Clotrimazole inhibits growth of multiple myeloma cells in vitro via G0/G1 arrest and mitochondrial apoptosis.

Patients with multiple myeloma (MM) experience relapse and drug resistance; therefore, novel treatments are essential. Clotrimazole (CTZ) is a wide-spectrum antifungal drug with antitumor activity. However, CTZ's effects on MM are unclear. We investigated CTZ's effect on MM cell proliferation and apoptosis induction mechanisms. CTZ's effects on MM.1S, NCI- H929, KMS-11, and U266 cell growth were investigated using Cell Counting Kit-8 (CCK-8) assay. The apoptotic cell percentage was quantified with annexin V-fluorescein isothiocyanate/7-amino actinomycin D staining. Mitochondrial membrane potential (MMP) and cell cycle progression were evaluated. Reactive oxygen species (ROS) levels were measured via fluorescence microscopy. Expression of apoptosis-related and nuclear factor (NF)-κB signaling proteins was analyzed using western blotting. The CCK-8 assay indicated that CTZ inhibited cell proliferation based on both dose and exposure time. Flow cytometry revealed that CTZ decreased apoptosis and MMP and induced G0/G1 arrest. Immunofluorescence demonstrated that CTZ dose-dependently elevated in both total and mitochondrial ROS production. Western blotting showed that CTZ enhanced Bax and cleaved poly ADP-ribose polymerase and caspase-3 while decreasing Bcl-2, p-p65, and p-IκBα. Therefore, CTZ inhibits MM cell proliferation by promoting ROS-mediated mitochondrial apoptosis, inducing G0/G1 arrest, inhibiting the NF-κB pathway, and has the potential for treating MM.

Rapid Mass Spectrometry-Based Multiattribute Method for Glycation Analysis with Integrated Afucosylation Detection Capability.

The multiattribute method (MAM) has emerged as a powerful tool for simultaneously screening multiple product quality attributes of therapeutic antibodies. One such potential critical quality attribute (CQA) is glycation, a common modification that can impact the heterogeneity, functional activity, and immunogenicity of therapeutic antibodies. However, current methods for monitoring glycation levels in MAM are rare and not sufficiently rapid and accurate. In this study, an improved mass spectrometry (MS)-based MAM was developed to simultaneously monitor glycation and other quality attributes including afucosylation. The method was evaluated using two therapeutic antibodies with different glycosylation site numbers. Treatment with IdeS, Endo F2, and dithiothreitol generated three distinct subunits, and the glycation results obtained were similar to those treated with PNGase F, which is routinely used to release glycans; the sample processing time was greatly reduced while providing additional quality attribute information. The MS-based MAM was also employed to assess the glycation progression following forced glycation in various buffer solutions. A significant increase in oxidation was observed when forced glycation was conducted in an ammonium bicarbonate buffer solution, and a total of 23 potential glycation sites and 4 significantly oxidized sites were identified. Notably, we found that ammonium bicarbonate was found to specifically stimulate oxidation, while glycation had a synergistic effect on oxidation. These findings establish this study as a novel methodology for achieving a technologically advanced platform and concept that enhances the efficacy of product development and quality control, characterized by its broad-spectrum, rapid, and accurate nature.

Magnetite enhances As immobilization during nitrate reduction and Fe(II) oxidation by Acidovorax sp. strain BoFeN1.

