Uncatalyzed Diboron Activation by a Strained Hydrocarbon: Experimental and Theoretical Study of [1.1.1]Propellane Diborylation.

The synthesis of strained carbocyclic building blocks is relevant for Medicinal Chemistry, and methylenecyclobutanes are particularly challenging with current synthetic technology. Careful inspection of the reactivity of [1.1.1]propellane and diboron reagents has revealed that bis(catecholato)diboron (B2cat2) can produce a bis(borylated) methylenecyclobutane in a few minutes at room temperature. This reaction constitutes the first example of B-B bond activation by a special apolar hydrocarbon and also the first time that propellane is electrophilically activated by boron. Mechanistic studies including in situ NMR kinetics and DFT calculations demonstrate that the diboron moiety can be directly activated through coordination with the inverted sigma bond of propellane, and reveal that DMF is involved in the stabilization of diboronate ylide intermediates rather than the activation of the B-B bond. These results enable new possibilities for both diboron and propellane chemistry, and for further developments in the synthesis of methylenecyclobutanes based on propellane strain release.

Effects of electroacupuncture combined with paliperidone palmitate long-acting injection on withdrawal symptoms and neurotransmitters in methamphetamine addicts.

OBJECTIVE: To investigate the effects of electroacupuncture combined with paliperidone palmitate long-acting injection (PP-LAI) on withdrawal symptoms and neurotransmitters in methamphetamine (MA) addicts. MATERIALS AND METHODS: A total of 109 methamphetamine addicts, who were treated in the hospital from October 2021 to October 2022, were selected. According to the random number table, the patients were divided into the study group (n=54) and the control group (n=55), in which the control group was treated with PP-LAI and the study group was treated with electroacupuncture on the basis of the control group; the methamphetamine withdrawal symptom score scale was used to assess the therapeutic effect before treatment and within 12 months after treatment; the changes of brain neurotransmitters dopamine, γ-aminobutyric acid, serotonin, acetylcholine values were compared between the two groups. RESULTS: 1) There was no statistical difference in MA withdrawal symptom scores between the two groups before treatment (p>0.05); 2) MA withdrawal symptom scores have a statistically significant difference between the study group and the control group after 3 and 6 months of treatment; 3) dopamine levels in the study group were significantly higher than those in the control group after 6 months of completion of treatment, and γ-aminobutyric acid values and 5- serotonin values in the study group were significantly lower than those in the control group (p<0.05). CONCLUSIONS: Electroacupuncture combined with PP-LAI can partially improve the withdrawal symptoms and anxiety of methamphetamine addicts. This is a potential treatment for preventing relapse of withdrawal symptoms.

Assessing environmental and human health risks: Insight from the enantioselective metabolism and degradation of fenpropidin.

Fenpropidin (FPD), a widely employed chiral fungicide, is frequently detected in diverse environments. In an in vitro rat liver microsomes cultivation (RLMs), the metabolism exhibited the order of R-FPD > S-FPD, with respective half-lives of 10.42 ± 0.11 and 12.06 ± 0.15 min, aligning with kinetic analysis results. CYP3A2 has been demonstrated to be the most significant oxidative enzyme through CYP450 enzyme inhibition experiments. Molecular dynamics simulations unveiled the enantioselective metabolic mechanism, demonstrating that R-FPD forms hydrogen bonds with the CYP3A2 protein, resulting in a higher binding affinity (-6.58 kcal mol-1) than S-FPD. Seven new metabolites were identified by Liquid chromatography time-of-flight high-resolution mass spectrometry, which were mainly generated through oxidation, reduction, hydroxylation, and N-dealkylation reactions. The toxicity of the major metabolites predicted by the TEST procedure was found to be stronger than the predicted toxicity of FPD. Moreover, the enantioselective fate of FPD was studied by examining its degradation in three soils with varying physical and chemical properties under aerobic, anaerobic, and sterile conditions. Enantioselective degradation of FPD occurred in soils without enantiomeric transformation, displaying a preference for R-FPD degradation. R-FPD is a low-risk stereoisomer both in the environment and in mammals. The research presented a systematic and comprehensive method for analyzing the metabolic and degradation system of FPD enantiomers. This approach aids in understanding the behavior of FPD in the environment and provides valuable insights into their potential risks to human health.

