Long-pulsed ultrasound-mediated microbubble thrombolysis in a rat model of microvascular obstruction.

In up to 30% patients who experience acute myocardial infarction, successful recanalization of the epicardial coronary artery cannot provide adequate microvascular reperfusion. In this study, we sought to determine whether long-pulsed ultrasound (US)-mediated microbubble (MB) cavitation was useful for the treatment of microvascular obstruction, and the therapeutic effects were compared within different long-pulse-length and short-pulsed US. Microvascular obstruction model was established by injecting micro-thrombi into common iliac artery of a rat's hind limb. About 1 MHz US with different long pulse lengths (ranging from 100 to 50,000 cycles) was delivered, compared to short pulse (5 cycles). The control group was given MB only without therapeutic US. Contrast perfusion images were performed at baseline, emboli, and 1, 5, 10 min post-embolization, and peak plateau video intensity (A) was obtained to evaluate the therapeutic effects. Long-tone-burst US showed better thrombolytic effects than short-pulsed US (1,000, 5,000 cycles >500 cycles, >5 cycles, and control) (P < 0.01). 1,000 cycles group showed the optimal thrombolytic effect, but microvascular hemorrhage was observed in 50,000 cycles group. In conclusion, long-tone-burst US-enhanced MB therapy mediated successful thrombolysis and may offer a powerful approach for the treatment for microvascular obstruction within a certain pulse length.

Identification of multiple plasma lipids as diagnostic biomarkers of hypercholesterolemia and the underlying mechanisms based on pseudo-targeted lipidomics.

RATIONALE: Hypercholesterolemia is an important risk factor for cardiovascular diseases and death. This study performed pseudo-targeted lipidomics to identify differentially expressed plasma lipids in hypercholesterolemia, to provide a scientific basis for the diagnosis and pathogenesis of hypercholesterolemia. METHODS: Pseudo-targeted lipidomic analyses of plasma lipids from 20 patients with hypercholesterolemia and 20 normal control subjects were performed using liquid chromatography-mass spectrometry. Differentially expressed lipids were identified by principal component analysis and orthogonal partial least squares discriminant analysis. Receiver operating characteristic curves were used to identify differentially expressed lipids with high diagnostic value. The Kyoto Encyclopedia of Genes and Genomes pathway database was used to identify enriched metabolic pathways. RESULTS: We identified 13 differentially expressed lipids in hypercholesterolemia using variable importance of projection > 1 and p < 0.05 as threshold parameters. The levels of eight sphingomyelins and cholesterol sulfate were higher and those of three triacylglycerols and lysophosphatidylcholine were reduced in hypercholesterolemia. Seven differentially expressed plasma lipids showed high diagnostic value for hypercholesterolemia. Functional enrichment analyses showed that pathways related to necroptosis, sphingolipid signaling, sphingolipid metabolism, and steroid hormone biosynthesis were enriched. CONCLUSIONS: This pseudo-targeted lipidomics study demonstrated that multiple sphingomyelins and cholesterol sulfate were differentially expressed in the plasma of patients with hypercholesterolemia. We also identified seven plasma lipids, including six sphingomyelins and cholesterol sulfate, with high diagnostic value.

Ultrasonic shear wave elastography predicts the quality of the residual tendon before the rotator cuff repair.

BACKGROUND AND PURPOSE: Effective evaluation of rotator cuff tear residual tendon quality is the key to surgical repair. However, until now, the evaluation of rotator cuff tissue by ultrasonic shear wave elasticity (SWE) has been controversial. This prospective study analyzed the association between preoperative SWE and arthroscopic residual tendon quality scores. METHODS: The shear wave velocity (SWV) of the deltoid muscle, the supraspinatus tendon, and the supraspinatus muscle were measured in full-thickness rotator cuff tear patients. Tendon quality was scored according to tear size, tendon margin, tendon thickness, and footprint coverage during arthroscopy. The arthroscopic scores were used as the gold standard, and the SWV ratio of tendon and muscle (supraspinatus tendon/deltoid and supraspinatus muscle/deltoid) were calculated and correlated with the arthroscopic scores. RESULT: Eighty-nine patients (129 shoulders) were enrolled, including 89 operation shoulders and 40 control shoulders. In the group of operation shoulders, both the SWV ratios of tendon (SWV-RT) and the SWV ratio of muscle (SWV-RM) were negatively correlated with arthroscopic scores (The correlation coefficient (R) ranged from -0.722 to -0.884 and -0.569 to -0.689). The SWV-RT and SWV-RM of the operation shoulders were significantly lower than that of the control shoulders (p < 0.05). CONCLUSION: SWE could be used to predict the quality of the residual tendon before the rotator cuff repair. SWV of the supraspinatus tendon and muscle was a useful parameter to predict the quality of the residual tendon. CRITICAL RELEVANCE STATEMENT: Measuring the shear wave velocity of the supraspinatus tendon and muscle with SWE is useful for predicting the quality of the residual tendon which is one of the key factors for a successful rotator cuff repair. KEY POINTS: • Evaluating the quality of the residual tendon is important before surgery. • Elasticity measurements were negatively correlated with the arthroscopic score. • SWE is useful for predicting the quality of the residual tendon.

