Iodine-Catalyzed Cyclization of o-Nitrothiophenols with Cyclohexanones to Phenothiazines.

Here, a novel iodine-catalyzed direct cyclization of o-nitrothiophenols with cyclohexanones to phenothiazines has been described without external oxidants and hydrogen acceptors. The nitro of o-nitrothiophenol works as both a hydrogen acceptor and a coupling group, and water is the only byproduct. The reaction involves the reduction of nitro groups, C-H bond thioetherification, and C-H bond dehydroaromatization. This scheme offers broad synthetic value for further elaborations, as exemplified by a 3-step total synthesis of antipsychotic chlorpromazine.

Palladium-catalyzed dehydrogenation of α-cyclohexene-substituted nitriles to α-aryl nitriles.

The development of a practical, inexpensive, and cyanide-free method for synthesizing α-aryl nitriles remains a challenging goal in synthetic chemistry. Here, we report an approach for synthesizing α-aryl nitriles toward achieving this goal, by which α-cyclohexenyl acetonitriles and α-cyclohexenyl alkenyl nitriles are dehydrogenated to α-aryl nitriles.

Psychological stress induces hair regenerative disorders through corticotropin-releasing hormone-mediated autophagy inhibition.

Psychosocial stress is increasing, causing a growing number of people to suffer from hair loss. Stress-related corticotropin-releasing hormone (CRH) is associated with hair loss, but the mechanism by which hair follicles respond to stress and CRH remain poorly understood. The aim of the study is to elucidate the association between CRH and stress-related hair regenerative disorders, and reveal the potential pathological mechanisms. A chronic unpredictable stress mouse model and a chronic social defeat stress mouse model were used to examine the role of CRH and stress-related hair regrowth. Chronic unpredictable stress and chronic social defeat stress increased the expression of CRH and CRH receptors (CRHRs), and contributed to the onset of hair-cycle abnormalities. Psychoemotional stress and stress-related CRH blocked hair follicle regrowth, which could be restored by astressin, a CRHR antagonist. Long-term exposure to either chronic unpredictable stress or CRH induced a decrease in autophagy, which could be partially rescued by astressin. Activating CRHR, by stress or CRH administration, decreased autophagy via the mTOR-ULK1 signaling pathway to mediate hair regenerative disorders, which could be partially reversed through enhancing autophagy by administration of brefeldin A. These findings indicate that CRH-mediated autophagy inhibition play an important role in stress-induced hair regenerative disorders. CRH regulates the local hypothalamic-pituitary-adrenal axis of hair follicles, but also plays an independent pathogenic role in stress-related hair regenerative disorders through CRH-mediated autophagy inhibition. This work contributes to the present understanding of hair loss and suggests that enhancing autophagy may have a therapeutic effect on stress-induced hair loss.

Sympathetic Reinnervation of Intact and Upper Follicle Xenografts into BALB/c-nu/nu Mice.

Increasing concerns about hair loss affect people's quality of life. Recent studies have found that sympathetic nerves play a positive role in regulating hair follicle stem cell activity to promote hair growth. However, no study has investigated sympathetic innervation of transplanted follicles. Rat vibrissa follicles were extracted and implanted under the dorsal skin of BALB/c-nu/nu mice using one of two types of follicles: (1) intact follicles, where transplants included bulbs, and (2) upper follicles, where transplants excluded bulbs. Follicular samples were collected for hematoxylin and eosin staining, immunofluorescence staining for tyrosine hydroxylase (TH, a sympathetic marker) and enzyme-linked immunosorbent assays. At 37 days after implantation in both groups, follicles had entered anagen, with the growth of long hair shafts; tyrosine-hydroxylase-positive nerves were innervating follicles (1.45-fold); and norepinephrine concentrations (2.03-fold) were significantly increased compared to 5 days, but did not return to normal. We demonstrate the survival of intact and upper follicle xenografts and the partial restoration of sympathetic reinnervations of both transplanted follicles.