Arsenic (As) cycling in groundwater is commonly coupled to the biogeochemical cycling of iron (Fe) and the associated transformation of Fe minerals present. Numerous laboratory studies suggested that Fe minerals can act as nucleation sites for further crystal growth and as catalysts for abiotic Fe(II) oxidation. In view of the widespread existence of magnetite in anoxic environments where As is often dissolved, we firstly exploited magnetite to enhance As immobilization during nitrate-reducing Fe(II) oxidation (NRFO) induced by Acidovorax sp. strain BoFeN1, a mixotrophic nitrate-reducing Fe(II)-oxidizing bacterium that can oxidize Fe(II) through both enzymatic and abiotic pathways. Subsequently, we investigated how magnetite affects NRFO and As immobilization. Results demonstrated a significant increase in As(III) removal efficiency from 75.4 % to 97.2 % with magnetite, attributed to the higher amount of NRFO and As(III) oxidation promoted by magnetite. It was found that magnetite stimulated the production of extracellular polymeric substances (EPS), which could decrease the diffusion of nitrate in the periplasm of bacteria and shield them against encrustation, resulting in a more rapid reduction of nitrate in the system with magnetite than that without magnetite. Meanwhile, Fe(II) was almost completely oxidized in the presence of magnetite during the whole 72 h experiment, while in the absence of magnetite, 47.7 % of Fe(II) remained, indicating that magnetite could obviously accelerate the chemical oxidation of Fe(II) with nitrite (the intermediates of nitrate bioreduction). Furthermore, the formation of labile Fe(III), an intermediate product of electron transfer between Fe(II) and magnetite, was reasonably deduced to be vital for anoxic As(III) oxidation. Additionally, the XPS analysis of the solid phase confirmed the oxidation of 43.8 % of As(III) to As(V). This study helps to understand the biogeochemical cycling of Fe and As in the environment, and provides a cost-effective and environmentally friendly option for in situ remediation of As-contaminated groundwater.

Mental health among U.S. College students: implications of COVID-19 and roles of institutional and individual characteristics.

Previous research on college campus environments, student mental health, and COVID-19 has primarily focused on individual-level factors, with limited attention to the broader institutional characteristics. Objective and Methods: Using the national survey data from the American College Health Association, this study examines the influence of both individual-level and institutional-level characteristics on college students' stress, psychological distress, and psychological well-being, before and during COVID-19. Results: (1) COVID-19 significantly impacted students' mental health; (2) institutional-level factors, such as school size, locale, region, and religiously affiliation, were significant predictors of mental health outcomes; and (3) individual-level variables, including gender, age, race/ethnicity, relationship status, moderated the relationship between COVID-19 and mental health. Conclusion: This study suggests the need to consider various institutional contexts in future efforts to understand predictors of mental health conditions and resilience.

Flexible Humidity Sensor Based on a Graphene Oxide-Carbon Nanotube-Modified Co3O4 Nanoparticle-Embedded Laser-Induced Graphene Electrode.

To meet evolving humidity monitoring needs, the development of flexible, high-performance humidity sensors is crucial. This study introduces an innovative flexible humidity sensor using a single-step laser scribing technique to fabricate a flexible in situ Co3O4 nanoparticle-embedded laser-induced graphene (Co3O4-LIG) composite electrode. Compared to conventional LIG electrodes, the Co3O4-LIG electrode exhibits improved conductivity and hydrophilicity, enhancing charge transfer and water molecule affinity. The unique two-dimensional structure and exceptional water permeability of graphene oxide (GO) combine with the rapid water response and high specific surface area of carboxylated multiwalled carbon nanotubes (MWCNTs), thereby assuming a crucial function in the modification and optimization of the performance of humidity sensors. Through the application of a homogenously blended aqueous solution comprising GO and MWCNTs in precise proportions onto the Co3O4-LIG composite electrode, an excellent humidity-responsive layer is established, culminating in the realization of a cutting-edge GO-MWCNTs@Co3O4-LIG flexible humidity sensor. Noteworthy attributes of this sensor include a heightened sensitivity [959.1% (ΔR/R0)], rapid response and recovery times (within 5 and 26 s, respectively), and a noteworthy linearity (R2 = 0.994) across a relative humidity range of 14 to 95%. The findings presented herein offer valuable insights and a practical blueprint for the design and production of flexible humidity sensors.

Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.

Synthetic community derived from grafted watermelon rhizosphere provides protection for ungrafted watermelon against Fusarium oxysporum via microbial synergistic effects.

