Neuronal and Molecular Mechanisms Underlying Chronic Pain and Depression Comorbidity in the Paraventricular Thalamus.

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs, which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development.

Proximal binding of dCas9 at a DNA double strand break stimulates homology-directed repair as a local inhibitor of classical non-homologous end joining.

In CRISPR/Cas9 genome editing, the tight and persistent target binding of Cas9 provides an opportunity for efficient genetic and epigenetic modification on genome. In particular, technologies based on catalytically dead Cas9 (dCas9) have been developed to enable genomic regulation and live imaging in a site-specific manner. While post-cleavage target residence of CRISPR/Cas9 could alter the pathway choice in repair of Cas9-induced DNA double strand breaks (DSBs), it is possible that dCas9 residing adjacent to a break may also determine the repair pathway for this DSB, providing an opportunity to control genome editing. Here, we found that loading dCas9 onto a DSB-adjacent site stimulated homology-directed repair (HDR) of this DSB by locally blocking recruitment of classical non-homologous end-joining (c-NHEJ) factors and suppressing c-NHEJ in mammalian cells. We further repurposed dCas9 proximal binding to increase HDR-mediated CRISPR genome editing by up to 4-fold while avoiding exacerbation of off-target effects. This dCas9-based local inhibitor provided a novel strategy of c-NHEJ inhibition in CRISPR genome editing in place of small molecule c-NHEJ inhibitors, which are often used to increase HDR-mediated genome editing but undesirably exacerbate off-target effects.

Disruption of DNA-PKcs-mediated cGAS retention on damaged chromatin potentiates DNA damage-inducing agent-induced anti-multiple myeloma activity.

BACKGROUND: Targeting DNA damage repair factors, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs), may offer an opportunity for effective treatment of multiple myeloma (MM). In combination with DNA damage-inducing agents, this strategy has been shown to improve chemotherapies partially via activation of cGAS-STING pathway by an elevated level of cytosolic DNA. However, as cGAS is primarily sequestered by chromatin in the nucleus, it remains unclear how cGAS is released from chromatin and translocated into the cytoplasm upon DNA damage, leading to cGAS-STING activation. METHODS: We examined the role of DNA-PKcs inhibition on cGAS-STING-mediated MM chemosensitivity by performing mass spectrometry and mechanism study. RESULTS: Here, we found DNA-PKcs inhibition potentiated DNA damage-inducing agent doxorubicin-induced anti-MM effect by activating cGAS-STING signaling. The cGAS-STING activation in MM cells caused cell death partly via IRF3-NOXA-BAK axis and induced M1 polarization of macrophages. Moreover, this activation was not caused by defective classical non-homologous end joining (c-NHEJ). Instead, upon DNA damage induced by doxorubicin, inhibition of DNA-PKcs promoted cGAS release from cytoplasmic chromatin fragments and increased the amount of cytosolic cGAS and DNA, activating cGAS-STING. CONCLUSIONS: Inhibition of DNA-PKcs could improve the efficacy of doxorubicin in treatment of MM by de-sequestrating cGAS in damaged chromatin.

Widespread reductions in cortical thickness following ketamine abuse.

BACKGROUND: Esketamine is a version of ketamine that has been approved for treatment-resistant depression, but our previous studies showed a link between non-medical use of ketamine and brain structural and functional alterations, including dorsal prefrontal grey matter reduction among chronic ketamine users. In this study, we sought to determine cortical thickness abnormalities following long-term, non-medical use of ketamine. METHODS: We acquired structural brain images for patients with ketamine use disorder and drug-free healthy controls. We used FreeSurfer software to measure cortical thickness for 68 brain regions. We compared cortical thickness between the 2 groups using analysis of covariance with covariates of age, gender, educational level, smoking, drinking, and whole-brain mean cortical thickness. RESULTS: We included images from 95 patients with ketamine use disorder and 169 controls. Compared with healthy controls, patients with ketamine use disorder had widespread decreased cortical thickness, with the most extensive reductions in the frontal (including the dorsolateral prefrontal cortex) and parietal (including the precuneus) lobes. Increased cortical thickness was not observed among ketamine users relative to comparison participants. Estimated total lifetime ketamine consumption was correlated with reductions in the right inferior parietal and the right rostral middle frontal cortical thickness. LIMITATIONS: We conducted a retrospective cross-sectional study, but longitudinal studies are needed to further validate decreased cortical thickness after nonmedical use of ketamine. CONCLUSION: This study provided evidence that, compared with healthy controls, chronic ketamine users have widespread reductions in cortical thickness. Our study underscores the importance of the long-term effects of ketamine on brain structure and serves as a reference for the antidepressant use of ketamine.