Direct Synthesis of Esters from Alkylarenes and Carboxylic Acids: The C-H Bond Dehydroesterification.

Herein, a reaction in which the benzyl C-H bonds of alkylarenes are directly esterified by carboxylic acids to produce benzyl esters in high yields is reported. This reaction is catalyzed by Pd nanoparticles (NPs) on N-doped carbon (CN) composites based on a carbonizing Al-MIL-101(NH2) material, and no oxidants or hydrogen acceptors are required. Use of o-alkylbenzoic acids as substrates leads to phthalides, whereas with carboxylic acids and alkylarenes as the feedstock, the reaction produces the benzyl esters. These reactions that use readily available alkylarenes instead of benzyl halides or benzyl alcohols as raw materials for one-step synthesis of benzyl esters without oxidants are inherently atom- and step-efficient. The CN composites and the CN-supported Pd NP catalysts were prepared and are well characterized. The proposed mechanism involves dehydrogenation of both the carboxylic groups and the benzylic groups and the transformation of benzylic C-H bond into the C-O bond via hydrogen abstraction from the benzylic group through an organopalladium intermediate. The kinetic isotope effect (kH/kD = 2.77) indicated that C(sp3)-H bond cleavage of the alkane aromatics is the rate-determining step.

[Percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation for the treatment of moderate hallux valgus].

OBJECTIVE: To observe clinical effect of percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation in treating moderate hallux valgus. METHODS: Totally 23 patients with moderate hallux valgus were treated with percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation from August 2019 to January 2021, and 1 patient was loss to follow-up, and finally 22 patients(30 feet) were included, 4 males (6 feet) and 18 females(24 feet), aged from 27 to 66 years old with an average of(50.59±11.95) years old. Hallux valgus angle (HVA), intermetatarsal angle (IMA), metatarsal span (the distance between the first and the fifth metatarsal bones), changed of soft tissue width, American Orthopaedic Foot and Ankle Society(AOFAS) score, and Visual Analogue Scale (VAS) were collected and compared before operation and 6 months after operation. RESULTS: Twenty-two patients were followed up from 5.7 to 6.4 months with an average of (6.13±0.85) months. The first metatarsal osteotomy of patients were obtained bone union, and deformity of the toes was corrected. Complications such as avascular necrosis of metatarsal head and transfer metatarsalgia were not occurred. Postoperative HVA, IMA, metatarsal span, soft tissue width, VAS, AOFAS score at 6 months were significantly improved compared with pre-operation (P<0.01). According to AOFAS score at 6 months after operation, 10 feet were excellent, 18 good and 2 poor. Two feet with poor were excellent after prolonged 8-shaped bandage and hallux valgus splint fixation time. CONCLUSION: Percutaneous minimally invasive osteotomy with 8-shaped bandage and hallux valgus splint fixation for the treatment of moderate hallux valgus could better correct deformity of hallux valgus, relieve foot symptoms, good recovery of postoperative function, and has a significant clinical efficacy.

Aptasensing a class of small molecules based on split aptamers and hybridization chain reaction-assisted AuNPs nanozyme.

Constructing robust group-specific probes and non-competitive analysis methods for small molecules in the fields of food analysis is of great significance. In this study, three diarrhetic shellfish poisons (DSPs) with high safety risks to humans were taken as models of group targets, and a non-competitive and turn-on format colorimetric aptasensor was constructed for simultaneous and highly sensitive detection of the class of DSPs. A pair of anti-DSP split aptamers were generated with group-specific binding affinity to the three targets. The split aptamers were then fabricated with a hybridization chain reaction (HCR)-enhanced AuNPs nanozyme. The aptasensor realized linear detection range of 187.5-3000 pM, high sensitivity with a limit of detection (LOD) as low as 65.36 pM, good selectivity, as well as good accuracy when analyzing the DSPs in shellfish samples. This study provides good reference for developing robust probes and facile biosensors to detect multiple small molecules in food matrix.