Selenium binding protein 1 protects renal tubular epithelial cells from ferroptosis by upregulating glutathione peroxidase 4.

Ferroptosis is a form of programmed cell death involved in various types of acute kidney injury (AKI). It is characterized by inactivation of the selenoprotein, glutathione peroxidase 4 (GPX4), and upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4). Since urinary selenium binding protein 1 (SBP1/SELENBP1) is a potential biomarker for AKI, this study investigated whether SBP1 plays a role in AKI. First, we showed that SBP1 is expressed in proximal tubular cells in normal human kidney, but is significant downregulated in cases of AKI in association with reduced GPX4 expression and increased ACSL4 expression. In mouse renal ischemia-reperfusion injury (I/R), the rapid downregulation of SBP1 protein levels preceded downregulation of GPX4 and the onset of necrosis. In vitro, hypoxia/reoxygenation (H/R) stimulation in human proximal tubular epithelial (HK-2) cells induced ferroptotic cell death in associated with an acute reduction in SBP1 and GPX4 expression, and increased oxidative stress. Knockdown of SBP1 reduced GPX4 expression and increased the susceptibility of HK-2 cells to H/R-induced cell death, whereas overexpression of SBP1 reduced oxidative stress, maintained GPX4 expression, reduced mitochondrial damage, and reduced H/R-induced cell death. Finally, selenium deficiency reduced GPX4 expression and promoted H/R-induced cell death, whereas addition of selenium was protective against H/R-induced oxidative stress. In conclusion, SBP1 plays a functional role in hypoxia-induced tubular cell death. Enhancing SBP1 expression is a potential therapeutic approach for the treatment of AKI.

DPP8/9 inhibition attenuates the TGF-ß1-induced excessive deposition of extracellular matrix (ECM) in human mesangial cells via Smad and Akt signaling pathways.

The pathogenesis of glomerular diseases is strongly influenced by abnormal extracellular matrix (ECM) deposition in mesangial cells. Dipeptidyl peptidase IV (DPPIV) enzyme family contains DPP8 and DPP9, which are involved in multiple diseases. However, the pathogenic roles of DPP8 and DPP9 in mesangial cells ECM deposition remain unclear. In this study, we observed that DPP8 and DPP9 were significantly increased in glomerular mesangial cells and podocytes in CKD patients compared with healthy individuals, and DPP9 levels were higher in the urine of IgA nephropathy (IgAN) patients than in control urine. Therefore, we further explored the mechanism of DPP8 and DPP9 in mesangial cells and revealed a significant increase in the expression of DPP8 and DPP9 in human mesangial cells (HMCs) following TGF-ß1 stimulation. Silencing DPP8 and DPP9 by siRNAs alleviated the expression of ECM-related proteins including collagen Ⅲ, collagen Ⅳ, fibronectin, MMP2, in TGF-ß1-treated HMCs. Furthermore, DPP8 siRNA and DPP9 siRNA inhibited TGF-ß1-induced phosphorylation of Smad2 and Smad3, as well as the phosphorylation of Akt in HMCs. The findings suggested the inhibition of DPP8/9 may alleviate HMCs ECM deposition induced by TGF-ß1 via suppressing TGF-ß1/Smad and AKT signaling pathways.

Mediation of long-pulsed ultrasound enhanced microbubble recombinant tissue plasminogen activator thrombolysis in a rat model of platelet-rich thrombus.