BACKGROUND: Plant microbiota contributes to plant growth and health, including enhancing plant resistance to various diseases. Despite remarkable progress in understanding diseases resistance in plants, the precise role of rhizosphere microbiota in enhancing watermelon resistance against soil-borne diseases remains unclear. Here, we constructed a synthetic community (SynCom) of 16 core bacterial strains obtained from the rhizosphere of grafted watermelon plants. We further simplified SynCom and investigated the role of bacteria with synergistic interactions in promoting plant growth through a simple synthetic community. RESULTS: Our results demonstrated that the SynCom significantly enhanced the growth and disease resistance of ungrafted watermelon grown in non-sterile soil. Furthermore, analysis of the amplicon and metagenome data revealed the pivotal role of Pseudomonas in enhancing plant health, as evidenced by a significant increase in the relative abundance and biofilm-forming pathways of Pseudomonas post-SynCom inoculation. Based on in vitro co-culture experiments and bacterial metabolomic analysis, we selected Pseudomonas along with seven other members of the SynCom that exhibited synergistic effects with Pseudomonas. It enabled us to further refine the initially constructed SynCom into a simplified SynCom comprising the eight selected bacterial species. Notably, the plant-promoting effects of simplified SynCom were similar to those of the initial SynCom. Furthermore, the simplified SynCom protected plants through synergistic effects of bacteria. CONCLUSIONS: Our findings suggest that the SynCom proliferate in the rhizosphere and mitigate soil-borne diseases through microbial synergistic interactions, highlighting the potential of synergistic effects between microorganisms in enhancing plant health. This study provides a novel insight into using the functional SynCom as a promising solution for sustainable agriculture. Video Abstract.

Dynamic interactions of carbon trading, green certificate trading, and electricity markets: Insights from system dynamics modeling.

In the context of the evolving landscape of reduction in carbon emissions and integration of renewable energy, this study uses system dynamics (SD) modeling to explore the interconnected dynamics of carbon trading (CT), tradable green certificate (TGC) trading, and electricity markets. Using differential equations with time delays, the study provides a comprehensive analysis of structural relationships and feedback mechanisms within and between these markets. Key findings reveal the intricate interplay between carbon prices, green certificate prices, and electricity prices under various coupling mechanisms. For example, under the three-market coupling mechanism, carbon trading prices stabilize around 150 Yuan/ton, while green certificate prices reach a peak of 0.45 Yuan/KWH, impacting electricity prices, which fluctuate between 0.33 and 1.09 Yuan / KWH during the simulation period. These quantitative results shed light on nuanced fluctuations in market prices and the dynamics of anticipated purchases and sales volumes within each market. The insights gleaned from this study offer valuable implications for policy makers and market stakeholders in navigating the complexities of carbon emission reduction strategies, the integration of renewable energy and market equilibrium. By understanding the dynamics of multi-market coupling, stakeholders can better formulate policies and strategies to achieve sustainable energy transitions and mitigate impacts of climate change.

Comparison of lung lesion assessment using free-breathing dynamic contrast-enhanced 1.5-T MRI with a golden-angle radial stack-of-stars VIBE sequence and CT.

BACKGROUND: Few studies have investigated the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using a free-breathing golden-angle radial stack-of-stars volume-interpolated breath-hold examination (FB radial VIBE) sequence in the lung. PURPOSE: To investigate whether DCE-MRI using the FB radial VIBE sequence can assess morphological and kinetic parameters in patients with pulmonary lesions, with computed tomography (CT) as the reference. MATERIAL AND METHODS: In total, 43 patients (30 men; mean age = 64 years) with one lesion each were prospectively enrolled. Morphological and kinetic features on MRI were calculated. The diagnostic performance of morphological MR features was evaluated using a receiver operating characteristic (ROC) curve. Kinetic features were compared among subgroups based on histopathological subtype, lesion size, and lymph node metastasis. RESULTS: The maximum diameter was not significantly different between CT and MRI (3.66 ± 1.62 cm vs. 3.64 ± 1.72 cm; P = 0.663). Spiculation, lobulation, cavitation or bubble-like areas of low attenuation, and lymph node enlargement had an area under the ROC curve (AUC) >0.9, while pleural indentation yielded an AUC of 0.788. The lung cancer group had significantly lower Ktrans, Ve, and initial AUC values than the other cause inflammation group (0.203, 0.158, and 0.589 vs. 0.597, 0.385, and 1.626; P < 0.05) but significantly higher values than the tuberculosis group (P < 0.05). CONCLUSION: Morphology features derived from FB radial VIBE have high correlations with CT, and kinetic analyses show significant differences between benign and malignant lesions. DCE-MRI with FB radial VIBE could serve as a complementary quantification tool to CT for radiation-free assessments of lung lesions.

Chiral silver nanoparticles with surface-anchored L(D)-Cys exhibit dissimilar biological characteristics in vitro but not in vivo.

