Three-Step Ferroelastic Transitions from Hexagonal to Triclinic Phases in a Hybrid Perovskite: (1-Fluoromethyl-1-methylpyrrolidine)[CdCl3].

Hybrid ferroelastic crystals have emerged as a hot research topic in recent years owing to their prospective applications in piezoelectric sensors, mechanical switches, and optoelectronic devices. Nevertheless, most of the documented materials exhibit one-step or two-step ferroelastic phase transition(s), and those with multistep ferroelastic transitions are extremely scarce. We present a new hexagonal molecular perovskite based on a fluoro-substituted flexible cyclic ammonium cation, (1-fluoromethyl-1-methylpyrrolidine)[CdCl3] (1), undergoing unusual three-step ferroelastic phase transitions from hexagonal paraelastic phase to orthorhombic, monoclinic, and triclinic ferroelastic phases at 388, 376, and 311 K, respectively, with Aizu notation of 6/mmmFmmm, mmmF2/m, and 2/mF-1, featuring spontaneous strain of 0.002, 0.023, and 0.110, respectively. Furthermore, variable-temperature single-crystal diffraction reveals that the phase-transition mechanism in 1 principally originates from intriguing dynamic change of organic cations and synchronous displacement of inorganic chains. This scarce instance of multistep hybrid ferroelastic provides important clues for finding advanced ferroelastic materials.

Structural basis for the dual catalytic activity of the Legionella pneumophila ovarian tumor (OTU) domain deubiquitinase LotA.

Legionella pneumophila, a bacterial pathogen that causes a severe pneumonia known as Legionnaires' disease, extensively exploits the ubiquitin (Ub) pathway in the infected host cells through certain virulence effectors excreted by the Dot/Icm system. To date, several Dot/Icm effectors have been found to act as Ub ligases, and four effectors, including LotA, LotB, LotC, and Ceg7, have been identified as deubiquitinases (DUBs) from the ovarian tumor (OTU) domain family. LotA is unique among other OTU DUBs because it possesses two distinct DUB domains and exclusively exhibits catalytic activity against K6-linked diUb and polyUb chains. However, the structure of LotA and the molecular mechanism for the dual DUB activity remains elusive. In this study, we solved the structure of LotA in complex with proximally bound Ub and distal covalently bound Ub. Both Ub molecules are bound to the DUB1 domain and mimic a K6-linked diUb. Structural analysis reveals that the DUB1 domain utilizes a distinct mechanism for recognition of the K6-linked diUb within a large S1' binding site that is uncommon to OTU DUBs. Structural fold of the LotA DUB2 domain closely resembles LotB and LotC, similarly containing an extra α-helix lobe that has been demonstrated to play an important role in Ub binding. Collectively, our study uncovers the structural basis for the dual catalytic activity of the unique OTU family DUB LotA.

H/F Substitution Induced Large Increase of Tc in a 3D Hybrid Rare-Earth Double Perovskite Multifunctional Compound.

Increasing attention has been devoted to studying perovskite-type multifunctional stimuli-responsive materials with multiple channel physical characteristics. However, it remains challenging to simultaneously achieve multifunction and regulate structural phase transition temperature in hybrid perovskites. Here, we report two three-dimensional organic-inorganic hybrid rare-earth double perovskite compounds, (HQ)2 RbEu(NO3 )6 (1, HQ=quinuclidium) and (4FHQ)2 RbEu(NO3 )6 (2, 4FHQ=4-fluoro-quinuclidium), which exhibit ferroelasticity, dielectric switch, and excellent photoluminescence response. The phase transition temperature of 2 increases 169 K compared with 1 through H/F substitution. This result is attributed to the H/F substitution inducing the generation of the Rb-F coordination bond between cations and anions. Meanwhile, the photoluminescence emission intensity of 2 shows no quench with the increase of temperature, in particular, the emission spectrum achieves fine regulation at high temperatures. This work provides a new solution for the realization of multi-functions and regulations of the properties based on hybrid perovskite materials with high critical temperatures.