Life disturbance and hospital visit experiences among Chinese patients with benign prostatic hyperplasia: a qualitative study.

BACKGROUND: The impact of lower urinary tract symptoms (LUTS) on the quality of life of patients with benign prostatic hyperplasia (BPH) has been rarely reported. Additionally, the challenges faced by these patients in seeking medical care have often been overlooked. In order to explore the personal struggles caused by LUTS and the difficulties or barriers experienced by Chinese patients with BPH when seeking help, we conducted a qualitative interview study. METHODS: Qualitative interviews were conducted among 46 patients with BPH who were hospitalized in three tertiary hospitals in China from July 2021 to November 2022. Grounded theory was adopted as the methodology for the qualitative study. After obtaining written informed consent from the study participants, semi-structured interviews were conducted according to the question guidelines. The interview process was audio-recorded; subsequently, the recordings were transcribed, coded, and thematically analyzed. RESULTS: The difficulties faced by Chinese patients with BPH were classified into seven main themes: (i) disturbed life, (ii) mental burden, (iii) disease cognition and communication, (iv) delayed treatment, (v) medication status, (vi) hospital visits barriers, and (vii) medical insurance issues. Further, each theme was subdivided into 2-5 sub-themes. CONCLUSIONS: LUTS have a certain effect on the life and spirit of patients with BPH. These patients face different degrees of difficulties in treatment and hospital visits. Therefore, better healthcare systems and additional social support are crucial for improving the current plight of these patients.

A spatial transcriptome map of the developing maize ear.

A comprehensive understanding of inflorescence development is crucial for crop genetic improvement, as inflorescence meristems give rise to reproductive organs and determine grain yield. However, dissecting inflorescence development at the cellular level has been challenging owing to a lack of specific marker genes to distinguish among cell types, particularly in different types of meristems that are vital for organ formation. In this study, we used spatial enhanced resolution omics-sequencing (Stereo-seq) to construct a precise spatial transcriptome map of the developing maize ear primordium, identifying 12 cell types, including 4 newly defined cell types found mainly in the inflorescence meristem. By extracting the meristem components for detailed clustering, we identified three subtypes of meristem and validated two MADS-box genes that were specifically expressed at the apex of determinate meristems and involved in stem cell determinacy. Furthermore, by integrating single-cell RNA transcriptomes, we identified a series of spatially specific networks and hub genes that may provide new insights into the formation of different tissues. In summary, this study provides a valuable resource for research on cereal inflorescence development, offering new clues for yield improvement.

Non-equilibrium structural and dynamic behaviors of active polymers in complex and crowded environments.

Active matter systems, which convert internal chemical energy or energy from the environment into directed motion, are ubiquitous in nature and exhibit a range of emerging non-equilibrium behaviors. However, most of the current works on active matter have been devoted to particles, and the study of active polymers has only recently come into the spotlight due to their prevalence within living organisms. The intricate interplay between activity and conformational degrees of freedom gives rise to novel structural and dynamical behaviors of active polymers. Research in active polymers remarkably broadens diverse concepts of polymer physics, such as molecular architecture, dynamics, scaling and so on, which is of significant importance for the development of new polymer materials with unique performance. Furthermore, active polymers are often found in strongly interacting and crowded systems and in complex environments, so that the understanding of this behavior is essential for future developments of novel polymer-based biomaterials. This review thereby focuses on the study of active polymers in complex and crowded environments, and aims to provide insights into the fundamental physics underlying the adaptive and collective behaviors far from equilibrium, as well as the open challenges that the field is currently facing.

In Situ Unveiling of the Resistive Switching Mechanism of Halide Perovskite-Based Memristors.