This work investigated the influence of surface chirality on cellular internalization, cytotoxicity, and tissue distribution of silver nanoparticles (AgNPs). D-cysteine and L-cysteine are chiral forms of the amino acid cysteine. These enantiomers exhibit distinct spatial arrangements, with D-cysteine having a different configuration from L-cysteine. This structural dissimilarity can lead to variations in how these forms interact with biological systems, potentially impacting their cytotoxic responses. Four distinct types of AgNPs were synthesized, each possessing a unique surface coating: pristine AgNPs (pAgNPs), L-cysteine coated AgNPs (AgNPs@L-Cys), D-cysteine coated AgNPs (AgNPs@D-Cys), and racemic AgNPs coated with both L-Cys and D-Cys (AgNPs@L/D-Cys). We found chiral-dependent cytotoxicity of AgNPs on J774A.1 cells. Specifically, AgNPs@L-Cys exhibited the highest toxicity, and AgNPs@D-Cys exhibited the lowest toxicity. Meanwhile, the cellular uptake of the AgNPs correlated nicely with their cytotoxicity, with AgNPs@L-Cys being internalized to the greatest extent while AgNPs@D-Cys displays the least internalization. Scavenger receptors and clathrin predominantly mediate the cellular internalization of these AgNPs. Strikingly, the dissimilar cellular internalization and cytotoxicity of AgNPs with different chirality were eliminated upon protein corona coverage. Notably, following intravenous injection in mice, these four types of AgNPs showed similar patterns among various organs due to the inevitable protein adsorption in the bloodstream. These findings underscored the pivotal role of surface chirality in governing the biological interactions and toxicity of AgNPs.

Curved carbon-plated shoe may further reduce forefoot loads compared to flat plate during running.

Using a curved carbon-fiber plate (CFP) in running shoes may offer notable performance benefit over flat plates, yet there is a lack of research exploring the influence of CFP geometry on internal foot loading during running. The objective of this study was to investigate the effects of CFP mechanical characteristics on forefoot biomechanics in terms of plantar pressure, bone stress distribution, and contact force transmission during a simulated impact peak moment in forefoot strike running. We employed a finite element model of the foot-shoe system, wherein various CFP configurations, including three stiffnesses (stiff, stiffer, and stiffest) and two shapes (flat plate (FCFP) and curved plate (CCFP)), were integrated into the shoe sole. Comparing the shoes with no CFP (NCFP) to those with CFP, we consistently observed a reduction in peak forefoot plantar pressure with increasing CFP stiffness. This decrease in pressure was even more notable in a CCFP demonstrating a further reduction in peak pressure ranging from 5.51 to 12.62%, compared to FCFP models. Both FCFP and CCFP designs had a negligible impact on reducing the maximum stress experienced by the 2nd and 3rd metatarsals. However, they greatly influenced the stress distribution in other metatarsal bones. These CFP designs seem to optimize the load transfer pathway, enabling a more uniform force transmission by mainly reducing contact force on the medial columns (the first three rays, measuring 0.333 times body weight for FCFP and 0.335 for CCFP in stiffest condition, compared to 0.373 in NCFP). We concluded that employing a curved CFP in running shoes could be more beneficial from an injury prevention perspective by inducing less peak pressure under the metatarsal heads while not worsening their stress state compared to flat plates.

A cell type-specific approach to elucidate the role of miR-96 in inner ear hair cells.

Introduction: Mutations in microRNA-96 (miR-96), a microRNA expressed within the hair cells (HCs) of the inner ear, result in progressive hearing loss in both mouse models and humans. In this study, we present the first HC-specific RNA-sequencing (RNA-seq) dataset from newborn Mir96Dmdo heterozygous, homozygous mutant, and wildtype mice. Methods: Bulk RNA-seq was performed on HCs of newborn Mir96Dmdo heterozygous, homozygous mutant, and wildtype mice. Differentially expressed gene analysis was conducted on Mir96Dmdo homozygous mutant HCs compared to wildtype littermate controls, followed by GO term and protein-protein interaction analysis on these differentially expressed genes. Results: We identify 215 upregulated and 428 downregulated genes in the HCs of the Mir96Dmdo homozygous mutant mice compared to their wildtype littermate controls. Many of the significantly downregulated genes in Mir96Dmdo homozygous mutant HCs have established roles in HC development and/or known roles in deafness including Myo15a, Myo7a, Ush1c, Gfi1, and Ptprq and have enrichment in gene ontology (GO) terms with biological functions such as sensory perception of sound. Interestingly, upregulated genes in Mir96Dmdo homozygous mutants, including possible miR-96 direct targets, show higher wildtype expression in supporting cells compared to HCs. Conclusion: Our data further support a role for miR-96 in HC development, possibly as a repressor of supporting cell transcriptional programs in HCs. The HC-specific Mir96Dmdo RNA-seq data set generated from this manuscript are now publicly available in a dedicated profile in the gene expression analysis resource (gEAR-https://umgear.org/p?l=miR96).