H/F Substitution Induced Large Increase of Tc in a 3D Hybrid Rare-Earth Double Perovskite Multifunctional Compound.

Invited for the cover of this issue are Le-Ping Miao, Chao Shi, Yi Zhang and co-workers at Jiangxi University of Science and Technology. The image depicts the structure diagrams of the 3D hybrid rare-earth double perovskite compounds. The phase transition temperatures of the two compounds were indicated by the "ice and fire", respectively. It implies the increase of the phase transition temperature of the compounds. Read the full text of the article at 10.1002/chem.202103913.

Alteration in the expression of inflammatory cytokines in primary hippocampal astrocytes in response to MK-801 through ERK1/2 and PI3K signals.

Our previous study showed that dizocilpine (MK-801) induced schizophrenia-like behavior in rats, enhanced GFAP expression, and activated primary cultured hippocampal astrocytes. Astrocytes play an essential role in neuroinflammation and contribute to the crosstalk that generates chronic neuro-inflammation in neurological diseases. However, the effects of MK-801 treatment on astrocytic neuroinflammatory responses and its mechanism of action have not been studied in detail. To address this issue, IL1ß, IL6, TNFα and IL10 expression and secretion levels were evaluated in hippocampal astrocytes in response to MK-801 for 24 h by ELISA and real-time PCR, with and without pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. Cell apoptosis, viability, and proliferation were also examined. MK-801 treatment did not induce hippocampal astrocytes apoptosis or proliferation, however, MK-801 enhanced astrocytes viability. Additionally, the expression and secretion levels of IL1ß, IL6 and TNFα were elevated, but that of IL10 was decreased, in which ERK1/2 and PI3K signals were involved. These findings suggest that hippocampal astrocytes may regulate the expressions of inflammatory cytokines through ERK1/2 and PI3K signaling pathway to participate in the pathogenesis of schizophrenia.

Two-Dimensional Organic-Inorganic Hybrid Rare-Earth Double Perovskite Ferroelectrics.

As a major branch of hybrid perovskites, two-dimensional (2D) hybrid double perovskites are expected to be ideal systems for exploring novel ferroelectric properties, because they can accommodate a variety of organic cations and allow diverse combinations of different metal elements. However, no 2D hybrid double perovskite ferroelectric has been reported since the discovery of halide double perovskites in the 1930s. Based on trivalent rare-earth ions and chiral organic cations, we have designed a new family of 2D rare-earth double perovskite ferroelectrics, A4MIMIII(NO3)8, where A is the organic cation, MI is the alkaline metal or ammonium ion, and MIII is the rare-earth ion. This is the first time that ferroelectricity is realized in 2D hybrid double perovskite systems. These ferroelectrics have achieved high-temperature ferroelectricity and photoluminescent properties. By varying the rare-earth ion, variable photoluminescent properties can be achieved. The results reveal that the 2D rare-earth double perovskite systems provide a promising platform for achieving multifunctional ferroelectricity.

Hybrid Organic-Inorganic Antiperovskites.

Substitution of A-site and/or X-site ions of ABX3 -type perovskites with organic groups can give rise to hybrid perovskites, many of which display intriguing properties beyond their parent compounds. However, this method cannot be extended effectively to hybrid antiperovskites. Now, the design of hybrid antiperovskites under the guidance of the concept of Goldschmidt's tolerance factor is presented. Spherical anions were chosen for the A and B sites and spherical organic cations for the X site, and seven hybrid antiperovskites were obtained, including (F3 (H2 O)x )(AlF6 )(H2 dabco)3 , ((Co(CN)6 )(H2 O)5 )(MF6 )(H2 dabco)3 (M=Al3+ , Cr3+ , or In3+ ), (Co(CN)6 )(MF6 )(H2 pip)3 (M=Al3+ or Cr3+ ), and (SbI6 )(AlF6 )(H2 dabco)3 . These new structures reveal that all ions at A, B, and X sites of inorganic antiperovskites can be replaced by molecular ions to form hybrid antiperovskites. This work will lead to the synthesis of a large family of hybrid antiperovskites.