A SARS-CoV-2 Mpro fluorescent sensor for exploring pharmacodynamic substances from traditional Chinese medicine.

The main protease of SARS-CoV-2 (SARS-CoV-2 Mpro) plays a critical role in the replication and life cycle of the virus. Currently, how to screen SARS-CoV-2 Mpro inhibitors from complex traditional Chinese medicine (TCM) is the bottleneck for exploring the pharmacodynamic substances of TCM against SARS-CoV-2. In this study, a simple, cost-effective, rapid, and selective fluorescent sensor (TPE-S-TLG sensor) was designed with an AIE (aggregation-induced emission) probe (TPE-Ph-In) and the SARS-CoV-2 Mpro substrate (S-TLG). The TPE-S-TLG sensor was characterized using UV-Vis absorption spectroscopy, fluorescence spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), zeta potential, and Fourier transform infrared (FTIR) spectroscopy techniques. The limit of detection of this method to detect SARS-CoV-2 Mpro was measured to be 5 ng mL-1. Furthermore, the TPE-S-TLG sensor was also successfully applied to screen Mpro inhibitors from Xuebijing injection using the separation and collection of the HPLC-fully automatic partial fraction collector (HPLC-FC). Six active compounds, including protocatechualdehyde, chlorogenic acid, hydroxysafflower yellow A, caffeic acid, isoquercetin, and pentagalloylglucose, were identified using UHPLC-Q-TOF/MS that could achieve 90% of the Mpro inhibition rate for the Xuebijing injection. Accordingly, the strategy can be broadly applied in the detection of disease-related proteases as well as screening active substances from TCM.

Alterations and Significance of Computed Tomography Pulmonary Angiography-Derived Parameters in Older Patients With Acute Pulmonary Embolism.

OBJECTIVE: This study aimed to investigate changes of computed tomography pulmonary angiography (CTPA)-derived parameters in older adults with acute pulmonary embolism (APE). METHODS: According to the pulmonary artery obstruction index (PAOI), patients with APE were divided into the A1 (PAOI ≥30%, n = 57) and A2 (PAOI <30%, n = 40) groups. Participants without APE were placed in group B (n = 170). The left atrial (LA) and left ventricular (LV) parameters among the three groups were compared, and the parameter changes in the 44 patients with APE were analyzed before and after treatment. The correlation between APE severity and the parameters was analyzed using correlation analysis. RESULTS: The left-to-right diameters (LR) of LA, and LR × anteroposterior diameters (AP) of LA and LV: A1 < A2 < B; LR of LV: A1 < A2, B; AP of LA and LV: A1, A2 < B. After treatment, LR and LR × AP of the LA and LV were significantly increased in the group A1 and LR of the LV and LR × AP of the LA and LV were elevated in the group A2. Acute pulmonary embolism severity was closely associated with LR × AP ( r = -0.557) and LR ( r = -0.477) of LA. CONCLUSIONS: With an increase in the degree of obstruction, older adults had a smaller LA and LV. Furthermore, the LR and LR × AP values of the LA were significantly decreased. These results contribute to in-time risk stratification.

The Effectiveness of Low-dose Esmketamine Versus Remifentanil Adjunct to Propofol for Sedation in Patients Undergoing Radiofrequency Thermocoagulation for Trigeminal Neuralgia.

