Engineering Streptomyces sp. CPCC 204095 for the targeted high-level production of isatropolone A by elucidating its pathway-specific regulatory mechanism.

BACKGROUND: Isatropolone A and C, produced by Streptomyces sp. CPCC 204095, belong to an unusual class of non-benzenoid aromatic compounds and contain a rare seven-membered ring structure. Isatropolone A exhibits potent activity against Leishmania donovani, comparable to the only oral drug miltefosine. However, its variably low productivity represents a limitation for this lead compound in the future development of new anti-leishmaniasis drugs to meet unmet clinical needs. RESULTS: Here we first elucidated the regulatory cascade of biosynthesis of isatropolones, which consists of two SARP family regulators, IsaF and IsaJ. Through a series of in vivo and in vitro experiments, IsaF was identified as a pathway-specific activator that orchestrates the transcription of the gene cluster essential for isatropolone biosynthesis. Interestingly, IsaJ was found to only upregulate the expression of the cytochrome P450 monooxygenase IsaS, which is crucial for the yield and proportion of isatropolone A and C. Through targeted gene deletions of isaJ or isaS, we effectively impeded the conversion of isatropolone A to C. Concurrently, the facilitation of isaF overexpression governed by selected promoters, prompted the comprehensive activation of the production of isatropolone A. Furthermore, meticulous optimization of the fermentation parameters was conducted. These strategies culminated in the attainment of an unprecedented maximum yield-980.8 mg/L of isatropolone A-achieved in small-scale solid-state fermentation utilizing the genetically modified strains, thereby establishing the highest reported titer to date. CONCLUSION: In Streptomyces sp. CPCC 204095, the production of isatropolone A and C is modulated by the SARP regulators IsaF and IsaJ. IsaF serves as a master pathway-specific regulator for the production of isatropolones. IsaJ, on the other hand, only dictates the transcription of IsaS, the enzyme responsible for the conversion of isatropolone A and C. By engineering the expression of these pivotal genes, we have devised a strategy for genetic modification aimed at the selective and high-yield biosynthesis of isatropolone A. This study not only unveils the unique regulatory mechanisms governing isatropolone biosynthesis for the first time, but also establishes an essential engineering framework for the targeted high-level production of isatropolone A.

Exploring the body surface temperature of the lumbosacral region and relevant back-shu points in patients with lumbar disc herniation induced low back pain based on infrared thermography. / åŸºäºŽçº¢å¤–çƒ­æˆåƒæŠ€æœ¯æŽ¢è®¨è °æ¤Žé—´ç›˜çªå‡ºç—‡è °ç—›æ‚£è€ è °éª¶éƒ¨åŠç›¸å ³èƒŒä¿žç©´è¡¨çš®æ¸©åº¦.

OBJECTIVES: To observe the body surface temperature of the lumbosacral region and relevant back-shu points in patients with lumbar disc herniation (LDH) induced low back pain utilizing infrared thermography, and to explore the functional attribute changes of acupoints under pathological conditions. METHODS: A total of 50 patients with LDH induced low back pain were included as the observation group, and 45 healthy subjects were included as the control group. Using infrared thermography, the body surface temperature of the lumbosacral region and bilateral Sanjiaoshu (BL 22), Shenshu (BL 23), Qihaishu (BL 24), Dachangshu (BL 25), Guanyuanshu (BL 26), Xiaochangshu (BL 27), and Pangguangshu (BL 28) was measured in both groups. The temperature difference values between the bilateral lumbosacral regions and back-shu points of the two groups were calculated. Additionally, the body surface temperature of the affected and healthy sides of the lumbosacral region and relevant back-shu points was compared in the observation group. RESULTS: Compared with the control group, the body surface temperature of the lumbosacral region and the bilateral temperature difference values of the lumbosacral regions were increased in the observation group (P<0.001). The body surface temperature difference values of bilateral Shenshu (BL 23), Qihaishu (BL 24), Dachangshu (BL 25), Guanyuanshu (BL 26) and Xiaochangshu (BL 27) in the observation group were higher than those in the control group (P<0.05, P<0.01, P<0.001). In the observation group, the body surface temperature of the affected side of the lumbosacral region as well as Shenshu (BL 23) and Dachangshu (BL 25) was elevated compared with that of healthy side (P<0.001). CONCLUSIONS: The patients with LDH induced low back pain have imbalanced and asymmetrical distribution of body surface temperature in the lumbosacral region and related back-shu points, Shenshu (BL 23) and Dachangshu (BL 25) have the relative specificity.