Autophagy maintains the integrity of endothelial barrier in LPS-induced lung injury.

Understanding the role and underlying regulation mechanism of autophagy in lipopolysaccharide-induced lung injury (LPS-LI) may provide potentially new pharmacological targets for treatment of acute lung injury. The aim of this study was to investigate the functional significance of autophagy in LPS-LI. The autophagy of human pulmonary microvascular endothelial cells (HPMVECs) and mice was inhibited before they were challenged with LPS. In vitro, permeability, vitality, and the LDH release rate of the cells were detected, the zonula occluden-1 (ZO-1) expression and the stress fiber formation were determined. In vivo, the lung injury was assessed. We found LPS caused high permeability and increased lactate dehydrogenase (LDH) release rate, lowered viability of the cells, inhibited the ZO-1 expression and induced stress fiber formation, these effects were further aggravated by prohibiting the level of autophagy. Consistently, in in vivo experiments, LPS-induced serious lung injury, which was reflected as edema, leukocyte infiltration and hemorrhage in lung tissue, and the high concentration of pro-inflammation cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in bronchoalveolar lavage fluid (BALF). Inhibiting autophagy further exacerbated LPS-LI. It appears that autophagy played a protective role in LPS-LI in part through restricting the injury of lung microvascular barrier.

Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis.

Vascular endothelial cells are highly sensitive to oxidative stress, and this is one of the mechanisms by which widespread endothelial dysfunction is induced in most cardiovascular diseases and disorders. However, how these cells can survive in oxidative stress environments remains unclear. Salidroside, a traditional Chinese medicine, has been shown to confer vascular protective effects. We aimed to understand the role of autophagy and its regulatory mechanisms by treating human umbilical vein endothelial cells (HUVECs) with salidroside under oxidative stress. HUVECs were treated with salidroside and exposed to hydrogen peroxide (H2O2). The results indicated that salidroside exerted cytoprotective effects in an H2O2-induced HUVEC injury model and suppressed H2O2-induced apoptosis of HUVECs. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased oxidative stress-induced HUVEC apoptosis, while the autophagy activator rapamycin induced anti-apoptosis effects in HUVECs. Salidroside increased autophagy and decreased apoptosis of HUVECs in a dose-dependent manner under oxidative stress. Moreover, 3-MA attenuated salidroside-induced HUVEC autophagy and promoted apoptosis, whereas rapamycin had no additional effects compared with salidroside alone. Salidroside upregulated AMPK phosphorylation but downregulated mTOR phosphorylation under oxidative stress; however, administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with salidroside alone. These results suggest that autophagy is a protective mechanism in HUVECs under oxidative stress and that salidroside might promote autophagy through activation of the AMPK pathway and downregulation of mTOR pathway.

Downregulation of paraoxonase 3 contributes to aggressive human hepatocellular carcinoma progression and associates with poor prognosis.

Paraoxonase (PON) enzymes possess antioxidant properties and protect against cardiovascular diseases. As a member of PON family, PON3 is primarily synthesized in the liver and poorly investigated. This study aimed to examine the expression of PON3 in human hepatocellular carcinoma (HCC) and investigate the clinical significance and biological function of PON3 in HCC patients. We first analyzed PON3 expression in 50 paired HCC samples (HCC tissues vs matched para-cancerous tissues) and 160 clinical HCC specimens by using immunohistochemistry (IHC). Our results showed that the expression of PON3 was downregulated in HCC and significantly associated with tumor-node-metastasis (TNM) stage, tumor size, and tumor number. Kaplan-Meier survival and Cox regression analyses showed that PON3 was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR). Finally, we aimed to reveal the biological function of PON3 in HCC growth and metastasis, and our results showed that overexpression of PON3 potently inhibited growth and metastasis of HCC. Collectively, our study demonstrated that PON3 exhibited tumor-suppressive effects toward HCC and it might serve as a novel prognostic marker in HCC.