The organic-inorganic halide perovskite has become one of the most promising candidates for next-generation memory devices, i.e. memristors, with excellent performance and solution-processable preparation. Yet, the mechanism of resistive switching in perovskite-based memristors remains ambiguous due to a lack of in situ visualized characterization methods. Here, we directly observe the switching process of perovskite memristors with in situ photoluminescence (PL) imaging microscopy under an external electric field. Furthermore, the corresponding element composition of conductive filaments (CFs) is studied, indicating that the metallic CFs with respect to the activity of the top electrode are essential for device performance. Finally, electrochemical impedance spectroscopy (EIS) is conducted to reveal that the transition of ion states is associated with the formation of metallic CFs. This study provides in-depth insights into the switching mechanism of perovskite memristors, paving a pathway to develop and optimize high-performance perovskite memristors for large-scale applications.

Diurnal retinal and choroidal gene expression patterns support a role for circadian biology in myopia pathogenesis.

The prevalence of myopia (nearsightedness) is increasing to alarming levels, but its etiology remains poorly understood. Because both laboratory and clinical findings suggest an etiologic role for circadian rhythms in myopia development, we assayed gene expression by RNA-Seq in retina and choroid at the onset of unilateral experimental myopia in chick, isolating tissues every 4 h during a single 24-h period from myopic and contralateral control eyes. Occluded versus open eye gene expression differences varied considerably over the 24-h sampling period, with some occurring at multiple times of day but with others showing differences at only a single investigated timepoint. Some of the genes identified in retina or choroid of chick myopia were previously identified as candidate genes for common human myopia. Like differentially expressed genes, pathways identified by Gene Set Enrichment Analysis also varied dramatically by sampling time. Considered with other laboratory data, human genetic and epidemiology data, these findings further implicate circadian events in myopia pathogenesis. The present results emphasize a need to include time of day in mechanistic studies of myopia and to assess circadian biology directly in trying to understand better the origin of myopia and to develop more effective therapies.

EIF4A3-mediated biogenesis of circSTX6 promotes bladder cancer metastasis and cisplatin resistance.

BACKGROUND: Cisplatin (CDDP)-based chemotherapy is a standard first-line treatment for metastatic bladder cancer (BCa) patients, and chemoresistance remains a major challenge in clinical practice. Circular RNAs (circRNAs) have emerged as essential regulators in carcinogenesis and cancer progression. However, the role of circRNAs in mediating CDDP chemosensitivity has yet to be well elucidated in BCa. METHODS: CircSTX6 (hsa_circ_0007905) was identified by mining the public circRNA datasets and verified by Sanger sequencing, agarose gel electrophoresis, RNase R treatment and qRT-PCR assays. Then, function experiments were performed to evaluate the effects of circSTX6 on BCa metastasis. Luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), RNA stability assay, Fluorescence in situ hybridization (FISH) and Immunofluorescence (IF) were conducted to evaluate the interaction among circSTX6, miR-515-3p, PABPC1 and SUZ12. Animal experiments were performed to explore the function of circSTX6 in tumor metastasis and CDDP sensitivity. RESULTS: We identified that circSTX6 was significantly upregulated in clinical samples and cells of BCa. Functionally, circSTX6 promoted cell migration and invasion both in vitro and in vivo. Mechanistically, circSTX6 could act as a miR-515-3p sponge and abolish its effect on SUZ12. Moreover, circSTX6 was confirmed to increase the stability of SUZ12 mRNA by interacting with a mRNA stabilizer PABPC1 and subsequently promote the expression of SUZ12. Importantly, silencing of circSTX6 improved the chemosensitivity of CDDP-resistant bladder cancer cells to CDDP. Furthermore, in vivo analysis supported that knockdown of circSTX6 attenuated CDDP resistance in BCa tumors. CONCLUSION: These studies demonstrate that circSTX6 plays a pivotal role in BCa metastasis and chemoresistance, and has potential to serve as a therapeutic target for treatment of BCa.

