaths were reported.
Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma.
National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University.
For the Chinese translation of the abstract see Supplementary Materials section.
Abstract
Objective
Breakdown of tolerance and abnormal activation of B cells is an important mechanism in the pathogenesis of Graves' disease (GD). High levels of thyroid hormones (THs) play ...important roles in GD progression. However, the interactions between THs and abnormal activation of B cells remain elusive. This study aimed to explore the effect of high levels of THs on TLR4 expression and abnormal B cell differentiation.
Materials and Methods
Blood samples were collected from patients with GD and healthy controls (HCs) to evaluate the frequency of B cells, their subsets, and TLR4 expression in B cells. A high‐level T3 mouse model was used to study the interaction between THs and the TLR4 signalling pathway.
Results
We found that the frequencies of CD19
+
, CD19
+
TLR4
+
, CD19
+
CD86
+
, and CD19
+
CD138
+
B cells were significantly higher, as were the expression levels of MRP8/MRP14 and MRP6 and MRP8, MRP14, and MRP6 messenger RNA (mRNA) in peripheral blood mononuclear cells in patients with GD. In high‐level T3 mice models, the serum MRP8/MRP14 and MRP6 levels and the TLR4 mRNA expression in PBMCs were significantly higher. TLR4 mRNA, protein expression, and cytokines downstream of TLR4, such as myeloid differentiation factor 88 (MyD88) and nuclear transcription factor‐κB, were also increased in mouse spleen mononuclear cells.
Conclusion
The present study indicated that high levels of T3 can induce abnormal differentiation and activation of B cells by promoting TLR4 overexpression and provide novel insights into the roles of THs in the pathogenesis of GD.
Norepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in ...part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRABNE) sensors with a 230% peak ΔF/F0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRABNE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRABNE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.
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•GRABNE sensors are genetically encoded GPCR activation-based norepinephrine sensors•GRABNE distinguishes norepinephrine from dopamine with 1,000-fold specificity•The norepinephrine measurements are sensitive, with high spatiotemporal resolution•Norepinephrine dynamics are observed during stressful behaviors in zebrafish and mice
Feng et al. develop and validate a pair of genetically encoded GPCR-activation-based norepinephrine sensors, which, for the first time, enable specific in vivo measurement of norepinephrine dynamics during stressful behaviors with high spatiotemporal resolution in zebrafish and mice.
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