Background: Ultrasound (US)-enhanced microbubble (MB) therapy has been investigated as a therapeutic technique to facilitate the thrombolysis for the treatment of pericardial and microvascular obstruction. This study sought to assess the therapeutic effects of long-pulsed US-assisted MB-mediated recombinant tissue plasminogen activator (rt-PA) thrombolysis in a rat model of platelet-rich thrombus. Methods: Ferric chloride (10%) was used to induce total arterial occlusion before formation of platelet-rich thrombi. Therapeutic long-tone-burst US (1 MHz, 0.6 MPa, 1,000-µs pulse length) was used, and 2.9×109/mL of lipid MBs and 1 mg/mL of rt-PA were infused. Subsequently, 42 Sprague-Dawley (SD) male rats were randomly divided into seven groups: (I) control; (II) rt-PA; (III) high duty cycle US + MB; (IV) low duty cycle US + rt-PA; (V) high duty cycle US + rt-PA; (VI) low duty cycle US + rt-PA + MB; and (VII) high duty cycle US + rt-PA + MB. The recanalization grades were evaluated after 20 minutes' treatment. Results: Compared to the control, there was significant improvement in recanalization in the US + rt-PA groups (P=0.01 vs. control), US (low duty cycle) + rt-PA + MB (P=0.003 vs. control) and US (high duty cycle) + rt-PA + MB (P<0.001 vs. control) groups, in which recanalization was successfully achieved in all rats. Conclusions: Long-pulsed US-enhanced MB-mediated rt-PA thrombolysis offered a powerful approach in the treatment of platelet-rich thrombus.

In-situ gelation of fibrin gel encapsulating platelet-rich plasma-derived exosomes promotes rotator cuff healing.

Although platelet-rich plasma-derived exosomes (PRP-Exos) hold significant repair potential, their efficacy in treating rotator cuff tear (RCT) remains unknown. In light of the potential for clinical translation of fibrin gel and PRP-Exos, we evaluated their combined impact on RCT healing and explored suitable gel implantation techniques. In vitro experiments demonstrated that PRP-Exos effectively enhanced key phenotypes changes in tendon stem/progenitor cells. Multi-modality imaging, including conventional ultrasound, shear wave elastography ultrasound, and micro-computed tomography, and histopathological assessments were performed to collectively evaluate the regenerative effects on RCT. The regenerated tendons exhibited a well-ordered structure, while bone and cartilage regeneration were significantly improved. PRP-Exos participated in the healing process of RCT. In-situ gelation of fibrin gel-encapsulated PRP-Exos at the bone-tendon interface during surgery proved to be a feasible gel implantation method that benefits the healing outcome. Comprehensive multi-modality postoperative evaluations were necessary, providing a reliable foundation for post-injury repair.

HucMSCs delay muscle atrophy after peripheral nerve injury through exosomes by repressing muscle-specific ubiquitin ligases.

Cell therapy based on mesenchymal stem cells (MSCs) alleviates muscle atrophy caused by diabetes and aging，however, the impact of human umbilical cord mesenchymal stem cells on muscle atrophy following nerve injury and the underlying mechanisms remain unclear. In this study, we evaluated the therapeutic efficacy of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (hucMSC-EXOs) for muscle atrophy following nerve injury and identified the underlying molecular mechanisms. Sciatic nerve crush injury in rats and the induction of myotubes in L6 cells were used to determine the ameliorating effect of hucMSCs and hucMSC-EXOs on muscle atrophy. Q-PCR and western blot analyses were used to measure the expression of muscle-specific ubiquitin ligases Fbxo32 (Atrogin1, MAFbx) and Trim63 (MuRF-1). Dual-luciferase reporter gene experiments were conducted to validate the direct binding of miRNAs to their target genes. Local injection of hucMSCs and hucMSC-EXOs mitigated atrophy in the rat gastrocnemius muscle following sciatic nerve crush injury. In vitro, hucMSC-EXOs alleviated atrophy in L6 myotubes. Mechanistic analysis indicated the upregulation of miR-23b-3p levels in L6 myotubes following hucMSC-EXOs treatment. MiR-23b-3p significantly inhibited the expression of its target genes, Fbxo32 and Trim63, and suppressed myotube atrophy. Notably, a miR-23b-3p inhibitor reversed the inhibitory effect of miR-23b-3p on myotube atrophy in vitro. These results suggest that hucMSCs and their exosomes alleviate muscle atrophy following nerve injury. MiR-23b-3p in exosomes secreted by hucMSCs contributes to this mechanism by inhibiting the muscle specific ubiquitination ligases Fbxo32 and Trim63.

