Low-intensity ultrasound ameliorates brain organoid integration and rescues microcephaly deficits.

Human brain organoids represent a remarkable platform for modeling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses reveal that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays reveal that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage.

Physiochemistry and sources of individual particles in response to intensified controls during the 2022 Winter Olympics in Beijing.

To investigate the particle sources before, during, and after the 2022 Beijing Winter Olympic and Paralympic (WOP) in Beijing, ambient particles were passively collected from January to March 2022. The physicochemical properties including morphology, size, shape parameters, and elemental compositions were analyzed by the IntelliSEM EPAS (an advanced computer-controlled scanning electron microscopy [CCSEM] system). Using the user-defined classification rules, 37,174 individual particles were automatically classified into 27 major groups and further attributed to seven major sources based on the source-associated characteristics, including mineral dust, secondary aerosol, combustion/industry, carbonaceous particles, salt-related particles, biological particles, and fiber particles. Our results showed that mineral dust (66.5%), combustion/industry (12.6%), and secondary aerosol (6.3%) were the three major sources in a wide size range of 0.2-42.8 µm. During the Winter Olympic Games period, low emission of anthropogenic particles and favorable meteorological conditions contributed to significantly improved air quality. During the Winter Paralympic Games period, more particles sourced from the dust storm, secondary formed particles, and the adverse meteorological conditions resulted in relatively worse air quality. The secondary aerosol all decreased during the competition period, while increased during the non-competition period. Sulfate-related particles had explosive growth and further aggravate the pollution degree during the non-competition period, especially under adverse meteorological conditions. These results provide microscopic evidence revealing variations of physicochemical properties and sources in response to the control measures and meteorological conditions.

The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants.

Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.

Curcumin protects against manganese-induced neurotoxicity in rat by regulating oxidative stress-related gene expression via H3K27 acetylation.

Long-term manganese exposure causes a neurodegenerative disorder referred to as manganese poisoning, but the mechanism remains unclear and no specific treatment is available. Oxidative stress is widely recognised as one of the main causes of manganese-induced neurotoxicity. In recent years, the role of histone acetylation in neurodegenerative diseases has been widely concerned. curcumin is a natural polyphenol compound extracted from the rhizome of turmeric and exhibits both antioxidant and neuroprotective properties. Therefore, we aimed to investigate whether and how curcumin protects against manganese-induced neurotoxicity from the perspective of histone acetylation, based on the reversibility of histone acetylation modification. In this study, rats were treated with or without curcumin and subjected to long-term manganese exposure. Results that treatment of manganese decreased the protein expression of H3K18 acetylation and H3K27 acetylation at the promoters of oxidative stress-related genes and inhibited the expression of these genes. Nevertheless, curcumin increased the H3K27 acetylation level at the manganese superoxide dismutase (SOD2) gene promoter and promoted the expression of SOD2 gene. Oxidative damage in the rat striatum as well as learning and memory dysfunction were ameliorated after curcumin treatment. Taken together, our results suggest that the regulation of oxidative stress by histone acetylation may be a key mechanism of manganese-induced neurotoxicity. In addition, curcumin ameliorates Mn-induced neurotoxicity may be due to alleviation of oxidative damage mediated by increased activation of H3K27 acetylation at the SOD2 gene promoter.

Nickel-Catalyzed Switchable Site-Selective Alkene Hydroalkylation by Temperature Regulation.

Regiodivergent alkene functionalization that produces either regioisomer starting from the same raw materials is desirable. Herein, we report a nickel-catalyzed switchable site-selective alkene hydroalkylation. The selection of reaction temperatures leads to protocols that provide regiodivergent hydroalkylated products starting from a single alkene substrate. This protocol allows the convenient synthesis of α- and ß-branched protected amines, both of which are important to the fields of pharmaceutical chemistry and biochemistry. In addition, enantioenriched ß-branched alkylamines can be accessed in a catalytic asymmetric variant. Preliminary mechanistic studies indicate that the formation of a more stable nickelacycle provides the driving force of migration. The thermodynamic and kinetic properties of different reduction elimination intermediates are responsible for the switchable site-selectivity.

The Value of Ultrasonography in Assessing Fetal Lung Maturity.

OBJECTIVE: To establish the normal parameters of fetal lung development at different gestational ages and to study their correlation with gestational age, thereby providing clinicians with a noninvasive method for assessing fetal lung maturity. METHODS: Two hundred eight cases with pregnancy of 22 to 39 weeks plus 6 days were divided into 18 groups according to gestational age. Ultrasound Doppler was used to measure the relevant parameters of fetal pulmonary development, including right pulmonary left and right diameter, right pulmonary upper and lower diameter, right pulmonary anterior and posterior diameter, right pulmonary area, thoracic area, inner diameter of fetal main pulmonary artery, and Doppler velocity curve parameters of main pulmonary artery: systolic acceleration time (AT), ejection time (ET), AT/ET. RESULTS: This study establishes normal parameters of lung development at different gestational weeks, draws scatter plots, correlation, and regression analysis of fetal main pulmonary artery AT, ET, AT/ET, and gestational weeks; selects the optimal equation; and analyzes the correlation among right pulmonary left and right diameter, right pulmonary upper and lower diameter, right pulmonary anterior and posterior diameter, right lung diameter, right lung area, thoracic area, and gestational weeks; and draw growth curve. The diameter of main pulmonary artery, AT, and AT/ET increased with the increase of gestational age and were positively correlated with gestational age (r = 0.948, 0.875, 0.810; P = 0.012). Ejection time had no correlation with gestational weeks. There were significant differences in the diameter of main pulmonary artery, AT, AT/ET between different gestational weeks (F = 240.67, 41.137, 23.067; P = 0.024); left and right diameter of right lung, anterior and posterior diameter of right lung, upper and lower diameter of right lung, chest area and right lung area were positively correlated with gestational weeks, and there were significant differences between different gestational weeks (F = 190.85, 105.74, 34.97, 172.33, 35.33, P = 0.018). CONCLUSIONS: Ultrasound Doppler can be used as a noninvasive detecting equipment to evaluate the growth of fetal lung, thus providing a basis for the evaluation of fetal lung maturity.