Rapid Eye Movement Sleep Deprivation Enhances Adenosine Receptor Activation and the CREB1/YAP1/c-Myc Axis to Alleviate Depressive-like Behaviors in Rats.

As neuromodulators, adenosine and its receptors are mediators of sleep-wake regulation. A putative correlation between CREB1 and depression has been predicted in our bioinformatics analyses, and its expression was also predicted to be upregulated in response to sleep deprivation. Therefore, this study aims to elaborate the A1 and A2A adenosine receptors and CREB1-associated mechanism underlying the antidepressant effect of rapid eye movement sleep deprivation (REMSD) in rats with chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors. The modeled rats were injected with adenosine A1 receptor antagonist DPCPX or adenosine A2A receptor antagonist ZM241385 to assess the role of adenosine receptors in depression. In addition, ectopic expression and depletion experiments of CREB1 and YAP1 were also conducted in vivo and in vitro. It was found that REMSD alleviated depressive-like behaviors in CUMS rats, as shown by increased spontaneous activity, sucrose consumption and percentage, and shortened escape latency and immobility duration. Meanwhile, A1 or A2A adenosine receptor antagonists negated the antidepressant effect of REMSD. REMSD enhanced adenosine receptor activation and promoted the phosphorylation of CREB1, thus increasing the expression of CREB1. In addition, the overexpression of CREB1 activated the YAP1/c-Myc axis and consequently alleviated depressive-like behaviors. Collectively, our results provide new mechanistic insights for an understanding of the antidepressant effect of REMSD, which is associated with the activation of adenosine receptors and the CREB1/YAP1/c-Myc axis.

Development of a colorimetric aptasensor fabricated with a group-specific aptamer and AuNPs@Fe2+ nanozyme for simultaneous detection of multiple diarrheic shellfish poisons.

Okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2) are the main diarrheic shellfish poisons (DSPs). Detection methods to achieve simultaneous detection of the three toxins are urgently needed. In this paper, a terminal fixation design proposed in our previous study was further explored to engineer an aptamer with group-specific recognition ability from an original aptamer binding to one target. Both molecular docking assay and biolayer interferometry assay were applied to reveal the binding mechanisms between three DSPs and the engineered aptamer. Then, a label-free colorimetric aptasensor by fabricating the aptamer with AuNPs@Fe2+ nanozyme was constructed, which provided a wide linear detection range (0.4688-7.5 nM), a very low limit of detection (LOD, 86.28 pM), and good recoveries (96.02-104.9%) when analyzing DSPs in seawater and scallop samples, indicating the engineered aptamer and the developed aptasensor had great potential in recognizing and detecting multiple DSPs in real world.

Emerging roles of the aptasensors as superior bioaffinity sensors for monitoring shellfish toxins in marine food chain.

Shellfish toxins are derived from harmful algae and are easily accumulated in environment and marine food through the food chain, exposing high risks on human health. Preliminary rapid screening is one of the most effective monitoring ways to reduce the potential risks; however, the traditional methods encounter with many limitations, such as complicated procedures, low sensitivity and specificity, and ethical problems. Alternatively, bioaffinity sensors are proposed and draw particular attention. Among them, the aptasensors are springing up and emerging as superior alternatives in recent years, exhibiting high practicability to analyze shellfish toxins in real samples in the marine food chain. Herein, the latest research progresses of aptasensors towards shellfish toxins in the marine food chain in the past five years was reviewed for the first time, in terms of the aptamers applied in these aptasensors, construction principles, signal transduction techniques, response types, individual performance properties, practical applications, and advantages/disadvantages of these aptasensors. Synchronously, critical discussions were given and future perspectives were prospected. We hope this review can serve as a powerful reference to promote further development and application of aptasensors to monitor shellfish toxins, as well as other analytes with similar demands.