Mapping the neck disability index to SF-6D in patients with chronic neck pain.

BACKGROUND: This study sought to statistically map the neck disability index (NDI) to the six-dimension health state short form (SF-6D) to estimate algorithms for use in economic analyses in patients with chronic neck pain (CNP). METHODS: The relationships between NDI and SF-6D scores were estimated by using data from a cohort of patients with chronic neck pain (n = 272). By using ordinary least squares (OLS), generalized linear modeling (GLM), censored least absolute deviations (CLAD) and Tobit regression, scores from all 10 items of the NDI instruments were univariately tested against SF-6D values and retained in a multivariate regression model, if statistically significant. The predictive ability of the model was assessed by mean absolute error (MAE), root mean square error (RMSE) and normalized RMSE. RESULTS: The mean age of the 272 CNP patients was 39.9 ± 12.3 years; 57.8 % of the CNP patients were female. An OLS regression equation that included recreation item of NDI was optimal, with a MAE of 0.04and 0.04 and an RMSE of 0.06and 0.05in the derivation set and validation set, respectively. Predicted utilities accurately represented the observed ones. CONCLUSIONS: We have provided algorithms for the estimation of health state utility values from the response of NDI. Future economic evaluations of the interventions for chronic neck pain could be informed by these algorithms.

Clinicopathological significance and potential drug target of O6-methylguanine-DNA methyltransferase in colorectal cancer: a meta-analysis.

Emerging evidence indicates that O(6)-methylguanine-DNA methyltransferase (MGMT) is a candidate for tumor suppression in several types of human tumors including colorectal cancer (CRC). However, the correlation between MGMT hypermethylation and clinicopathological characteristics of CRC remains unclear. In this study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of MGMT hypermethylation on the incidence of CRC and clinicopathological characteristics. A comprehensive literature search was done from Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and the Chinese Biomedical Database for related research publications written in English and Chinese. Methodological quality of the studies was also evaluated. Analyses of pooled data were performed with Review Manager 5.2. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized, respectively. Final analysis from 28 eligible studies was performed. MGMT hypermethylation is found to be significantly higher in CRC than in normal colorectal mucosa, the pooled OR from 13 studies including 1085 CRC and 899 normal colorectal mucosa, OR = 6.04, 95 % confidence interval (CI) = 4.69-7.77, p < 0.00001. MGMT hypermethylation is also significantly higher in colorectal adenoma than in normal colorectal mucosa, but it is significantly less compared to that in CRC patients. Interestingly, MGMT hypermethylation is correlated with sex status and is significantly higher in female than in male. MGMT hypermethylation is also associated with high levels of microsatellite instability (MSI). The pooled HR for overall survival (OS) shows that MGMT hypermethylation is not associated with worse survival in CRC patients. The results of this meta-analysis suggest that MGMT hypermethylation is associated with an increased risk and high levels of MSI and may play an important role in CRC initiation. However, MGMT hypermethylation may play an important role in the early stage of CRC progression and development, as well as having limited value in prediction of prognosis in CRC patients. We also discussed that MGMT may serve as a potential drug target of CRC.

Aberrant expression of long noncoding RNAs in colorectal cancer with liver metastasis.