Stabilizing Mechanisms in Patients Treated Using Hill-Sachs Remplissage With Bankart Repair in Abduction-External Rotation Position.

BACKGROUND: Hill-Sachs lesion (HSL) remplissage with Bankart repair (RMBR) provides a minimally invasive solution for treating HSLs and glenoid bone defects of <25%. The infraspinatus tendon is inserted into the HSL during the remplissage process, causing the infraspinatus to shift medially, leading to an unknown effect on glenohumeral alignment during the resting abduction-external rotation (ABER) and muscle-active states. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate the possible check-rein effect and muscle-active control in stabilizing the glenohumeral joint after RMBR in vivo. We hypothesized that the check-rein effect and active control would stabilize the glenohumeral joint in the ABER position in patients after RMBR. STUDY DESIGN: Controlled laboratory study. METHODS: We included 42 participants-22 patients in group A who met the inclusion criteria after RMBR and 20 healthy participants in group B without shoulder laxity. Three-dimensional magnetic resonance imaging was performed to analyze the alignment relationship of the glenohumeral joint with and without muscular activity. Ultrasonic shear wave elastography was used to evaluate the elastic properties of the anterior capsule covered with the anterior bands of the inferior glenohumeral ligament. RESULTS: Patients who underwent RMBR demonstrated more posterior (-1.81 ± 1.19 mm vs -0.76 ± 1.25 mm; P = .008) and inferior (-1.05 ± 0.62 mm vs -0.45 ± 0.48 mm; P = .001) shifts of the humeral head rotation center and less anterior capsular elasticity (70.07 ± 22.60 kPa vs 84.01 ± 14.08 kPa; P = .023) than healthy participants in the resting ABER state. More posterior (-3.17 ± 0.84 mm vs -1.81 ± 1.19 mm; P < .001) and less-inferior (-0.34 ± 0.56 mm vs -1.05 ± 0.62 mm; P < .001) shifts of the humeral head rotation center and less anterior capsular elasticity (36.57 ± 13.89 kPa vs 70.07 ± 22.60 kPa; P < .001) were observed in the operative shoulder during muscle-active ABER than in resting ABER states. CONCLUSION: The check-rein effect and muscle-active control act as stabilizing mechanisms in RMBR during the ABER position. CLINICAL RELEVANCE: Stabilizing mechanisms in RMBR during the ABER position include the check-rein effect and muscle-active control.

The ERF transcription factor LTF1 activates DIR1 to control stereoselective synthesis of antiviral lignans and stress defense in Isatis indigotica roots.

Lignans are a powerful weapon for plants to resist stresses and have diverse bioactive functions to protect human health. Elucidating the mechanisms of stereoselective biosynthesis and response to stresses of lignans is important for the guidance of plant improvement. Here, we identified the complete pathway to stereoselectively synthesize antiviral (-)-lariciresinol glucosides in Isatis indigotica roots, which consists of three-step sequential stereoselective enzymes DIR1/2, PLR, and UGT71B2. DIR1 was further identified as the key gene in respoJanuary 2024nse to stresses and was able to trigger stress defenses by mediating the elevation in lignan content. Mechanistically, the phytohormone-responsive ERF transcription factor LTF1 colocalized with DIR1 in the cell periphery of the vascular regions in mature roots and helped resist biotic and abiotic stresses by directly regulating the expression of DIR1. These systematic results suggest that DIR1 as the first common step of the lignan pathway cooperates with PLR and UGT71B2 to stereoselectively synthesize (-)-lariciresinol derived antiviral lignans in I. indigotica roots and is also a part of the LTF1-mediated regulatory network to resist stresses. In conclusion, the LTF1-DIR1 module is an ideal engineering target to improve plant Defenses while increasing the content of valuable lignans in plants.