Objectives: To access the effectiveness of propofol-esketamine versus propofol-remifentanyl in patients undergoing radiofrequency Thermocoagulation for Trigeminal Neuralgia of gasserian ganglion. Methods: In this clinical trial, 80 patients were candidates for RFT were randomly divided into two groups (n= 40). These patients aged from 21 to 81 years old. Before the start of the procedure, both groups received propofol TCI with a target level of 1.5 µgml-1. The intervention group (group E) received esketamine 0.15 mgkg-1, and the control group (group R) received remifentanyl 1.0 µgkg-1. The patients, the anesthetists and the surgeons were unaware of the medication regimen. Sedation level (based on a MOAA/S), blood pressure, oxygen saturation, the dosage of propofol, recovery time (based on Aldrete scores), postoperation pain (based on NRS), surgeons and patient satisfaction, and Pittsburgh Sleep Quality Index (PQSI) were recorded. Results: Data from 80 patients were analyzed. The sedative effects were equal in the two groups (P = .680) and the MOAA/s scores of both groups were basically maintained at or below 2 points, however, the dosage of propofol in group E was significantly less than that in group R [5.3mgkg-1h-1 (5.0 to 5.7) vs 5.8 mgkg-1h-1 ( 5.3 to 6.3), P = .000]. The group E had higher blood pressure levels during the procedure (PSBP = .002, PDBP = .023). Surgeons and patient satisfaction (Ps = .164, Pp = .580), recovery time (P = .228),The NRS values after 24hrs (P = .777)and PQSI showed no significant differences between the two groups (P = .133). Conclusions: Low-dose esketamine reduces the total amount of propofol necessary for sedation and incidence of respiratory depression during RFT of gasserian ganglion in American Society of Anesthesiologists I to III patients without affecting recovery time, satisfaction of surgeons and patients, cardiovascular adverse events, when compared with remifentanil.

Self-Assembled Matrine-PROTAC Encapsulating Zinc(II) Phthalocyanine with GSH-Depletion-Enhanced ROS Generation for Cancer Therapy.

The integration of a multidimensional treatment dominated by active ingredients of traditional Chinese medicine (TCM), including enhanced chemotherapy and synergistically amplification of oxidative damage, into a nanoplatform would be of great significance for furthering accurate and effective cancer treatment with the active ingredients of TCM. Herein, in this study, we designed and synthesized four matrine-proteolysis-targeting chimeras (PROTACs) (depending on different lengths of the chains named LST-1, LST-2, LST-3, and LST-4) based on PROTAC technology to overcome the limitations of matrine. LST-4, with better anti-tumor activity than matrine, still degrades p-Erk and p-Akt proteins. Moreover, LST-4 NPs formed via LST-4 self-assembly with stronger anti-tumor activity and glutathione (GSH) depletion ability could be enriched in lysosomes through their outstanding enhanced permeability and retention (EPR) effect. Then, we synthesized LST-4@ZnPc NPs with a low-pH-triggered drug release property that could release zinc(II) phthalocyanine (ZnPc) in tumor sites. LST-4@ZnPc NPs combine the application of chemotherapy and phototherapy, including both enhanced chemotherapy from LST-4 NPs and the synergistic amplification of oxidative damage, through increasing the reactive oxygen species (ROS) by photodynamic therapy (PDT), causing an GSH decrease via LST-4 mediation to effectively kill tumor cells. Therefore, multifunctional LST-4@ZnPc NPs are a promising method for killing cancer cells, which also provides a new paradigm for using natural products to kill tumors.

A Rapid and Accurate UHPLC Method for Determination of Monosaccharides in Polysaccharides of Different Sources of Radix Astragali and Its Immune Activity Analysis.