Decolorization, spectral broadening, and luminescence enhancement in Tb:Y2O3 transparent ceramics through vacuum thermal reduction.

Tb3+ is extensively employed in magneto-optical devices and luminescent materials owing to its distinctive physical properties. However, under certain conditions, trivalent Tb3+ readily undergoes oxidation to tetravalent Tb4+, significantly reducing the performance of devices containing Tb3+. In this Letter, we report a technique called dual-annealing (DA) post-treatment, which effectively solves Tb oxidation issues by utilizing the reducibility of the vacuum environment. High-quality Tb:Y2O3 transparent ceramics were prepared with in-line transmittance of ∼80% at 800 nm. Subsequently, the prepared ceramics were subjected to DA treatment. The optical, photoluminescence, radioluminescence, and x-ray imaging properties of DA samples were comprehensively compared with those of conventionally single-annealed (SA) samples. The coloration of Tb:Y2O3 transparent ceramics due to Tb4+ absorption was eliminated by DA. Notably, the DA sample showed a 3.28-fold increase in photoluminescence intensity and a 2.73-fold increase in radioluminescence intensity compared with the traditional SA sample. DA post-treatment enables Tb: Y2O3 transparent ceramics to achieve x-ray imaging capabilities. This Letter presents a simple, efficient, and universally applicable post-treatment technique expected to replace conventional hydrogen annealing in numerous scenarios.

Pairwise Tomlinson-Harashima precoding for multiple-lane IM-DD transmissions.

As for the photonic interconnection based on the multiple-lane intensity modulation direct detection (IM-DD) transmission, both intra-channel inter-symbol-interference (ISI) originating from bandwidth constraint, and inter-channel performance discrepancy emerging from inter-channel component differences are the major bottleneck for the throughput enhancement. Here, we propose a pairwise Tomlinson-Harshima precoding (P-THP) scheme, in order to simultaneously deal with both intra-channel ISI and inter-channel performance discrepancy. The effective function of the proposed P-THP scheme is experimentally evaluated by transmitting 4-channel 81-GBaud PAM4 signals over 2 km standard single-mode fiber (SSMF). Compared with the conventional scheme with only applying THP on individual wavelength channel, the required optical received power (ROP) under the back-to-back (B2B) transmission can be reduced by 0.75∼1 dB with the help of proposed P-THP in different experimental component configurations, at the 7% hard decision forward error correction (HD-FEC) threshold of BER = 3.8 × 10-3. After the 2 km SSMF transmission, only the use of proposed P-THP can guarantee to reach the designated HD-FEC threshold, leading to a net rate of >600 Gbit/s.

Simultaneous realization of high gain and low DMG of four-mode EDFA under bidirectional hybrid-mode pump.

We theoretically and experimentally verify that, the bidirectional hybrid-mode pumping scheme can address the optimization problem of trade-off between high gain and low differential modal gain (DMG) of four-mode erbium-doped fiber amplifier (4M-EDFA), in comparison with traditional both forward and backward hybrid-mode pumping scheme. It is noticed that, when the total pump power is fixed, the bidirectional hybrid-mode pumping scheme can not only achieve higher gain, but also suppress DMG due to different overlap integrals for the forward and backward pumping schemes. The bidirectional hybrid-mode pumped 4M-EDFA is developed with the forward pumping at LP02 mode and the backward pumping at LP21 mode, under a pump power ratio of 30%:70%. Thus, we can achieve an average gain of up to 21.16 dB and a low DMG of 0.43 dB at 1550 nm, and an average gain of up to 20.64 dB with a DMG of less than 1.6 dB over the C-band. In particular, the bidirectional hybrid-mode pumping scheme allows us to tailor the gain characteristics of the few-mode erbium-doped fiber amplifiers (FM-EDFAs), by adjusting the power ratio between forward and backward pumps.