Relevance of pyroptosis-associated genes in nasopharyngeal carcinoma diagnosis and subtype classification.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a highly aggressive and metastatic malignancy originating in the nasopharyngeal tissue. Pyroptosis is a relatively newly discovered, regulated form of necrotic cell death induced by inflammatory caspases that is associated with a variety of diseases. However, the role and mechanism of pyroptosis in NPC are not fully understood. METHODS: We analyzed the differential expression of pyroptosis-related genes (PRGs) between patients with and without NPC from the GSE53819 and GSE64634 datasets of the Gene Expression Omnibus (GEO) database. We mapped receptor operating characteristic profiles for these key PRGs to assess the accuracy of the genes for disease diagnosis and prediction of patient prognosis. In addition, we constructed a nomogram based on these key PRGs and carried out a decision curve analysis. The NPC patients were classified into different pyroptosis gene clusters by the consensus clustering method based on key PRGs, whereas the expression profiles of the key PRGs were analyzed by applying principal component analysis. We also analyzed the differences in key PRGs, immune cell infiltration and NPC-related genes between the clusters. Finally, we performed differential expression analysis for pyroptosis clusters and obtained differentially expressed genes (DEGs) and performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. RESULTS: We obtained 14 differentially expressed PRGs from GEO database. Based on these 14 differentially expressed PRGs, we applied least absolute shrinkage and selection operator analysis and the random forest algorithm to obtain four key PRGs (CHMP7, IL1A, TP63 and GSDMB). We completely distinguished the NPC patients into two pyroptosis gene clusters (pyroptosis clusters A and B) based on four key PRGs. Furthermore, we determined the immune cell abundance of each NPC sample, estimated the association between the four PRGs and immune cells, and determined the difference in immune cell infiltration between the two pyroptosis gene clusters. Finally, we obtained and functional enrichment analyses 259 DEGs by differential expression analysis for both pyroptosis clusters. CONCLUSIONS: PRGs are critical in the development of NPC, and our research on the pyroptosis gene cluster may help direct future NPC therapeutic approaches.

The value of combined ultrasound contrast arthrography and subacromial-subdeltoid bursography for detecting and differentiating the rotator cuff tear subtypes in patients with the uncertain rotator cuff tear.

OBJECTIVES: In this study, ultrasound (US) contrast arthrography and subacromial-subdeltoid bursography with the contrast agent of SonoVue were performed to evaluate their value for detecting and differentiating the rotator cuff tear (RCT) subtypes in patients with the uncertain RCT. METHODS: A total of 102 patients with the clinically suspected RCTs in the orthopedic clinic were prospectively recruited and underwent conventional high-frequency US for the category of undoubted full-thickness RCT, uncertain RCT, and intact rotator cuff. Among these patients, the patients with uncertain RCT underwent the subsequent US contrast arthrography and subacromial-subdeltoid bursography. The arthroscopic findings were used as the gold standard in this study. RESULTS: After the conventional US screening, 62 patients with uncertain RCT underwent the subsequent US contrast arthrography and subacromial-subdeltoid bursography. All the US contrast arthrography and subacromial-subdeltoid bursography were successfully performed and no severe side effects were observed in all the patients. For full-thickness tears, the sensitivity and specificity of the combined US contrast arthrography and subacromial-subdeltoid bursography were 94.7% (CI: 0.72-1.0) and 81.4% (CI: 0.66-0.91), respectively, and for articular-side tears 100% (CI: 0.51-1) and 100% (CI: 0.92-1), respectively, and for the bursal-side tears 84.6% (CI: 0.54-0.97) and 97.9% (CI: 0.88-1.0), respectively. The main inconsistency between the contrast-enhanced US and arthroscopy was that 7 patients with arthroscopic proved concurrent articular- and bursal-side tears were indicated as full-thickness RCTs on contrast-enhanced US. CONCLUSIONS: Combined US contrast arthrography and subacromial-subdeltoid bursography are useful for detecting the RCT subtypes in patients with the uncertain RCTs. CLINICAL RELEVANCE STATEMENT: When conventional high-frequency US has some difficulty in differentiating the full-thickness from partial-thickness RCTs, combined US contrast arthrography and subacromial-subdeltoid bursography could be used to improve the detection accuracy of RCT subtypes. KEY POINTS: • This is the first study by injection of the US contrast agent SonoVue into the shoulder joint cavity and subacromial-subdeltoid bursa for the detection and differentiation of the RCT subtypes among the people with the uncertain RCT by conventional US screening. • The SonoVue was injected into the glenohumeral joint cavity under US guidance to differentiate the full-thickness RCTs from partial-thickness RCTs. • Combined US contrast arthrography and subacromial-subdeltoid bursography are useful for detecting the RCT subtypes in patients with the uncertain RCTs.