With the escalating demand for Astragalus polysaccharides products developed from Radix Astragali (RA), the necessity for quality control of polysaccharides in RA has become increasingly urgent. In this study, a specific method for the simultaneous determination of seven monosaccharides in polysaccharides extracted from Radix Astragali (RA) has been developed and validated using ultra-performance liquid chromatography equipped with an ultraviolet detector (UHPLC-UV) for the first time. The 1-phenyl-3-methyl-5-pyrazolone (PMP) derivatizations were separated on a C18 column (Waters ACQUITYTM, Milfor, MA, USA, 1.8 µm, 2.1 × 100 mm) using gradient elution with a binary system of 5 mm ammonium formate (0.1% formic acid)-acetonitrile for 24 min. Additionally, seven monosaccharides showed good linear relationships (R2, 0.9971-0.9995), adequate precision (RSD < 4.21%), and high recoveries (RSD < 4.70%). The established method was used to analyze 109 batches of RA. Results showed that the Astragalus polysaccharides (APSs) mainly consist of mannose (Man), rhamnose (Rha), glucose (Glu), galactose (Gal), arabinose (Ara), xylose (Xyl); and fucose (Fuc); however, their composition was different among RA samples from different growth patterns, species, growth years, and origins, and the growth mode of RA and the age of wild-simulated RA can be accurately distinguished by principal component analysis (PCA). In addition, the immunological activity of APSs were also evaluated jointly by measurement of the NO release with RAW264.7, with the results showing that APSs have a promoting effect on the release of NO and exhibit a significant correlation with Man, Glu, Xyl, and Fuc contents. Accordingly, the new established monosaccharides analytical method and APS-immune activity determination in this study can provide a reference for quality evaluation and the establishment of quality standards for RA.

[Transition metal accumulation and cellular senescence].

Aging refers to a progressive decline in biological functions, leading to age-related diseases and mortality. The transition metals, including iron, copper, and manganese, play important roles in human physiological and pathological processes. Substantial research has demonstrated that senescent cells accumulate higher levels of transition metals, which in turn accelerates the process of cellular senescence and related diseases through mechanisms such as production of excessive reactive oxygen species (ROS), induction of oxidative stress, DNA damage, and mitochondrial dysfunction. This review article provides a comprehensive overview of the causes of transition metal accumulation in senescent cells, as well as the mechanisms by which it further promotes cellular senescence and related diseases. The aim is to provide insights into anti-aging and treatment of aging-related diseases caused by transition metal accumulation.

WDR3 promotes stem cell-like properties in prostate cancer by inhibiting USF2-mediated transcription of RASSF1A.

BACKGROUND: WD repeat domain 3 (WDR3) is involved in tumor growth and proliferation, but its role in the pathological mechanism of prostate cancer (PCa) is still unclear. METHODS: WDR3 gene expression levels were obtained by analyzing databases and our clinical specimens. The expression levels of genes and proteins were determined by a real-time polymerase chain reaction, western blotting and immunohistochemistry, respectively. Cell-counting kit-8 assays were used to measure the proliferation of PCa cells. Cell transfection was used to investigate the role of WDR3 and USF2 in PCa. Fluorescence reporter and chromatin immunoprecipitation assays were used to detect USF2 binding to the promoter region of RASSF1A. Mouse experiments were used to confirm the mechanism in vivo. RESULTS: By analyzing the database and our clinical specimens, we found that WDR3 expression was significantly increased in PCa tissues. Overexpression of WDR3 enhanced PCa cell proliferation, decreased cell apoptosis rate, increased spherical cell number and increased indicators of stem cell-like properties. However, these effects were reversed by WDR3 knockdown. WDR3 was negatively correlated with USF2, which was degraded by promoting ubiquitination of USF2, and USF2 interacted with promoter region-binding elements of RASSF1A to depress PCa stemness and growth. In vivo studies showed that WDR3 knockdown reduced tumor size and weight, reduced cell proliferation and enhanced cell apoptosis. CONCLUSIONS: WDR3 ubiquitinated USF2 and inhibited its stability, whereas USF2 interacted with promoter region-binding elements of RASSF1A. USF2 transcriptionally activated RASSF1A, which inhibited the carcinogenic effect of WDR3 overexpression.

IL-18 mediates sickle cell cardiomyopathy and ventricular arrhythmias.