The mutation of NSUN5 R295C promotes preeclampsia by impairing decidualization through downregulating IL-11Rα.

Preeclampsia (PE) is a pregnancy-specific hypertensive disorder that severely impairs maternal and fetal health. However, its pathogenesis remains elusive. NOP2/Sun5 (NSUN5) is an RNA methyltransferase. This study discovered a significant correlation between rs77133388 of NSUN5 and PE in a cohort of 868 severe PE patients and 982 healthy controls. To further explore this association, the researchers generated single-base mutant mice (NSUN5 R295C) at rs77133388. The pregnant NSUN5 R295C mice exhibited PE symptoms. Additionally, compared to the controls, the decidual area of the placenta was significantly reduced in NSUN5 R295C mice, and their decidualization was impaired with a significantly decrease in polyploid cell numbers after artificially induced decidualization. The study also found a decrease in phosphorylated JAK2, STAT3, and IL-11Rα, Cyclin D3 expression in NSUN5 R295C mice. Overall, these findings suggest that NSUN5 mutation potentially alters decidualization through the IL-11Rα/JAK2/STAT3/Cyclin D3 pathway, ultimately impairing placental development and contributing to PE occurrence.

Improvement of diabetes-induced spinal cord axon injury with taurine via nerve growth factor-dependent Akt/mTOR pathway.

Diabetic neuropathy (DN) is a common neurological complication caused by diabetes mellitus (DM). Axonal degeneration is generally accepted to be the major pathological change in peripheral DN. Taurine has been evidenced to be neuroprotective in various aspects, but its effect on spinal cord axon injury (SCAI) in DN remains barely reported. This study showed that taurine significantly ameliorated axonal damage of spinal cord (SC), based on morphological and functional analyses, in a rat model of DN induced by streptozotocin (STZ). Taurine was also found to induce neurite outgrowth in cultured cerebral cortex neurons with high glucose exposure. Moreover, taurine up-regulated the expression of nerve growth factor (NGF) and neurite outgrowth relative protein GAP-43 in rat DN model and cultured cortical neurons/VSC4.1 cells. Besides, taurine increased the activating phosphorylation signals of TrkA, Akt, and mTOR. Mechanistically, the neuroprotection by taurine was related to the NGF-pAKT-mTOR axis, because either NGF-neutralizing antibody or Akt or mTOR inhibitors was found to attenuate its beneficial effects. Together, our results demonstrated that taurine promotes spinal cord axon repair in a model of SCAI in STZ-induced diabetic rats, mechanistically associating with the NGF-dependent activation of Akt/mTOR pathway.

A framework for longitudinal latent factor modelling of treatment response in clinical trials with applications to Psoriatic Arthritis and Rheumatoid Arthritis.

OBJECTIVE: Clinical trials involve the collection of a wealth of data, comprising multiple diverse measurements performed at baseline and follow-up visits over the course of a trial. The most common primary analysis is restricted to a single, potentially composite endpoint at one time point. While such an analytical focus promotes simple and replicable conclusions, it does not necessarily fully capture the multi-faceted effects of a drug in a complex disease setting. Therefore, to complement existing approaches, we set out here to design a longitudinal multivariate analytical framework that accepts as input an entire clinical trial database, comprising all measurements, patients, and time points across multiple trials. METHODS: Our framework composes probabilistic principal component analysis with a longitudinal linear mixed effects model, thereby enabling clinical interpretation of multivariate results, while handling data missing at random, and incorporating covariates and covariance structure in a computationally efficient and principled way. RESULTS: We illustrate our approach by applying it to four phase III clinical trials of secukinumab in Psoriatic Arthritis (PsA) and Rheumatoid Arthritis (RA). We identify three clinically plausible latent factors that collectively explain 74.5% of empirical variation in the longitudinal patient database. We estimate longitudinal trajectories of these factors, thereby enabling joint characterisation of disease progression and drug effect. We perform benchmarking experiments demonstrating our method's competitive performance at estimating average treatment effects compared to existing statistical and machine learning methods, and showing that our modular approach leads to relatively computationally efficient model fitting. CONCLUSION: Our multivariate longitudinal framework has the potential to illuminate the properties of existing composite endpoint methods, and to enable the development of novel clinical endpoints that provide enhanced and complementary perspectives on treatment response.