Disulfiram: A novel repurposed drug for cancer therapy.

ABSTRACT: Cancer is a major global health issue. Effective therapeutic strategies can prolong patients' survival and reduce the costs of treatment. Drug repurposing, which identifies new therapeutic uses for approved drugs, is a promising approach with the advantages of reducing research costs, shortening development time, and increasing efficiency and safety. Disulfiram (DSF), a Food and Drug Administration (FDA)-approved drug used to treat chronic alcoholism, has a great potential as an anticancer drug by targeting diverse human malignancies. Several studies show the antitumor effects of DSF, particularly the combination of DSF and copper (DSF/Cu), on a wide range of cancers such as glioblastoma (GBM), breast cancer, liver cancer, pancreatic cancer, and melanoma. In this review, we summarize the antitumor mechanisms of DSF/Cu, including induction of intracellular reactive oxygen species (ROS) and various cell death signaling pathways, and inhibition of proteasome activity, as well as inhibition of nuclear factor-kappa B (NF-κB) signaling. Furthermore, we highlight the ability of DSF/Cu to target cancer stem cells (CSCs), which provides a new approach to prevent tumor recurrence and metastasis. Strikingly, DSF/Cu inhibits several molecular targets associated with drug resistance, and therefore it is becoming a novel option to increase the sensitivity of chemo-resistant and radio-resistant patients. Studies of DSF/Cu may shed light on its improved application to clinical tumor treatment.

The temporal association of CapZ with early endosomes regulates endosomal trafficking and viral entry into host cells.

BACKGROUND: Many viruses enter host cells by hijacking endosomal trafficking. CapZ, a canonical actin capping protein, participates in endosomal trafficking, yet its precise role in endocytosis and virus infection remains elusive. RESULTS: Here, we showed that CapZ was transiently associated with early endosomes (EEs) and was subsequently released from the matured EEs after the fusion of two EEs, which was facilitated by PI(3)P to PI(3,5)P2 conversion. Vacuolin-1 (a triazine compound) stabilized CapZ at EEs and thus blocked the transition of EEs to late endosomes (LEs). Likewise, artificially tethering CapZ to EEs via a rapamycin-induced protein-protein interaction system blocked the early-to-late endosome transition. Remarkably, CapZ knockout or artificially tethering CapZ to EEs via rapamycin significantly inhibited flaviviruses, e.g., Zika virus (ZIKV) and dengue virus (DENV), or beta-coronavirus, e.g., murine hepatitis virus (MHV), infection by preventing the escape of RNA genome from endocytic vesicles. CONCLUSIONS: These results indicate that the temporal association of CapZ with EEs facilitates early-to-late endosome transition (physiologically) and the release of the viral genome from endocytic vesicles (pathologically).

Unconventionally fast transport through sliding dynamics of rodlike particles in macromolecular networks.

Transport of rodlike particles in confinement environments of macromolecular networks plays crucial roles in many important biological processes and technological applications. The relevant understanding has been limited to thin rods with diameter much smaller than network mesh size, although the opposite case, of which the dynamical behaviors and underlying physical mechanisms remain unclear, is ubiquitous. Here, we solve this issue by combining experiments, simulations and theory. We find a nonmonotonic dependence of translational diffusion on rod length, characterized by length commensuration-governed unconventionally fast dynamics which is in striking contrast to the monotonic dependence for thin rods. Our results clarify that such a fast diffusion of thick rods with length of integral multiple of mesh size follows sliding dynamics and demonstrate it to be anomalous yet Brownian. Moreover, good agreement between theoretical analysis and simulations corroborates that the sliding dynamics is an intermediate regime between hopping and Brownian dynamics, and provides a mechanistic interpretation based on the rod-length dependent entropic free energy barrier. The findings yield a principle, that is, length commensuration, for optimal design of rodlike particles with highly efficient transport in confined environments of macromolecular networks, and might enrich the physics of the diffusion dynamics in heterogeneous media.