Ultrasound-Targeted Microbubble Destruction Assisted Delivery of Platelet-Rich Plasma-Derived Exosomes Promoting Peripheral Nerve Regeneration.

Peripheral nerve injury is prevalent and has a high disability rate in clinical settings. Current therapeutic methods have not achieved satisfactory efficacy, underscoring the need for novel approaches to nerve restoration that remains an active area of research in neuroscience and regenerative medicine. In this study, we isolated platelet-rich plasma-derived exosomes (PRP-exos) and found that they can significantly enhance the proliferation, migration, and secretion of trophic factors by Schwann cells (SCs). In addition, there were marked changes in transcriptional and expression profiles of SCs, particularly via the upregulation of genes related to biological functions involved in nerve regeneration and repair. In the rat model of sciatic nerve crush injury, ultrasound-targeted microbubble destruction (UTMD) enhanced the efficiency of PRP-exos delivery to the injury site. This approach ensured a high concentration of PRP-exos in the injured nerve and improved the therapeutic outcomes. In conclusion, PRP-exos may promote nerve regeneration and repair, and UTMD may increase the effectiveness of targeted PRP-exos delivery to the injured nerve and enhance the therapeutic effect.

Spectral separation degree method for Vis-NIR spectroscopic discriminant analysis of milk powder adulteration.

Adulteration detection of adding ordinary milk powder to high-end dedicated milk powder is challenging due to the high similarity. Using visible and near-infrared (Vis-NIR) spectroscopy combined with k-nearest neighbor (kNN), the discriminant analysis models of pure brand milk powder and its adulterated milk powder (including unary and binary adulteration) were established. Standard normal variate transformation and Norris derivative filter (D = 2, S = 11, G = 5) were jointly used for spectral preprocessing. The separation degree and separation degree spectrum between two spectral populations were proposed and used to describe the differences between the two spectral populations, based on which, a novel wavelength selection method, named separation degree priority combination-kNN (SDPC-kNN), was proposed for wavelength optimization. SDPC-wavelength step-by-step phase-out-kNN (SDPC-WSP-kNN) models were established to further eliminate interference wavelengths and improve the model effect. The nineteen wavelengths in long-NIR region (1100-2498 nm) with a separation degree greater than 0 were used to establish single-wavelength kNN models, the total recognition-accuracy rates in prediction (RARP) all reached 100%, and the total recognition-accuracy rate in validation (RARV) of the optimal model (1174 nm) reached 97.4%. In the visible (400-780 nm) and short-NIR (780-1100 nm) regions with the separation degree all less than 0, the SDPC-WSP-kNN models were established. The two optimal models (N = 7, 22) were determined, the RARP values reached 100% and 97.4% respectively, and the RARV values reached 96.1% and 94.3% respectively. The results indicated that Vis-NIR spectroscopy combined with few-wavelength kNN has feasibility of high-precision milk powder adulteration discriminant. The few-wavelength schemes provided a valuable reference for designing dedicated miniaturized spectrometer of different spectral regions. The separation degree spectrum and SDPC can be used to improve the performance of spectral discriminant analysis. The SDPC method based on the separation degree priority proposed is a novel and effective wavelength selection method. It only needs to calculate the distance between two types of spectral sets at each wavelength with low computational complexity and good performance. In addition to combining with kNN, SDPC can also be combined with other classifier algorithms (e.g. PLS-DA, PCA-LDA) to expand the application scope of the method.

VPA improves ferroptosis in tubular epithelial cells after cisplatin-induced acute kidney injury.