A label-free colorimetric aptasensor based on split aptamers-chitosan oligosaccharide-AuNPs nanocomposites for sensitive and selective detection of kanamycin.

Herein, the split aptamers, chitosan oligosaccharide, and AuNPs were combined as nanocomposites that present different formations to develop a label-free colorimetric aptasensor for rapid detection of small molecules. Kanamycin was chosen as a model target. Computational studies were performed to assist in the design of orientated immobilization of the split aptamers onto the AuNPs surface. Chitosan oligosaccharide was initially applied as an aggregation inducer of AuNPs, and chitopentaose was screened as the optimal. Under optimized conditions, the proposed aptasensor showed high sensitivity and selectivity, with a limit of detection of 20.58 nM, a linear range of 25-800 nM, and good recoveries of 98.49-104.9% and 85.69-107.0% when employed to detect kanamycin in tap water and milk samples, respectively. Only 55 min was needed for the whole assay. More importantly, this study can serve as a novel and robust reference for the aptasensing detection of other small molecules.

Chronic social defeat stress caused region-specific oligodendrogenesis impairment in adolescent mice.

Introduction: Social stress in adolescents precipitates stress-related emotional disorders. In this study we aimed to investigate oligodendrogenesis in three stress-associated brain regions, medial prefrontal cortex (mPFC), habenula, and amygdala in adolescent mice exposed to social defeat stress. Methods: Four-week-old adolescent mice were subjected to social defeat for 10 days, followed by behavioral tests and evaluations of oligodendroglial proliferation and differentiation. Results: Stressed mice showed reduced social interaction, more stretched approach posture, lower sucrose preference, but no changes in the forced swimming test. EdU labeled proliferative cells, newly formed NG2+EdU + oligodendrocyte precursor cells (OPCs), and Olig2+EdU+ oligodendrocyte lineage cells (OLLs) were significantly decreased in the mPFC and the lateral habenula, but not in the amygdala and the medial habenula in socially defeated mice. APC+Edu+ newly-generated mature oligodendrocytes (OLs) were decreased in the mPFC in stressed mice. However, the total number of NG2+ OPCs, APC+ mature OLs, and Olig2+ OLLs were comparable in all the brain regions examined between stressed and control mice except for a decrease of APC+ mature OLs in the prelimbic cortex of stressed mice. Conclusion: Our findings indicate that adolescent social stress causes emotion-related behavioral changes and region-specific impairment of oligodendrogenesis.

Advances and perspectives of aptasensors for the detection of tetracyclines: A class of model compounds of food analysis.

The residual tetracyclines in food are frequently applied as the model compounds to develop aptasensors. Until now, more than 100 advanced aptasensors towards tetracyclines have been developed and published in English. This review summarizes and discusses comprehensively these advanced aptasensors, in terms of the principle designs, applied frontier transducers/materials, working performance, and advantages/disadvantages. The aptasensors are classified according to the inherent transduction techniques, i.e., optics, optics-electricity, optics-mass, and electricity-mass. Moreover, the present challenges such as the limited specificity and limited affinity of the aptamers, the future prospects and trends such as further combination with other advanced materials and technologies, and the urgent need of expanding the practical application were discussed and prospected. We hope this review can serve as a powerful tool for both tracing the development progresses of aptasensors and providing adequate references for further development of aptasensing methods for food-related analytes.

A competitive colorimetric aptasensor transduced by hybridization chain reaction-facilitated catalysis of AuNPs nanozyme for highly sensitive detection of saxitoxin.