Previous reports indicate that IL18 is a novel candidate gene for diastolic dysfunction in sickle cell disease (SCD)-related cardiomyopathy. We hypothesize that interleukin-18 (IL-18) mediates the development of cardiomyopathy and ventricular tachycardia (VT) in SCD. Compared with control mice, a humanized mouse model of SCD exhibited increased cardiac fibrosis, prolonged duration of action potential, higher VT inducibility in vivo, higher cardiac NF-κB phosphorylation, and higher circulating IL-18 levels, as well as reduced voltage-gated potassium channel expression, which translates to reduced transient outward potassium current (Ito) in isolated cardiomyocytes. Administering IL-18 to isolated mouse hearts resulted in VT originating from the right ventricle and further reduced Ito in SCD mouse cardiomyocytes. Sustained IL-18 inhibition via IL-18-binding protein resulted in decreased cardiac fibrosis and NF-κB phosphorylation, improved diastolic function, normalized electrical remodeling, and attenuated IL-18-mediated VT in SCD mice. Patients with SCD and either myocardial fibrosis or increased QTc displayed greater IL18 gene expression in peripheral blood mononuclear cells (PBMCs), and QTc was strongly correlated with plasma IL-18 levels. PBMC-derived IL18 gene expression was increased in patients who did not survive compared with those who did. IL-18 is a mediator of sickle cell cardiomyopathy and VT in mice and a novel therapeutic target in patients at risk for sudden death.

Reduction of venous air embolism in coronary computed tomography angiography using a modified method of saline test injection.

OBJECTIVES: This paper analyzed the feasibility of reducing venous air emboli introduced during tube connection in computed tomography angiography (CTA) through a modified method of saline test injection. METHODS: A total of 386 cases of patients undergoing coronary CTA examination were randomly arranged into a control group (199 patients underwent conventional saline injection before the CTA examination) and a case group (187 patients underwent modified saline injection before the CTA examination). The two groups were compared for the location (Fisher's exact test), number (χ2 test), and diameter (Mann-Whitney rank sum test) of the air emboli along the inflow direction of contrast agent within the scan. RESULTS: The occurrence rate was 10.55% in the control group and 3.74% in the case group respectively, with a statistically different significance (P = 0.010). In the case group, there were 7 cases of small-grade venous air emboli. In the control group, there were 15 cases of small-grade venous air emboli and 6 cases of moderate-grade venous air emboli. No cases of large-grade venous air emboli were found in both groups. CONCLUSIONS: The use of this modified method of saline test injection before CTA examination is able to effectively decrease the occurrence of venous air emboli introduced during tube connection, which has some certain practical significance.

Detection of Occluded Small Commodities Based on Feature Enhancement under Super-Resolution.

As small commodity features are often few in number and easily occluded by hands, the overall detection accuracy is low, and small commodity detection is still a great challenge. Therefore, in this study, a new algorithm for occlusion detection is proposed. Firstly, a super-resolution algorithm with an outline feature extraction module is used to process the input video frames to restore high-frequency details, such as the contours and textures of the commodities. Next, residual dense networks are used for feature extraction, and the network is guided to extract commodity feature information under the effects of an attention mechanism. As small commodity features are easily ignored by the network, a new local adaptive feature enhancement module is designed to enhance the regional commodity features in the shallow feature map to enhance the expression of the small commodity feature information. Finally, a small commodity detection box is generated through the regional regression network to complete the small commodity detection task. Compared to RetinaNet, the F1-score improved by 2.6%, and the mean average precision improved by 2.45%. The experimental results reveal that the proposed method can effectively enhance the expressions of the salient features of small commodities and further improve the detection accuracy for small commodities.

MTX-211 Inhibits GSH Synthesis through Keap1/NRF2/GCLM Axis and Exerts Antitumor Effects in Bladder Cancer.