Background: As a novel non-apoptotic cell death, ferroptosis has been reported to play a crucial role in acute kidney injury (AKI), especially cisplatin-induced AKI. Valproic acid (VPA), an inhibitor of histone deacetylase (HDAC) 1 and 2, is used as an antiepileptic drug. Consistent with our data, a few studies have demonstrated that VPA protects against kidney injury in several models, but the detailed mechanism remains unclear. Results: In this study, we found that VPA prevents against cisplatin-induced renal injury via regulating glutathione peroxidase 4 (GPX4) and inhibiting ferroptosis. Our results mainly indicated that ferroptosis presented in tubular epithelial cells of AKI humans and cisplatin-induced AKI mice. VPA or ferrostatin-1 (ferroptosis inhibitor, Fer-1) reduced cisplatin-induced AKI functionally and pathologically, which was characterized by reduced serum creatinine, blood urea nitrogen, and tissue damage in mice. Meanwhile, VPA or Fer-1 treatment in both in vivo and in vitro models, decreased cell death, lipid peroxidation, and expression of acyl-CoA synthetase long-chain family member 4 (ACSL4), reversing downregulation of GPX4. In addition, our study in vitro indicated that GPX4 inhibition by siRNA significantly weakened the protective effect of VPA after cisplatin treatment. Conclusion: Ferroptosis plays an essential role in cisplatin-induced AKI and inhibiting ferroptosis through VPA to protect against renal injury is a viable treatment in cisplatin-induced AKI.

[Human Platelet-Rich Plasma-Derived Exosomes Promote the Proliferation of Schwann Cells Cultured in Vitro].

Objective To investigate the effect of human platelet-rich plasma-derived exosomes(PRP-exos)on the proliferation of Schwann cell(SC)cultured in vitro. Methods PRP-exos were extracted by polymerization-precipitation combined with ultracentrifugation.The morphology of PRP-exos was observed by transmission electron microscopy,and the concentration and particle size distribution of PRP-exos were determined by nanoparticle tracking analysis.Western blotting was employed to determine the expression of the marker proteins CD63,CD81,and CD9 on exosome surface and the platelet membrane glycoprotein CD41.The SCs of rats were isolated and cultured,and the expression of the SC marker S100ß was detected by immunofluorescence staining.The fluorescently labeled PRP-exos were co-cultured with SCs in vitro for observation of their interaction.EdU assay was employed to detect the effect of PRP-exos on SC proliferation,and CCK-8 assay to detect the effects of PRP-exos at different concentrations(0,10,20,40,80,and 160 µg/ml)on SC proliferation. Results The extracted PRP-exos appeared as uniform saucer-shaped vesicles with the average particle size of(122.8±38.7)nm and the concentration of 3.5×1012 particles/ml.CD63,CD81,CD9,and CD41 were highly expressed on PRP-exos surface(P<0.001,P=0.025,P=0.004,and P=0.032).The isolated SCs expressed S100ß,and PRP-exos could be taken up by SCs.PRP-exos of 40,80,and 160 µg/ml promoted the proliferation of SCs,and that of 40 µg/ml showed the best performance(all P<0.01). Conclusions High concentrations of PRP-exos can be extracted from PRP.PRP-exos can be taken up by SCs and promote the proliferation of SCs cultured in vitro.

Dynamic Behavior of Polymer Microbubbles During Long Ultrasound Tone-Burst Excitation and Its Application for Sonoreperfusion Therapy.

OBJECTIVE: Ultrasound (US)-targeted microbubble (MB) cavitation (UTMC)-mediated therapies have been found to restore perfusion and enhance drug/gene delivery. Because of the potentially longer circulation time and relative ease of storage and reconstitution of polymer-shelled MBs compared with lipid MBs, we investigated the dynamic behavior of polymer microbubbles and their therapeutic potential for sonoreperfusion (SRP) therapy. METHODS: The fate of polymer MBs during a single long tone-burst exposure (1 MHz, 5 ms) at various acoustic pressures and MB concentrations was recorded via high-speed microscopy and passive cavitation detection (PCD). SRP efficacy of the polymer MBs was investigated in an in vitro flow system and compared with that of lipid MBs. DISCUSSION: Microscopy videos indicated that polymer MBs formed gas-filled clusters that continued to oscillate, fragment and form new gas-filled clusters during the single US burst. PCD confirmed continued acoustic activity throughout the 5-ms US excitation. SRP efficacy with polymer MBs increased with pulse duration and acoustic pressure similarly to that with lipid MBs but no significant differences were found between polymer and lipid MBs. CONCLUSION: These data suggest that persistent cavitation activity from polymer MBs during long tone-burst US excitation confers excellent reperfusion efficacy.

Improved prediction of chlorophyll-a concentrations in reservoirs by GRU neural network based on particle swarm algorithm optimized variational modal decomposition.