The energetics of N2 reduction by vanadium containing nitrogenase.

The main class of nitrogenases has a molybdenum in its cofactor. A mechanism for Mo-nitrogenase has recently been described. In the present study, another class of nitrogenases has been studied, the one with a vanadium instead of a molybdenum in its cofactor. It is generally believed that these classes use the same general mechanism to activate nitrogen. The same methodology has been used here as the one used for Mo-nitrogenase. N2 activation is known to occur after four reductions in the catalytic cycle, in the E4 state. The main features of the mechanism for Mo-nitrogenase found in the previous study are an activation process in four steps prior to catalysis, the release of a sulfide during the activation steps and the formation of H2 from two hydrides in E4, just before N2 is activated. The same features have been found here for V-nitrogenase. A difference is that five steps are needed in the activation process, which explains why the ground state of V-nitrogenase is a triplet (even number) and the one for Mo-nitrogenase is a quartet (odd number). The reason an additional step is needed for V-nitrogenase is that V3+ can be reduced to V2+, in contrast to the case for Mo3+ in Mo-nitrogenase. The fact that V3+ is Jahn-Teller active has important consequences. N2H2 is formed in E4 with reasonably small barriers.

Disturbed meningeal lymphatic function associated with malignancy and progression in patients with intracranial malignant tumors.

BACKGROUND: Meningeal lymphatic vessels (mLVs) have proven to bear a relationship with tumor immunity and therapeutic efficacy of intracranial malignant tumors in pre-clinical animal studies. We aimed to explore the association between mLV function and intracranial malignant tumors in clinical participants. METHODS: The participants were allocated to a control group or a group of patients with intracranial tumors. Dynamic enhanced magnetic resonance was used to evaluate the wash-in and wash-out functions of mLVs around the superior sagittal sinus and the sigmoid sinus. FINDINGS: A total of 246 individuals were recruited for our study. The area under curve and wash-in rate of mLVs in the intracranial tumor group were higher than in the control group (2,749 vs. 2,110, p < 0.001 and 3.72 vs. 2.87, p < 0.001, respectively). The wash-out ratio of mLVs was lower in the intracranial tumor group than in the control group (0.65 vs. 0.73, p < 0.001). Decreased wash-out of mLVs was associated with tumor progression (ß = -0.118; p < 0.001). High-grade glioma and isocitrate dehydrogenase wild type were associated with a lower mLV wash-out function (ß = -0.057, p = 0.044 and ß = -0.069, p = 0.047, respectively). CONCLUSIONS: Intracranial malignant tumors were associated with elevated wash-in function and decreased wash-out function of mLVs. High-grade glioma and isocitrate dehydrogenase wild type were associated with low mLV wash-out function, and long-term decreased mLV wash-out function was a risk factor for tumor progression. FUNDING: There was no funding.

Mycobacterium porcinum Infection of Hilar and Mediastinal Lymph Nodes: A Case Report and Literature Review.

In the available reports on clinical medicine, the infection sites of Mycobacterium porcinum include wounds, bone marrow, respiratory tract, and catheters. A 61-year-old woman was admitted to our hospital; her hilar and mediastinal lymph nodes were found to be enlarged during health examination, but there was no specific discomfort. Initially, she had undergone a mediastinal lymph node biopsy and pathology, but the diagnosis was not confirmed. However, 16S rRNA gene sequencing revealed M. porcinum infection of hilar and mediastinal lymph nodes. Subsequently, she was treated with clarithromycin, amikacin, imipenem, and tigecycline. After 2 months, chest computed tomography showed a significant reduction in lymph nodes. M. porcinum infection was considered to be the cause of disease.

Promoting synchrony of power grids by restructuring network topologies.