TNIK Inhibition Sensitizes TNIK-Overexpressing Lung Squamous Cell Carcinoma to Radiotherapy.

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited because of dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for patients with LSCC. Moreover, other options for chemotherapy-ineligible patients are limited. As such, there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. In this study, we investigated inhibiting TRAF2- and NCK-interacting protein kinase (TNIK), which is amplified in 40% of patients with LSCC, as a strategy to sensitize LSCC tumors to chemotherapy and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in patients with LSCC with high TNIK expression.

Three new antinociceptive diterpenoids from the fruits of Rhododendron molle.

Investigation of the fruits of Rhododendron molle G. Don led to the isolation of three new grayanane-type diterpenoids, rhodomolleins LIV-LVI (1-3). The structures and absolute configurations of new compounds were fully elucidated by spectroscopic analysis and single-crystal X-ray diffraction, including HRESIMS, 1 D and 2 D NMR data. Compounds 1-3 were evaluated for analgesic activities utilizing an acetic acid-induced writhing test in mice. Compound 1 showed a significant antinociceptive effect with writhe inhibition rates of 72.9% and 100% at doses of 6 mg/kg and 20 mg/kg in mice, respectively. The binding mode of 1 to N-ethylmaleimide-sensitive factor (NSF, PDB: 6IP2) was explored by molecular docking, indicating the presence of hydrogen bond interactions which account for its analgesic activity.

Effect of External Electric Field on Nitrogen Activation on a Trimetal Cluster.

Efficient nitrogen (N2) fixation and activation under mild conditions are crucial for modern society. External electric fields (Felectric) can significantly affect N2 activation. In this work, the effect of Felectric on N2 activation by Nb3 clusters supported in a sumanene bowl was studied by density functional theory calculations. Four typical systems at different stages of N-N activation were studied, including two intermediates and two transition states. The impact of Felectric on various properties related to N2 activation was investigated, including the N-N bond length, overlap population density of states (OPDOS), total energy of the system, adsorption energy of N2, decomposition of energy changes, and electron transfer. The sumanene not only functions as a support and protective substrate, but also serves as a donor or acceptor under different Felectric conditions. Negative Felectric is beneficial to N-N bond activation because it promotes electron transfer to the N-N region and improves the d-π* orbital hybridization between metals and N2 in the activation process. Positive Felectric improves d-π* orbital hybridization only when the N-N is nearly dissociated. The microscopic mechanism of Felectric's effects provides insight into N2 activation and theoretical guidance for the design of catalytic reaction conditions for nitrogen reduction reactions (NRR).

Proton therapy re-irradiation outcomes and genomic landscape of patients with recurrent head and neck cancer.

INTRODUCTION: Re-irradiation (re-RT) for recurrent head and neck cancer (rHNC) is challenging. We describe clinical outcomes and toxicity of proton therapy (PT) for recurrent HNC, and report genomic alterations associated with patterns of failure. MATERIALS & METHODS: We performed a retrospective analysis of rHNC patients treated with PT. Outcomes were estimated using the Kaplan-Meier method. Univariate (UVA) and multivariate analyses (MVA) were performed to assess multiple patient factors. Next-generation sequencing and genomic analyses were performed on available samples. RESULTS: Eighty-nine patients treated with PBS-PT for rHNC with a median follow-up of 12 mo (0-71 mo) were included. The 1- and 2-y local control (LC) rates were 80.8 % (95 % CI: 70.8-90.8) and 66.2 % (95 % CI: 50.7-81.7), and 1- and 2-y distant metastasis-free survival (DMFS) were 41.0 % (95 % CI: 30.0-52.0) and 26.3 % (95 % CI: 15.7-36.9). The median overall survival (OS) was 13 mo (95 % CI: 9.3-16.7). On UVA and MVA, smaller gross tumor volume (GTV) was associated with improved OS (HR 1.002, P = 0.004), DMFS (HR 1.002, P = 0.004), and PFS (HR 1.002, P = 0.014). There were 35 late Gr3 + toxicity events (30.3 %). Patients with higher candidate gene-specific mutation burden (genes with [OR] > 2, P < 0.05) had inferior PFS. TP53, NOTCH4, and ARID1B mutations were associated with inferior DMFS (OR > 2, P < 0.05). CONCLUSIONS: PBS-PT is effective at achieving LC for rHNC with favorable toxicity. Distant metastases are common, and associated with TP53, NOTCH4, and ARID1B mutations. Inclusion of genomic alterations in the clinical decision process may be warranted.