Ultrafine Co-MoC particles in porous carbon derived from polyoxometalate-based metal organic framework for efficient hydrogen evolution reaction.

Accurately regulating ultrafine molybdenum carbide (MoC)-based catalysts is a significant challenge in the rational design of hydrogen evolution reaction (HER) electrocatalysts. Herein, under the guidance of the first principle calculations, we proposed an in-situ polyoxometalate-confined strategy for creating uniformly distributed ultrafine Co-MoC bimetallic nanoparticles in porous carbon nanostars, with the assistance of precisely designed metal-organic framework (MOF). The Co-MoC@C electrocatalyst has a high specific surface area of 969 m2·g-1 because of the conductive carbon substrate with abundant mesopores, which makes for exposing more active sites of Co-MoC nanocrystals (∼1.5 nm) and facilitating electron/ion transport. Thus, Co-MoC@C electrocatalyst shows the excellent electrochemical activity with overpotentials of 88.4 mV and 66.6 mV at a current density of 10 mA·cm-2 under acidic and alkaline conditions, respectively. The in-situ polyoxometalate-confined strategy will provide a new guideline for the design and preparation of efficient HER electrocatalysts.

Decision-Making With Speculative Opponent Models.

Opponent modeling has proven effective in enhancing the decision-making of the controlled agent by constructing models of opponent agents. However, existing methods often rely on access to the observations and actions of opponents, a requirement that is infeasible when such information is either unobservable or challenging to obtain. To address this issue, we introduce distributional opponent-aided multiagent actor-critic (DOMAC), the first speculative opponent modeling algorithm that relies solely on local information (i.e., the controlled agent's observations, actions, and rewards). Specifically, the actor maintains a speculated belief about the opponents using the tailored speculative opponent models that predict the opponents' actions using only local information. Moreover, DOMAC features distributional critic models that estimate the return distribution of the actor's policy, yielding a more fine-grained assessment of the actor's quality. This thus more effectively guides the training of the speculative opponent models that the actor depends upon. Furthermore, we formally derive a policy gradient theorem with the proposed opponent models. Extensive experiments under eight different challenging multiagent benchmark tasks within the MPE, Pommerman, and starcraft multiagent challenge (SMAC) demonstrate that our DOMAC successfully models opponents' behaviors and delivers superior performance against state-of-the-art (SOTA) methods with a faster convergence speed.

In-field and non-destructive determination of comprehensive maturity index and maturity stages of Camellia oleifera fruits using a portable hyperspectral imager.

To efficiently detect the maturity stages of Camellia oleifera fruits, this study proposed a non-invasive method based on hyperspectral imaging technology. First, a portable hyperspectral imager was used for the in-field image acquisition of Camellia oleifera fruits at three maturity stages, and ten quality indexes were measured as reference standards. Then, factor analysis was performed to obtain the comprehensive maturity index (CMI) by analyzing the change trends and correlations of different indexes. To reduce the high dimensionality of spectral data, the successive projection algorithm (SPA) was employed to select effective feature wavelengths. The prediction models for CMI, including partial least squares regression (PLSR), support vector regression (SVR), extreme learning machine (ELM), and convolutional neural network regression (CNNR), were constructed based on full spectra and feature wavelengths; for CNNR, only the raw spectra were used as input. The SPA-CNNR model exhibited more promising performance (RP = 0.839, RMSEP = 0.261, and RPD = 1.849). Furthermore, PLS-DA models for maturity discrimination of Camellia oleifera fruits were developed using full wavelength, characteristic wavelengths and their fusion CMI, respectively. The PLS-DA model using the fused dataset achieved the highest maturity classification accuracy, with the best simplified model achieving 88.6 % accuracy in prediction set. This study indicated that a portable hyperspectral imager can be used for in-field determination of the internal quality and maturity stages of Camellia oleifera fruits. It provides strong support for non-destructive quality inspection and timely harvesting of Camellia oleifera fruits in the field.