Long noncoding RNA (lncRNA) plays a crucial role in the regulation of various cellular processes and human diseases. However, little is known about the role of lncRNAs in colorectal liver metastasis (CLM). In the present study, we aimed to determine whether lncRNAs are differentially expressed in CLM tissue and to further assess their clinical value. lncRNA arrays were employed to screen for differentially expressed lncRNAs in colorectal cancer (CRC) tissues with synchronous, metachronous, or nonliver metastasis. Based on bioinformatics data, a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was performed to identify target lncRNAs in an expanded set of CRC samples with various subtypes of liver metastasis. The relationships between the target lncRNAs and the clinical characteristics and patient prognosis were further analyzed. After determining the expression profile of lncRNAs (n = 1332) in CLM tissue, 40 differentially expressed lncRNAs that were potentially related to CLM were selected for further examination in an expanded set of clinical samples, and three novel target lncRNAs, termed lncRNA-CLMAT1-3, were verified. High lncRNA-CLMAT3 expression strongly correlated with liver metastasis (P = 0.03) and lymph node metastasis (P = 0.009). Moreover, patients displaying high lncRNA-CLMAT3 expression exhibited a shorter median overall survival duration than those displaying low lncRNA-CLMAT3 expression (30.7 vs. 35.2 months, P = 0.007). Multivariate analysis demonstrated that the lncRNA-CLMAT3 expression level is an independent prognostic factor (hazard ratio 2.05, P = 0.02) after adjusting for other known prognostic factors. lncRNA-CLMAT3 over-expression was significantly associated with CLM and was an independent predictor of poor survival for patients with CRC.

Impact of early tumor shrinkage on clinical outcome in wild-type-KRAS colorectal liver metastases treated with cetuximab.

BACKGROUND AND AIM: To evaluate the impact of early tumor shrinkage (ETS) on long-term outcome in patients with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) unresectable colorectal liver metastases (CLM) receiving cetuximab plus chemotherapy. METHODS: A total of 138 patients in a randomized controlled trial (70 in armA received cetuximab plus chemotherapy, 68 in armB received chemotherapy alone), as previously reported (Ye et al., 2013) were included into this analysis. The cut-off date updated for overall survival (OS) was June 2014. ETS was defined as a ≥ 20% reduction of the longest diameters of the target lesions compared with baseline at the first evaluation (8 weeks). Outcome measures were progression-free survival (PFS) and OS. RESULTS: There were 132 patients available for evaluation, and ETS occurred more frequently in armA than that in armB (P = 0.003). ETS was associated with longer OS (armA: 35.7 vs. 19.5 months, P < 0.001; armB 28.7 vs. 18.7 months, P = 0.01) and PFS (armA: 13.4 vs. 4.2 months, P < 0.001; armB 7.0 vs. 4.2 months, P = 0.001) compared with patients with no-ETS. Among patients with ETS, there was a significant difference between armA and armB in PFS (P = 0.03), but not in OS (P = 0.19). All 23 patients who underwent liver surgery achieved ETS. In armA, for patients without liver surgery, patients observed ETS also gained an increased survival benefit over those no-ETS in OS (P = 0.02) and PFS (P < 0.001). ETS was an independent predictor of improved OS (hazard ratio 0.56, P = 0.007). CONCLUSION: ETS may serve as a predictor of favorable outcome in patients with wild-type KRAS CLM receiving cetuximab plus chemotherapy.

A comparative efficacy evaluation of ultrasound-guided pulsed radiofrequency treatment in the gastrocnemius in managing plantar heel pain: a randomized and controlled trial.

OBJECTIVE: The treatment of plantar heel pain is highly challenging. We report ultrasound-guided pulsed radiofrequency treatment (UG-PRF) in the gastrocnemius to treat plantar heel pain and minimize the safety issues. DESIGN: This study compared UG-PRF with sham treatment in 100 patients with plantar heel pain. Primary outcome measures include the pain subscale of the Foot Health Status Questionnaire (FHSQ-pain) and "first step" pain as measured on a visual analogue scale (VAS-"first-step" pain). The secondary outcome measures include the FHSQ-foot function and general foot health, and health related quality of life (assessed using the Short Form-36 questionnaire [SF-36]). All outcomes were measured at 3 and 6 months post-treatment. RESULTS: The results showed the efficacy of UG-PRF in terms of pain management, as reflected by higher FHSQ-pain score (increased by 20.0 (P < 0.0001) and 17.9 (P = 0.001) compared with the sham treatment at 3 or 6 months, respectively) and lower VAS-"first-step" pain (reduced by 26.1 (P < 0.0001) and 14.3 (P = 0.01) compared with the sham group at 3 or 6 months, respectively). The FHSQ-foot function and FHSQ-general foot health were increased by the UG-PRF (P < 0.05, vs sham treatment at 3 or 6 months). The SF-36 physical component score in the sham group was 10.8 (P = 0.042) and 10.4 (P = 0.044) lower than the UG-PRF group at 3 or 6 months, respectively. No severe complications were observed. CONCLUSIONS: We conclude that the UG-PRF is both safe and efficacious in managing plantar heel pain.