Saxitoxin (STX) is a small molecule toxin (Mw. ca. 299 g/mol) with high acute toxicity, and it has urgent need of facile analytical methods. Herein, a competitive colorimetric aptasensor was developed for highly sensitive detection of STX. An anti-STX aptamer was hybridized with a complementary strand on the magnetic beads and was competitively bound by STX. The supernatant containing the aptamer binding to STX was obtained by magnetic separation, which could trigger hybridization chain reaction (HCR) to generate rigid double stranded DNAs (dsDNAs) with sticky end and variable length. These HCR-dsDNAs were found to be able to facilitate significant enhancement on the peroxidase-like catalytic capability of AuNPs nanozyme towards 3,3,5,5-tetramethylbenzidine (TMB). The concentration of STX was responded in a "turn on" mode, based on the amplified colorimetric transduction thereof. The aptasensor realized high sensitivity, with a limit of detection (LOD) as low as 42.46 pM. Moreover, a wide linear detection range of 78.13-2500 pM, good selectivity, as well as good recovery rates of 106.2-113.5% when analyzing STX in real shellfish samples were obtained. This strategy could be referred to develop robust aptasensors for simple and highly sensitive detection of other small molecules and toxins.

Rehabilitation training combined acupuncture for limb hemiplegia caused by cerebral infarction: A protocol for a systematic review of randomized controlled trial.

BACKGROUND: Previous studies have reported that rehabilitation training combined acupuncture (RTA) can be used for the treatment of limb hemiplegia (LH) caused by cerebral infarction (CI). However, its effectiveness is still unclear. In this systematic review study, we aim to evaluate the effectiveness and safety of RTA for LH following CI. METHODS: We will retrieve the databases of CENTRAL, EMBASE, MEDILINE, CINAHL, AMED, CBM, PUBMED, and CNKI from inception to June 1, 2020 with no language restrictions. The randomized controlled trials of RTA for evaluating effectiveness and safety in patients with LH following CI will be included. Cochrane risk of bias tool will be used to measure the methodological quality for all included studies. Two authors will independently select the studies, extract the data, and assess the methodological quality of included studies. A third author will be invited to discuss if any disagreements exist between 2 authors. We will perform heterogeneity assessment before carrying out meta-analysis. According to the heterogeneity, we select random effect model or fixed effect model for meta-analysis of the included cohort studies. Cochrane risk of bias tool will be used to determine the methodological quality for included studies. RevMan 5.3 software (Cochrane Community, London, UK) will be utilized to perform statistical analysis. RESULTS: This systematic review will assess the effectiveness and safety of RTA for LH caused by CI. The primary outcome includes limbs function, as measured by the Wolf Motor Function Test (WMFT) Assessment scale, or other associated scales. The secondary outcomes consist of muscle strength, muscle tone, quality of life, and any adverse events. CONCLUSION: The findings of this study will summarize the current evidence of RTA for LH caused by CI, and may provide helpful evidence for the clinical treatment. DISSEMINATION AND ETHICS: The findings of this study are expected to be published in peer-reviewed journals. It does not require ethical approval, because no individual data will be utilized in this study. SYSTEMATIC REVIEW REGISTRATION: INPLASY202070114.

Deep rTMS Mitigates Behavioral and Neuropathologic Anomalies in Cuprizone-Exposed Mice Through Reducing Microglial Proinflammatory Cytokines.

In comparison to conventional repetitive transcranial magnetic stimulation (rTMS), theta burst stimulation is stronger and more effective as a brain stimulation approach within short periods. Although this deep rTMS technique is being applied in treating neuropsychiatric disorders, few animal studies have attempted to clarify the neurobiological mechanisms underlying its beneficial effects. This animal study examined the effects of deep rTMS on the cuprizone-induced neuropathologic and behavioral anomalies and explored the underlying mechanism. Adolescent male C57BL/6 mice were fed a rodent chow without or with cuprizone (CPZ; 0.2% w/w) for 5 weeks. Another two groups of mice were subjected to deep rTMS or sham rTMS once a day during weeks 2-5 of the CPZ-feeding period. The behaviors of all mice were assessed after the withdrawal of CPZ before neuropathological and immunological analyses. Compared to the CNT group, mice in CPZ and CPZ + Sham groups showed deficits in social recognition and spatial working memory as well as anxiety-like behavior, in addition to myelin breakdown and OL loss in the corpus callosum (CC), caudate putamen, cerebral cortex, and hippocampus of the brain. Deep rTMS effectively reduced behavioral anomalies and blocked myelin breakdown and OL loss in CPZ-fed mice. Besides, it also dampened microglia activation at lesion sites and rectified cytokines levels (IL-1ß, IL-6, and IL-10) in CPZ-affected regions. The most significant effect was seen in the cerebral cortex where alleviated neuropathology co-existed with less microglia activation and higher IL-10 level. These data provided experimental evidence for the beneficial effects of deep rTMS in CPZ-fed mice and revealed a neurobiological mechanism of the modality.