Causal association of monocytes with chronic kidney disease and the mediation role of frailty: A study integrating large-scale two-sample Mendelian randomization and single-cell analysis.

BACKGROUND: Recent research reported that frailty was prevalent among adults with chronic kidney disease (CKD) in clinical trials, and monocytes illustrated a similar difference in these two diseases compared to the normal. However, the scientific evidence for a causal relationship between these two diseases was lacking, with further exploration into whether monocytes co-regulate them. METHODS: We aimed to integrate large-scale Mendelian randomization (MR) and single-cell transcriptome analysis to determine whether there was a causal relationship between frailty and CKD (Bidirectional two-sample Mendelian determined the causal direction), whether monocytes impacted them, and whether the two diseases shared genetic variation sites. Based on 441 Genome-wide association study datasets, this study utilized five MR methods, multiple sensitivity analysis, and corresponding single-cell transcriptome datasets as proof. RESULTS: The association between frailty and CKD was significantly causal, and frailty increased the risk of CKD in patients (OR (95 %CI): 3.5597 (1.8369-6.8982), p = 0.000168909). The exposure monocyte can increase the risk of frailty and CKD in patients, especially with high expression of HLA genes in these cells. The existing two-sample MR results cannot reject the hypothesis that monocytes increase the risk of CKD by inducing frailty. rs9275271' 1mb genetic location above and below had been proven to be an effective genetic space for both frailty and CKD. CONCLUSION: We conducted the largest MR to date on frailty, monocyte, and CKD, and found a significant causal association between frailty and CKD, with the single-cell analysis confirmed. The exposure monocytes increased the risk of frailty and CKD, particularly with high expression of HLA genes in these cells. We identified a potential common genetic variant space, rs9275271, associated with frailty and CKD, providing insights into the genetic basis of these conditions.

Oxyberberine sensitizes liver cancer cells to sorafenib via inhibiting NOTCH1-USP7-c-Myc pathway.

BACKGROUND: Sorafenib is the first-line therapy for patients with advanced-stage HCC, but its clinical cure rate is unsatisfactory due to adverse reactions and drug resistance. Novel alternative strategies to overcome sorafenib resistance are urgently needed. Oxyberberine (OBB), a major metabolite of berberine in vivo, exhibits potential antitumor potency in various human malignancies, including liver cancer. However, it remains unknown whether and how OBB sensitizes liver cancer cells to sorafenib. METHODS: Cell viability, trypan blue staining and flow cytometry assays were employed to determine the synergistic effect of OBB and sorafenib on killing HCC cells. PCR, western blot, co-immunoprecipitation and RNA interference assays were used to decipher the mechanism by which OBB sensitizes sorafenib. HCC xenograft models and clinical HCC samples were utilized to consolidate our findings. RESULTS: We found for the first time that OBB sensitized liver cancer cells to sorafenib, enhancing its inhibitory effect on cell growth and induction of apoptosis in vitro. Interestingly, we observed that OBB enhanced the sensitivity of HCC cells to sorafenib by reducing ubiquitin-specific peptidase 7 (USP7) expression, a well-known tumor-promoting gene. Mechanistically, OBB inhibited notch homolog 1-mediated USP7 transcription, leading to the downregulation of V-Myc avian myelocytomatosis viral oncogene homolog (c-Myc), which synergized with sorafenib to suppress liver cancer. Furthermore, animal results showed that cotreatment with OBB and sorafenib significantly inhibited the tumor growth of liver cancer xenografts in mice. CONCLUSIONS: These results indicate that OBB enhances the sensitivity of liver cancer cells to sorafenib through inhibiting notch homolog 1-USP7-c-Myc signaling pathway, which potentially provides a novel therapeutic strategy for liver cancer to improve the effectiveness of sorafenib.

Gene expression profiling of peripheral blood in patients with steroid-induced osteonecrosis of the femoral head.