Overexpression of long non-coding RNA HOTAIR predicts poor patient prognosis and promotes tumor metastasis in epithelial ovarian cancer.

OBJECTIVES: Although long non-coding RNAs (lncRNAs) are emerging as new regulators in the cancer paradigm, the involvement of lncRNAs in epithelial ovarian cancer (EOC) is just beginning to be studied. In this study, we focused on lncRNA HOX transcript antisense RNA (HOTAIR) and investigated its expression pattern, clinical significance, and biological function in EOC. METHODS: HOTAIR expression in EOC tissues was examined and its correlation with clinicopathological factors and patient prognosis was analyzed. A series of in vitro and in vivo assays were performed to understand the role of HOTAIR in EOC metastasis. RESULTS: HOTAIR expression was elevated in EOC tissues, and HOTAIR levels were highly positively correlated with the FIGO stage, the histological grade of the tumor, lymph node metastasis, and reduced overall survival (OS) and disease-free survival (DFS). A multivariate analysis showed that HOTAIR expression is an independent prognostic factor of OS and DFS in patients with EOC. Additionally, the results of in vitro assays showed that the suppression of HOTAIR expression in the three highly metastatic EOC cell lines (SKOV3.ip1, HO8910-PM, and HEY-A8) significantly reduced cell migration/invasion. The results of in vivo assays further confirmed the pro-metastatic effects of HOTAIR. Moreover, the pro-metastatic effects of HOTAIR were partially mediated by the regulation of certain matrix metalloproteinases (MMPs) and epithelial-to-mesenchymal transition (EMT)-related genes. CONCLUSIONS: Our data suggest that HOTAIR plays a vital role in EOC metastasis and could represent a novel prognostic marker and potential therapeutic target in patients with EOC.

Tomography-guided palisade sacroiliac joint radiofrequency neurotomy versus celecoxib for ankylosing spondylitis: a open-label, randomized, and controlled trial.

Sacroiliac joint (SIJ) pain is a common symptom in ankylosing spondylitis (AS). Palisade sacroiliac joint radiofrequency neurotomy (PSRN) is a novel treatment for the SIJ pain. In the current clinical trial, we treated AS patients with significant SIJ pain using PSRN under computed tomography guidance and compared the results with the celecoxib treatment. The current study included 155 AS patients. Patients were randomly assigned to receive PSRN or celecoxib treatment (400 mg/day for 24 weeks). The primary endpoint was global pain intensity in visual analog scale, at week 12. Secondary endpoints included pain intensity at week 24, disease activity, functional and mobility capacities, and adverse events at week 24. In comparison with the baseline collected immediately prior to the interventions, global pain intensity was significantly lower at both 12 and 24 weeks after the treatment in both arms. Pain reduction was more robust in the PSRN arm (by more than 1.9 and 2.2 cm at 12 and 24 weeks in comparison with the celecoxib arm, P < 0.0001 for both). The PSRN was also more effective in improving physical function and spinal mobility (P < 0.05 vs. celecoxib for both). Gastrointestional irritation was more frequent in the celecoxib arm than in the PSRN arm (P < 0.05). No severe complications were noted in either arm. PSRN is both efficacious and safe in managing SIJ pain in patients with AS.

A 62.2dB SNDR Event-Driven Level-Crossing ADC with SAR-Assisted Delay Compensation Loop for Time-Sparse Biomedical Signal Acquisition.