The accurate and reliable prediction of chlorophyll-a (Chl-a) concentration is of great significance in reservoir environment management and pollution control. To improve the accuracy of Chl-a index prediction, a novel hybrid water quality prediction method was proposed for gated recurrent unit (GRU) neural network based on particle swarm algorithm optimized variational modal decomposition (PV-GRU). The results showed that the variational mode decomposition (VMD) optimized by particle swarm optimization (PSO) in this study effectively reduced the non-smooth of water quality data. In addition, the GRU neural network reduced the risk of overfitting the deep-learning model with small sample data. Overall, the PV-GRU prediction model exhibited significant superiority in predicting non-smooth and non-linear Chl-a sequences with a relatively small sample size. The prediction errors of PV-GRU model were all less than those of other comparative models, and the fitting determination coefficient R2 was 94.21%. These results indicated that the proposed PV-GRU model can effectively predict the content of Chl-a in reservoirs, which provides an alternative new method for water quality prediction to prevent and control eutrophication in reservoirs.

Clinical value of three-dimensional ultrasonography in the morphologic evaluation of rotator cuff tear: a prospective study.

OBJECTIVE: To study the clinical value of three-dimensional ultrasonography (3D-US) in the morphological evaluation of rotator cuff tears (RCTs). METHODS: Based on previously published literature, RCT patterns in our study were divided into crescent, L-shaped with the remnant tendon retracted to the anterior rotator cuff (aL-shaped), L-shaped with the remnant tendon retracted to the posterior rotator cuff (pL-shaped), T-shaped (a tear pattern that is a combination of aL-shaped and pL-shaped), U-shaped, and massive type. Two radiologists prospectively assessed the tear patterns using 3D-US as well as magnetic resonance imaging (MRI) and compared these results using arthroscopy to calculate diagnostic accuracy. RESULT: Fifty-two patients (52 shoulders) were enrolled. The overall diagnostic accuracy of 3D-US in evaluating RCT patterns (82.7%, 43/52; 95% CI: 72.1-93.3%) was significantly higher (p = 0.008) than that of the MRI (57.7%, 31/52; 95% CI: 45.8-73.4%). The accuracy of 3D-US was higher than that of MRI for most types of tears (crescent: 95.0% vs. 55.0%, aL-shaped: 83.3% vs. 77.8%, pL-shaped: 50.0% vs. 25.0%, T-shaped: 75.0% vs. 0.0%, and massive type: 80.0% vs. 100.0%). The accuracies of 3D-US with respect to evaluation by the two radiologists were 84.6% (44/52) and 76.9% (40/52), and there was substantial agreement evident (κ = 0.709). The time taken by the two radiologists to reconstruct the 3D-US images and evaluate the tear pattern was < 5 min. CONCLUSION: The 3D-US can be used for the preoperative evaluation of RCT patterns, and thus be useful for the correct selection of the surgical repair technique for RCTs. KEY POINTS: • Few studies have been found exploring the value of 3D-US for the morphological evaluation of RCTs and correlated with the arthroscopic findings. • Based on previous studies on the morphological classification, anterior L shape (aL-shaped), and posterior L shape (pL-shaped) were used for the first time to describe the torn patterns of RCT.

Metagenomic identification of pathogens and antimicrobial-resistant genes in bacterial positive blood cultures by nanopore sequencing.

Nanopore sequencing workflows have attracted increasing attention owing to their fast, real-time, and convenient portability. Positive blood culture samples were collected from patients with bacterial bloodstream infection and tested by nanopore sequencing. This study compared the sequencing results for pathogen taxonomic profiling and antimicrobial resistance genes to those of species identification and phenotypic drug susceptibility using traditional microbiology testing. A total of 37 bacterial positive blood culture results of strain genotyping by nanopore sequencing were consistent with those of mass spectrometry. Among them, one mixed infection of bacteria and fungi was identified using nanopore sequencing and confirmatory quantitative polymerase chain reaction. The amount of sequencing data was 21.89 ± 8.46 MB for species identification, and 1.0 MB microbial strain data enabled accurate determination. Data volumes greater than or equal to 94.6 MB nearly covered all the antimicrobial resistance genes of the bacteria in our study. In addition, the results of the antimicrobial resistance genes were compared with those of phenotypic drug susceptibility testing for Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. Therefore, the nanopore sequencing platform for rapid identification of causing pathogens and relevant antimicrobial resistance genes complementary to conventional blood culture outcomes may optimize antimicrobial stewardship management for patients with bacterial bloodstream infection.