Globally, bladder cancer (BLCA) is still the leading cause of death in patients with tumors. The function and underlying mechanism of MTX-211, an EFGR and PI3K kinase inhibitor, have not been elucidated. This study examined the function of MTX-211 in BLCA cells using in vitro and in vivo assays. RNA sequencing, quantitative real-time polymerase chain reaction, Western blotting, co-immunoprecipitation, and immunofluorescence were performed to elucidate the underlying mechanism. Our observations revealed that MTX-211 has a time- and concentration-dependent inhibitory effect on bladder cancer cell proliferation. Flow cytometry analysis showed that cell apoptosis and G0/G1 cell cycle arrest were significantly induced by MTX-211. MTX-211 inhibited intracellular glutathione (GSH) metabolism, leading to a decrease in GSH levels and an increase in reactive oxygen species. GSH supplementation partly reversed the inhibitory effects of MTX-211. Further experiments verified that MTX-211 promoted NFR2 protein ubiquitinated degradation via facilitating the binding of Keap1 and NRF2, subsequently resulting in the downregulated expression of GCLM, which plays a vital role in GSH synthesis. This study provided evidence that MTX-211 effectively inhibited BLCA cell proliferation via depleting GSH levels through Keap1/NRF2/GCLM signaling pathway. Thus, MTX-211 could be a promising therapeutic agent for cancer.

Discrimination of Radix Astragali from Different Growth Patterns, Origins, Species, and Growth Years by an H1-NMR Spectrogram of Polysaccharide Analysis Combined with Chemical Pattern Recognition and Determination of Its Polysaccharide Content and Immunological Activity.

The fraud phenomenon is currently widespread in the traditional Chinese medicine Radix Astragali (RA) market, especially where high-quality RA is substituted with low-quality RA. In this case, focused on polysaccharides from RA, the classification models were established for discrimination of RA from different growth patterns, origins, species, and growth years. 1H Nuclear Magnetic Resonance (H1-NMR) was used to establish the spectroscopy of polysaccharides from RA, which were used to distinguish RA via chemical pattern recognition methods. Specifically, orthogonal partial least squares discriminant analysis (OPLS-DA) and linear discriminant analysis (LDA) were used to successfully establish the classification models for RA from different growth patterns, origins, species, and growth years. The satisfactory parameters and high accuracy of internal and external verification of each model exhibited the reliable and good prediction ability of the developed models. In addition, the polysaccharide content and immunological activity were also tested, which was evaluated by the phagocytic activity of RAW 264.7. And the result showed that growth patterns and origins significantly affected the quality of RA. However, there was no significant difference in the aspects of origins and growth years. Accordingly, the developed strategy combined with chemical information, biological activity, and multivariate statistical method can provide new insight for the quality evaluation of traditional Chinese medicine.

Small-Molecule Photoacoustic Imaging Probe with Aggregation-Enhanced Amplitude for Real-Time Visualization of Acute Kidney Injury.

Acute kidney injury (AKI) has become a growing issue for patients with the extensive use of all kinds of drugs in clinic. Photoacoustic (PA) imaging provides a noninvasive and real-time imaging method for studying kidney injury, but it has inherent shortages in terms of high background signal and low detection sensitivity for exogenous imaging agents. Intriguingly, J-aggregation offers to tune the optical properties of the dyes, thus providing a platform for developing new PA probes with desired performance. In this study, a small-molecule PA probe (BDP-3) was designed and synthesized. We serendipitously discovered that BDP-3 can transform into renal clearable nanoaggregates under physiological conditions. The hydrodynamic diameter of the BDP-3 increased from 0.64 ± 0.11 to 3.74 ± 0.39 nm when the content of H2O increased from 40 to 90%. In addition, it was surprising that such a transforming process can significantly enhance its PA amplitude (2.06-fold). On this basis, PA imaging with BDP-3 was applied as a new method for the noninvasive detection of AKI induced by anticancer drugs, traditional Chinese medicine, and clinical contrast agents in animal models and exhibited higher sensitivity than the conventional serum index test, demonstrating great potential for further clinical diagnostic applications.

Higher glutamatergic activity in the medial prefrontal cortex in chronic ketamine users.