This paper proposed an event-driven clockless level-crossing ADC (LC-ADC) suitable for biomedical applications. Thanks to the LC loop, the sampling rate of the converter automatically adapts to the input activities. Activity-dependent power consumption and data compression can thus be realized, saving system power, especially during time-sparse signal acquisition. Meanwhile, a SAR-assisted loop is exploited to resolve the loop-delay-induced distortion in conventional LC-ADC. Therefore, the resolution and power efficiency of the LC-ADC are improved effectively while maintaining the event-driven feature. Implemented in a 55nm process, the proposed LC-ADC achieves a scalable power consumption and a peak SNDR of 62.2dB for a 20kHz input. It also achieves a Walden FoM of 29.7fJ/conv.-step and a Schreier FoM of 158.6dB, which is best in class, without using off-chip calibration. Sub µW power is realized when the input frequency is below 1.5kHz. The proposed LC-ADC is also verified by simulated electrocardiogram (ECG), neural spike, and electromyogram (EMG) signals. It provides a ~7X data compression for ECG input, providing an attractive solution for time-sparse signal acquisition in biomedical applications.

Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system.

Argonaute (Ago) proteins are ubiquitous across all kingdoms of life. Eukaryotic Agos (eAgos) use small RNAs to recognize transcripts for RNA silencing in eukaryotes. In contrast, the functions of prokaryotic counterparts (pAgo) are less well known. Recently, short pAgos in conjunction with the associated TIR or Sir2 (SPARTA or SPARSA) were found to serve as antiviral systems to combat phage infections. Herein, we present the cryo-EM structures of nicotinamide adenine dinucleotide (NAD+)-bound SPARSA with and without nucleic acids at resolutions of 3.1 Å and 3.6 Å, respectively. Our results reveal that the APAZ (Analogue of PAZ) domain and the short pAgo form a featured architecture similar to the long pAgo to accommodate nucleic acids. We further identified the key residues for NAD+ binding and elucidated the structural basis for guide RNA and target DNA recognition. Using structural comparisons, molecular dynamics simulations, and biochemical experiments, we proposed a putative mechanism for NAD+ hydrolysis in which an H186 loop mediates nucleophilic attack by catalytic water molecules. Overall, our study provides mechanistic insight into the antiphage role of the SPARSA system.

A wearable, minimally-invasive, fully electrochemically-controlled feedback minisystem for diabetes management.

Diabetes is a chronic disease affecting 10% of the population globally, and can lead to serious damage in the heart, kidneys, eyes, blood vessels or nerves. Commercial artificial closed-loop feedback systems can significantly improve diabetes management and save lives. However, they are large and expensive for users. Here, we demonstrate for the first time a wearable, minimally-invasive, fully electrochemically-controlled feedback minisystem for diabetes management. Both the working principles of the sensor and pump in the feedback system are based on electrochemical reactions. The smart minisystem was constructed based on integrating the thermoplastic polyurethane hollow microneedles with an electrochemical biosensing device on its outer layer and an electrochemical micropump facing the inner layer of the microneedles. The sensing device was constructed based on sputtering thin metal films through a shadow mask and electroplating Prussian blue on the surface of the microneedles, followed by the immobilization of glucose oxidase on the working electrode. The electrochemical micropump was constructed by sputtering the interdigital electrodes, followed by sealing with a thin elastic film, which was further integrated with the inner channels of the microneedles. Both the sensor and the pump were electrically powered. Via being controlled by a printed circuit board, the biosensing device monitored the levels of interstitial glucose continuously to drive the electrochemical pump to deliver insulin intelligently, in order to control blood glucose within the normal range. The closed-loop feedback system was studied for its capability in maintaining the blood glucose levels of diabetic rats under various physiological conditions. The utility of the intelligent feedback system was successfully demonstrated on diabetic rats for controlling the blood glucose levels within the normal range. The minisystem is wearable, small, cost-effective, precise, stable and painless. It is anticipated that this approach opens a new paradigm for the development of closed-loop diabetes minisystems and may lead to a compelling future for diabetes management.