Deep learning reconstruction for lumbar spine MRI acceleration: a prospective study.

BACKGROUND: We compared magnetic resonance imaging (MRI) turbo spin-echo images reconstructed using a deep learning technique (TSE-DL) with standard turbo spin-echo (TSE-SD) images of the lumbar spine regarding image quality and detection performance of common degenerative pathologies. METHODS: This prospective, single-center study included 31 patients (15 males and 16 females; aged 51 ± 16 years (mean ± standard deviation)) who underwent lumbar spine exams with both TSE-SD and TSE-DL acquisitions for degenerative spine diseases. Images were analyzed by two radiologists and assessed for qualitative image quality using a 4-point Likert scale, quantitative signal-to-noise ratio (SNR) of anatomic landmarks, and detection of common pathologies. Paired-sample t, Wilcoxon, and McNemar tests, unweighted/linearly weighted Cohen κ statistics, and intraclass correlation coefficients were used. RESULTS: Scan time for TSE-DL and TSE-SD protocols was 2:55 and 5:17 min:s, respectively. The overall image quality was either significantly higher for TSE-DL or not significantly different between TSE-SD and TSE-DL. TSE-DL demonstrated higher SNR and subject noise scores than TSE-SD. For pathology detection, the interreader agreement was substantial to almost perfect for TSE-DL, with κ values ranging from 0.61 to 1.00; the interprotocol agreement was almost perfect for both readers, with κ values ranging from 0.84 to 1.00. There was no significant difference in the diagnostic confidence or detection rate of common pathologies between the two sequences (p ≥ 0.081). CONCLUSIONS: TSE-DL allowed for a 45% reduction in scan time over TSE-SD in lumbar spine MRI without compromising the overall image quality and showed comparable detection performance of common pathologies in the evaluation of degenerative lumbar spine changes. RELEVANCE STATEMENT: Deep learning-reconstructed lumbar spine MRI protocol enabled a 45% reduction in scan time compared with conventional reconstruction, with comparable image quality and detection performance of common degenerative pathologies. KEY POINTS: • Lumbar spine MRI with deep learning reconstruction has broad application prospects. • Deep learning reconstruction of lumbar spine MRI saved 45% scan time without compromising overall image quality. • When compared with standard sequences, deep learning reconstruction showed similar detection performance of common degenerative lumbar spine pathologies.

Cardiovascular toxic effects of nanoparticles and corresponding molecular mechanisms.

Rapid advancements in nanotechnology have been integrated into various disciplines, leading to an increased prevalence of nanoparticle exposure. The widespread utilization of nanomaterials and heightened levels of particulate pollution have prompted government departments to intensify their focus on assessing the safety of nanoparticles (NPs). The cardiovascular system, crucial for maintaining human health, has emerged as vulnerable to damage from nanoparticle exposure. A mounting body of evidence indicates that interactions can occur when NPs come into contact with components of the cardiovascular system, contributing to adverse cardiovascular disease (CVD). However, the underlying molecular mechanisms driving these events remain elusive. This work provides a comprehensive review of recent advance on nanoparticle-induced adverse cardiovascular events and offers insight into the associated molecular mechanisms. Finally, the influencing factors of NPs-induced cardiovascular toxicity are discussed.

Ultrasensitive detection of trace Hg(â ¡) in acidic conditions using DMABR loaded on sepiolite: Function, application and mechanism studies.