Aim: Steroid-induced osteonecrosis of the femoral head (SONFH) is a severe complication following glucocorticoid therapy. This study aimed to identify the differential mRNA expression and investigate the molecular mechanisms of SONFH. Materials & methods: RNA sequencing was performed in eight SONFH patients, five non-SONFH patients and five healthy individuals. Results: A total of 1555, 3997 and 5276 differentially expressed mRNAs existed between the following combinations: SONFH versus non-SONFH, SONFH versus healthy subjects and non-SONFH versus healthy subjects. Increased ISM1 expression might contribute to a high risk of SONFH through antiangiogenesis. Decreased FOLR3 expression might affect the metabolism of homocysteine, leading to avascular necrosis of the femoral head. KCNJ2, which plays a pivotal role in regulating bone development, was also deregulated. Conclusion: ISM1, FOLR3 and KCNJ2 might be related to the occurrence of SONFH.

Ammonia distribution and ecological risk assessment in nine fresh lakes in China.

With the development of industry and economy, ammonia nitrogen pollutions in surface water are of great concern worldwide. This study investigated the historical contents of total ammonia nitrogen (TAN) and unionized ammonia molecules (NH3) in nine fresh lakes in China during 2014-2022. Three different classification methods (flood season, season, and geographical distribution) were used to analyze the concentration variation of TAN and NH3. The concentration of TAN first decreased and then increased in the flood season, showing a lower concentration in summer and a higher concentration in winter. The variation trend of NH3 was in an opposite way with TAN. Correlation analysis between ammonia and 10 water quality parameters and 4 pollution emission and treatment parameters showed that the correlation coefficient between TAN and total phosphorus (total nitrogen) was 0.44 (0.43), respectively. The correlation coefficients between average annual TAN concentration and total emissions (waste water treatment input) were 0.35 (0.53), respectively. Combined with ecotoxicity data from a series of aquatic species, the ecological risks of TAN and NH3 in lakes were evaluated using hazard quotient and joint probability curve methods. From 2014 to 2022, the probability of 5% species affected in the acute ecological risk of TAN and NH3 is lower than 0.01, but for the chronic ecological risk of TAN and NH3, the probabilities of 5% species affected are 0.003-0.030 and 0.04-0.14, respectively. The chronic ecological risks were higher than the acute ecological risks, and high risks in plateau lakes like Dianchi Lake should be paid more attention to.

The FAK/occludin/ZO-1 complex is critical for cadmium-induced testicular damage by disruption of the integrity of the blood-testis barrier in chickens.

Cadmium (Cd) is a well-known testis toxicant. The blood-testis barrier (BTB) is a crucial component of the testis. Cd can disrupt the integrity of the BTB and reproductive function. However, the mechanism of Cd-induced disruption of BTB and testicular damage has not been fully elucidated. Here, our study investigates the effects of Cd on BTB integrity and testicular dysfunction. 80 (aged 1 day) Hy-Line white variety chickens were randomly designed into 4 groups and treated for 90 days, as follows: control group (essential diet), 35 Cd, 70 Cd and 140 Cd groups (35, 70 and 140 mg/kg Cd). The results found that Cd exposure diminished volume of the testes and induced histopathological lesions in the testes. Exposure to Cd induced an inflammatory response, disrupted the structure and function of the FAK/occludin/ZO-1 protein complex and disrupted the tight junction and adherens junction in the BTB. In addition, Cd exposure reduced the expression of steroid-related proteins and inhibited testosterone synthesis. Taken together, these data elucidate that Cd disrupts the integrity of the BTB and further inhibits spermatogenesis by dissociating the FAK/occludin/ZO-1 complex, which provides a basis for further investigation into the mechanisms of Cd-induced impairment of male reproductive function and pharmacological protection.

The Protective Effects of Curcumin against Renal Toxicity.

Curcumin is a naturally polyphenolic compound used for hepatoprotective, thrombosuppressive, neuroprotective, cardioprotective, antineoplastic, antiproliferative, hypoglycemic, and antiarthritic effects. Kidney disease is a major public health problem associated with severe clinical complications worldwide. The protective effects of curcumin against nephrotoxicity have been evaluated in several experimental models. In this review, we discussed how curcumin exerts its protective effect against renal toxicity and also illustrated the mechanisms of action such as anti-inflammatory, antioxidant, regulating cell death, and anti-fibrotic. This provides new perspectives and directions for the clinical guidance and molecular mechanisms for the treatment of renal diseases by curcumin.