Design, synthesis and biological evaluation of 3,4-diaryl-1,2,5-oxadiazole-2/5-oxides as highly potent inhibitors of tubulin polymerization.

Structure-activity relationships for rigid analogues of combretastatin A-4 (CA-4) were investigated, leading to the discovery of a series of 3,4-diaryl-1,2,5-oxadiazole-N-oxides. Among them, 7n' and 7n'' showed remarkable antiproliferative activities against three cancer cell lines in nanomolar concentrations. Interestingly, 7n' inhibited tubulin polymerization much more efficiently than CA-4. Cellular mechanism investigation elucidated 7n' disrupted the cellular microtubule structure, arrested cell cycle at G2/M phase and induces apoptosis. Molecular modeling study revealed 1,2,5-oxadiazole-N-oxide ring could increase a hydrogen bond interaction with the binding site. These results provide impetus and further guidance for the development of new CA-4 analogues.

Ultra-efficient spin-orbit torque induced magnetic switching in W/CoFeB/MgO structures.

Spin-orbit torque (SOT) induced magnetic switching in heavy metal/ferromagnet structures with perpendicular magnetic anisotropy (PMA) is promising for energy efficient spintronic devices. Here, we studied the SOT induced magnetic switching in perpendicular W/Co20Fe60B20/MgO structures. We demonstrated the critical current density for the SOT induced switching is as low as 1.15 × 106 A cm-2 in the presence of an in-plane magnetic field, which is very energy efficient in terms of magnetic switching. We attribute this ultra-efficient magnetic switching to the high spin Hall angle of the W layer and the ultra-low domain wall pinning field of the CoFeB. The SOT induced switching procedure was directly observed by a high-resolution Kerr microscopy. Furthermore, the weak Dzyaloshinsky-Moriya interactions are shown to be favorable for switching. Our experiments physically explained the ultra-efficient SOT induced magnetic switching in W/CoFeB/MgO structures, and direct observation of the switching procedure can improve the comprehensive understanding of this dynamic process and further promote the study of SOT based memory devices.

Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly.

MicroRNAs (miRNAs) are short, highly conserved small non-coding RNA molecules, which post-transcriptionally regulate genes expression and play crucial roles in diverse biological processes. Recent studies have shown that dysregulation of miRNAs might modulate the resistance of cancer cells to chemotherapeutic agents. To investigate the possible role of miR-130a in the development of cisplatin resistance in human ovarian cancer cell line A2780, we evaluated the expression of microRNA-130a (miR-130a) in the cells by the quantitative real-time reverse transcription-polymerase chain reaction. The results showed that miR-130a was significantly down-regulated in cisplatin-resistant ovarian cancer cells. MTT assay and flow cytometry (FCM) results showed that over-expression of miR-130a regulated apoptotic activity, and thereby cisplatin chemosensitivity, in ovarian cancer cells. Furthermore, we found that miR-130a can directly target XIAP, and participate in the regulation of apoptosis. The up-regulation of miR-130a led to a significant decrease in the XIAP mRNA levels and protein levels. XIAP plays an important role in cisplatin resistance in ovarian cancer cell line A2780. Our findings suggested that miR-130a could play a role in the development of cisplatin resistance in ovarian cancer cell line A2780, at least in part by modulation of apoptosis via targeting XIAP.