The optimization of synchronization on distributed power grids is an important topic in recent years. We extensively study the optimization by restructuring grid topology in terms of connection rewirings. Due to the node-link dual property of power networks, i.e., the intrinsic generator-load dynamics of nodes and the multiple-attribute connections, we propose the frequency-correlation-optimization scheme to get grid topology with the largest anti-correlation by targeting the frequency-correlation function among nodes. The topology optimizations on both sparse and dense networks are successfully realized. The optimized topology exhibits more generator-consumer connections, indicating that a decentralization of the distribution of generator nodes on power grids favors synchronizability. The benefits of these frequency-correlation-optimized power grids to synchrony are verified. By comparing with the phase-coherence-optimization scheme that favors both the optimal topology and efficient synchronizability, we show that the frequency-correlation optimization and the phase-coherence optimization of power grids are usually compatible, while the former is more efficient and simpler in avoiding tedious simulations of high-dimensional nonlinear dynamics. Our explorations may shed light on the predesign and construction of modern distributed power grids, which are composed of decentralized miscellaneous power sources.

ARID1A Inactivation Increases Expression of circ0008399 and Promotes Cisplatin Resistance in Bladder Cancer.

OBJECTIVE: Cisplatin (CDDP)-based chemotherapy is a first-line, drug regimen for muscle-invasive bladder cancer (BC) and metastatic bladder cancer. Clinically, resistance to CDDP restricts the clinical benefit of some bladder cancer patients. AT-rich interaction domain 1A (ARID1A) gene mutation occurs frequently in bladder cancer; however, the role of CDDP sensitivity in BC has not been studied. METHODS: We established ARID1A knockout BC cell lines using CRISPR/Cas9 technology. IC50 determination, flow cytometry analysis of apoptosis, and tumor xenograft assays were performed to verify changes in the CDDP sensitivity of BC cells losing ARID1A. qRT-PCR, Western blotting, RNA interference, bioinformatic analysis, and ChIP-qPCR analysis were performed to further explore the potential mechanism of ARID1A inactivation in CDDP sensitivity in BC. RESULTS: It was found that ARID1A inactivation was associated with CDDP resistance in BC cells. Mechanically, loss of ARID1A promoted the expression of eukaryotic translation initiation factor 4A3 (EIF4A3) through epigenetic regulation. Increased expression of EIF4A3 promoted the expression of hsa_circ_0008399 (circ0008399), a novel circular RNA (circRNA) identified in our previous study, which, to some extent, showed that ARID1A deletion caused CDDP resistance through the inhibitory effect of circ0008399 on the apoptosis of BC cells. Importantly, EIF4A3-IN-2 specifically inhibited the activity of EIF4A3 to reduce circ0008399 production and restored the sensitivity of ARID1A inactivated BC cells to CDDP. CONCLUSION: Our research deepens the understanding of the mechanisms of CDDP resistance in BC and elucidates a potential strategy to improve the efficacy of CDDP in BC patients with ARID1A deletion through combination therapy targeting EIF4A3.

All-solution-processed perovskite/gallium nitride particles hybrid visible-blind ultraviolet photodetectors.

Last decades have witnessed the rapid development of ultraviolet (UV) photodetectors in diversity of applications. The III-nitride semiconductor and metal halide perovskite have both performed promising UV-sensing optoelectronic properties. However, they are still suffering from either the high temperature epitaxial-growth or low photocurrent generated in UV range. In this work, we demonstrate an innovative MAPbCl3/GaN particle hybrid device with all-solution-processed deposition methods. Comparing to the control MAPbCl3photoconductors, the photo-sensing ability of the hybrid device with the optimal concentration of GaN particles is more than one order of magnitude enhanced, and report a responsivity of 86 mA W-1, a detectivity of 3.1 × 1011Jones and a rise/fall time of 1.1/10.7 ms at 360 nm. The photocurrent increment could be attributed to the enhanced UV absorption of GaN particles and facilitated charge separation and photoconductive gain at MAPbCl3/GaN heterojunction. This work paves a pathway towards the large-scale low-cost UV photodetectors in versatile applications.