Drug resistance in ovarian cancer: from mechanism to clinical trial.

Ovarian cancer is the leading cause of gynecological cancer-related death. Drug resistance is the bottleneck in ovarian cancer treatment. The increasing use of novel drugs in clinical practice poses challenges for the treatment of drug-resistant ovarian cancer. Continuing to classify drug resistance according to drug type without understanding the underlying mechanisms is unsuitable for current clinical practice. We reviewed the literature regarding various drug resistance mechanisms in ovarian cancer and found that the main resistance mechanisms are as follows: abnormalities in transmembrane transport, alterations in DNA damage repair, dysregulation of cancer-associated signaling pathways, and epigenetic modifications. DNA methylation, histone modifications and noncoding RNA activity, three key classes of epigenetic modifications, constitute pivotal mechanisms of drug resistance. One drug can have multiple resistance mechanisms. Moreover, common chemotherapies and targeted drugs may have cross (overlapping) resistance mechanisms. MicroRNAs (miRNAs) can interfere with and thus regulate the abovementioned pathways. A subclass of miRNAs, "epi-miRNAs", can modulate epigenetic regulators to impact therapeutic responses. Thus, we also reviewed the regulatory influence of miRNAs on resistance mechanisms. Moreover, we summarized recent phase I/II clinical trials of novel drugs for ovarian cancer based on the abovementioned resistance mechanisms. A multitude of new therapies are under evaluation, and the preliminary results are encouraging. This review provides new insight into the classification of drug resistance mechanisms in ovarian cancer and may facilitate in the successful treatment of resistant ovarian cancer.

Low-intensity transcranial ultrasound stimulation improves memory in vascular dementia by enhancing neuronal activity and promoting spine formation.

Memory is closely associated with neuronal activity and dendritic spine formation. Low-intensity transcranial ultrasound stimulation (TUS) improves the memory of individuals with vascular dementia (VD). However, it is unclear whether neuronal activity and dendritic spine formation under ultrasound stimulation are involved in memory improvement in VD. In this study, we found that seven days of TUS improved memory in VD model while simultaneously increasing pyramidal neuron activity, promoting dendritic spine formation, and reducing dendritic spine elimination. These effects lasted for 7 days but disappeared on 14 d after TUS. Neuronal activity and dendritic spine formation strongly corresponded to improvements in memory behavior over time. In addition, we also found that the memory, neuronal activity and dendritic spine of VD mice cannot be restored again by TUS of 7 days after 28 d. Collectively, these findings suggest that TUS increases neuronal activity and promotes dendritic spine formation and is thus important for improving memory in patients with VD.

Discovery of Multiple Effects of Reactive Oxygen Species on Lung Adenocarcinoma at the Single-cell and Bulk Tissue Levels.

BACKGROUND: Reactive oxygen species (ROS) are potential targets for treating malignant tumors. AIMS: The aim of this study was to probe into the mechanisms of disease development and treatment in lung adenocarcinoma (LUAD). OBJECTIVE: This study investigated the impact of ROS on the progression of LUAD at different transcriptomic levels and analyzed key molecules involved in the regulation of LUAD. METHODS: Single-cell RNA-seq (scRNA-seq) data of LUAD were clustered and annotated to determine cell types. Scissor cells based on LUAD bulk transcriptome and epithelial scRNA-seq data were used to classify subsets associated with ROS phenotypes. Least absolute shrinkage and selection operator (LASSO) and stepwise multivariate regression analyses were performed between the Scissor-positive and Scissor-negative epithelial cells to select key differentially expressed genes (DEGs) for developing a ROS-related signature. RESULTS: The ROS score was significantly negatively correlated with the overall survival (OS) of LUAD. Seven cell types from the LUAD tissues were identified. The ROS-related gene signature was significantly correlated with metabolism, tumor microenvironment (TME) indicators, and the half-maximal inhibitory concentration (IC50) values of 10 drugs. The gene signature was verified as an independent indicator for LUAD prognosis. CONCLUSION: The current study provided novel insights into the impact of ROS on LUAD pathology at both single-cell and bulk-tissue levels, facilitating the prognostic evaluation and drug therapy development for patients with LUAD.