Fast and real-time detection of trace Hg(Ⅱ) by fluorescent probes under acidic conditions is urgently required due to the high toxicity and accessibility to creatures and human being. However, fluorescent probes for Hg(Ⅱ) detection in environmental samples are rarely reported due to the protonation potential of acidic mercury sources. In this study, the SD probe was developed by 5-(p-dimethylaminobenzylidene) rhodanine (DMABR) loaded on sepiolite by hydrothermal treatment, and showed excellent Hg(Ⅱ) detection performances for mercury sources at pH 4-10 due to buffering ability of the hyperconjugated lactam rings. Sepiolite functioned as the support skeleton to decrease intermolecular transition, and thus increased the sensitivity. At pH 4, the SD probe showed high selectivity and sensitivity for Hg(Ⅱ) among various species, with low LOD and binding constant of 4.78 × 10-9 M and 1.34 × 106 M-1, respectively. Through DFT calculations, MAS 1H NMR and 2D-COS analysis, the detection mechanism was demonstrated as SN1 substitution of the spontaneous leaving H on amino groups in the transient state during tautomeric equilibrium, rather than the expected high-affinity sulphydryl. Additionally, the SD probe exhibited promising potential in quantifying water-soluble and bioavailable Hg(Ⅱ) in acidic polluted soil and water samples. Moreover, real-time detection was realized by paper-based strips.

Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer.

BACKGROUND AND OBJECTIVE: Oligometastatic castration-sensitive prostate cancer (omCSPC) represents an early state in the progression of metastatic disease for which patients experience better outcomes in comparison to those with higher disease burden. Despite the generally more indolent nature, there is still much heterogeneity, with some patients experiencing a more aggressive clinical course unexplained by clinical features alone. Our aim was to investigate correlation of tumor genomics with the mode of progression (MOP) and pattern of failure (POF) following first treatment (metastasis-directed and/or systemic therapy) for omCSPC. METHODS: We performed an international multi-institutional retrospective study of men treated for metachronous omCSPC who underwent tumor next-generation sequencing with at least 1 yr of follow-up after their first treatment. Descriptive MOP and POF results are reported with respect to the presence of genomic alterations in pathways of interest. MOP was defined as class I, long-term control (LTC; no radiographic progression at last follow-up), class II, oligoprogression (1-3 lesions), or class III, polyprogression (≥4 lesions). POF included the location of lesions at first failure. Genomic pathways of interest included TP53, ATM, RB1, BRCA1/2, SPOP, and WNT (APC, CTNNB1, RNF43). Genomic associations with MOP/POF were compared using χ2 tests. Exploratory analyses revealed that the COSMIC mutational signature and differential gene expression were also correlated with MOP/POF. Overall survival (OS) was calculated via the Kaplan-Meier method from the time of first failure. KEY FINDINGS AND CLINICAL IMPLICATIONS: We included 267 patients in our analysis; the majority had either one (47%) or two (30%) metastatic lesions at oligometastasis. The 3-yr OS rate was significantly associated with MOP (71% for polyprogression vs 91% for oligoprogression; p = 0.005). TP53 mutation was associated with a significantly lower LTC rate (27.6% vs 42.3%; p = 0.04) and RB1 mutation was associated with a high rate of polyprogression (50% vs 19.9%; p = 0.022). Regarding POF, bone failure was significantly more common with tumors harboring TP53 mutations (44.8% vs25.9%; p = 0.005) and less common with SPOP mutations (7.1% vs 31.4%; p = 0.007). Visceral failure was more common with tumors harboring either WNT pathway mutations (17.2% vs 6.8%, p = 0.05) or SPOP mutations (17.9% vs 6.3%; p = 0.04). Finally, visceral and bone failures were associated with distinct gene-expression profiles. CONCLUSIONS AND CLINICAL IMPLICATIONS: Tumor genomics provides novel insight into MOP and POF following treatment for metachronous omCSPC. Patients with TP53 and RB1 mutations have a higher likelihood of progression, and TP53, SPOP, and WNT pathway mutations may have a role in metastatic organotropism. PATIENT SUMMARY: We evaluated cancer progression after a first treatment for metastatic prostate cancer with up to five metastases. We found that mutations in certain genes were associated with the location and extent of further metastasis in these patients.