BACKGROUND: The medial prefrontal cortex (mPFC) plays an important role in depression and addiction. Previous studies have shown alterations in glutamatergic activity in the mPFC following the administration of ketamine in patients with depression and healthy controls. However, it remains unclear whether chronic, nonmedical use of ketamine affects metabolites in the mPFC. METHODS: Using proton magnetic resonance spectroscopy, we measured metabolites (glutamate and glutamine [Glx]; phosphocreatine and creatine [PCr+Cr]; myo-inositol; N-acetyl-aspartate; and glycerophosphocholine and phosphocholine [GPC+PC]) in the mPFC of chronic ketamine users (n = 20) and healthy controls (n = 43). Among ketamine users, 60% consumed ketamine once per day or more, 10% consumed it every 2 days and 30% consumed it every 3 or more days. Using analysis of covariance, we evaluated between-group differences in the ratios of Glx:PCr+Cr, myo-inositol:PCr+Cr, N-acetyl-aspartate:PCr+Cr and GPC+PC:PCr+Cr. RESULTS: Chronic ketamine users showed significantly higher Glx:PCr+Cr ratios than healthy controls (median 1.05 v. 0.95, p = 0.008). We found no significant differences in myoinositol:PCr+Cr, N-acetyl-aspartate:PCr+Cr or GPC+PC:PCr+Cr ratios between the 2 groups. We found a positive relationship between N-acetyl-aspartate:PCr+Cr and Glx:PCr+Cr ratios in the healthy control group (R = 0.345, p = 0.023), but the ketamine use group failed to show such an association (ρ = 0.197, p = 0.40). LIMITATIONS: The cross-sectional design of this study did not permit causal inferences related to higher Glx:PCr+Cr ratios and chronic ketamine use. CONCLUSION: This study provides the first evidence that chronic ketamine users have higher glutamatergic activity in the mPFC than healthy controls; this finding may provide new insights relevant to the treatment of depression with ketamine.

Accurate identification of kidney injury progression via a fluorescent biosensor array.

Identifying the progress of kidney injury may aid the effective treatment and intervention. Herein, we developed a fluorescent biosensor array for instantaneous and accurate identification of the kidney injury progression via "doubled" signals. The multichannel biosensor array consisted of polydopamine-polyethyleneimine (PDA-PEI) and multicolor-labelled different length of DNAs including AAAAA-Cyanine7 (5A-Cy7), AAAAAAAAAA-Texas Red (10A-Texas Red), and AAAAAAAAAAAAAAAAAAAA-VIC (20A-VIC). Facing to the variety of protein in urine with alterable charge accompanied with different progress of kidney injury, the composition of urine replaces the DNA signal molecules, forming their special fluorescence patterns. Taking the size of protein into consideration, the original three variables induced by the protein charge were extended to six variables induced by the two factors of protein particle size and charge difference, which could provide a more accurate strategy to identify the progress of kidney injury. Notably, this strategy not only opened up new perspective for identification the progress of kidney injury via the size and charge of urine protein, but also improved the resolving power of sensor array by increasing the number of sensor elements for extending their potential application to various diseases.

Pulmonary CT scans of white rabbits using the selective photon shield technique of the third-generation dual-source CT.

This study aims to optimise the protocol for the low-dose pulmonary computed tomography (CT) scanning of infants by studying the effects of the selective photon shield (SPS) technique of the third-generation dual-source CT (DSCT) on the image quality and radiation dose of a chest CT in white rabbits under different tube currents. Twelve white rabbits of a similar weight to an infant were selected and randomly divided into an experimental group and a control group. The experimental groups (A1-A5) were scanned at low dose by the third-generation DSCT using SPS under different tube current × time (60, 50, 40, 30, and 20 mAs). The control group (B) was scanned under a conventional tube voltage (100 kV) and current × time (20 mAs). Advanced model iterative reconstruction at strength three was used for the objective and subjective evaluation of the image quality and radiation dose of the lung and mediastinal windows. With the standard deviation of the air in the trachea as image noise, the signal-to-noise ratio (SNR), contrast-to-noise ratio, and CT values of each site were evaluated. Radiation doses were compared using the volume CT dose index, dose length product, and effective dose. The differences in subjective image quality between groups A2 and B were not statistically significant (P= 0.34). The differences in the SNRs of the lung and mediastinal windows between groups A2 and B were not statistically significant (P> 0.05). The radiation dose of group A2 was 83.2% lower than that of group B. The SPS of the third-generation DSCT under 50 mAs might be applied in the pulmonary CT examination of infants.