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic-induced DNA damage and repair in normal human liver cells.

Long-term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic-induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L-02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic-induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N-methylpurine-DNA glycosylase [MPG], XRCC1 and poly(ADP-ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic-induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning.

Synthesis of Functionalized Indoles via Palladium-Catalyzed Cyclization of N-(2-allylphenyl) Benzamide: A Method for Synthesis of Indomethacin Precursor.

We developed an efficient method for synthesis of substituted N-benzoylindole via Pd(II)-catalyzed C-H functionalization of substituted N-(2-allylphenyl)benzamide. The reaction showed a broad substrate scope (including N-acetyl and N-Ts substrates) and substituted indoles were obtained in good to excellent yields. The most distinctive feature of this method lies in the high selectivity for N-benzoylindole over benzoxazine, and this is the first example of Pd(II)-catalyzed synthesis of substituted N-benzoylindole. Notably, this new method was applied for the synthesis of key intermediate of indomethacin.

Maximum Varma Entropy Distribution with Conditional Value at Risk Constraints.

It is well known that Markowitz's mean-variance model is the pioneer portfolio selection model. The mean-variance model assumes that the probability density distribution of returns is normal. However, empirical observations on financial markets show that the tails of the distribution decay slower than the log-normal distribution. The distribution shows a power law at tail. The variance of a portfolio may also be a random variable. In recent years, the maximum entropy method has been widely used to investigate the distribution of return of portfolios. However, the mean and variance constraints were still used to obtain Lagrangian multipliers. In this paper, we use Conditional Value at Risk constraints instead of the variance constraint to maximize the entropy of portfolios. Value at Risk is a financial metric that estimates the risk of an investment. Value at Risk measures the level of financial risk within a portfolio. The metric is most commonly used by investment bank to determine the extent and occurrence ratio of potential losses in portfolios. Value at Risk is a single number that indicates the extent of risk in a given portfolio. This makes the risk management relatively simple. The Value at Risk is widely used in investment bank and commercial bank. It has already become an accepted standard in buying and selling assets. We show that the maximum entropy distribution with Conditional Value at Risk constraints is a power law. Algebraic relations between the Lagrangian multipliers and Value at Risk constraints are presented explicitly. The Lagrangian multipliers can be fixed exactly by the Conditional Value at Risk constraints.

1.5 kW polarization-maintained Yb-doped amplifier with 13 GHz linewidth by suppressing the self-pulsing and stimulated Brillouin scattering.

In this work, we study the characteristics of self-pulsing in a polarization-maintained fiber amplifier operated with different linewidths based on white noise source phase modulation. It indicates that the self-pulsing is almost simultaneous with the stimulated Brillouin scattering process, and its threshold is increasing near-linearly with the linewidth. By optimizing the laser structure, the threshold of self-pulsing increases by a factor of 1.5. We demonstrate a high-power linear polarization and all-fiberized amplifier with narrow linewidth and near-diffraction-limited beam quality. The output power scales to 1.5 kW with the pumping efficiency of 83%. The full width at half-maximum linewidth was measured to be 13 GHz. The polarization extinction ratio was larger than 13 dB. The beam quality M2 was about 1.14 at the maximum laser power.

Differential Diagnosis of Benign and Malignant Breast Tumors Using Apparent Diffusion Coefficient Value Measured Through Diffusion-Weighted Magnetic Resonance Imaging.

OBJECTIVE: Apparent diffusion coefficient (ADC) value measurement of nodes in diffusion-weighted imaging was widely used in differentiating different types of human tumors. The aim of this meta-analysis was to evaluate the clinical value of ADC measurement through diffusion-weighted magnetic resonance imaging (DW-MRI) in the differential diagnosis of benign and malignant breast tumors. METHODS: Relevant studies were identified through computer-based search of databases, which were supplemented through manual search strategies. Case-control studies were selected in adherence with our strict inclusion and exclusion criteria. Statistical analysis was conducted using Stata 12.0 statistical software (StataCorp, College Station, Tex). RESULTS: Our database searches initially retrieved 602 studies (320 studies in Chinese and 282 studies in English), and 31 studies (18 studies in English and 13 studies in Chinese) were eventually selected for meta-analysis. These 31 case-control studies included a total of 926 normal breast tissues and 2323 breast tumors (911 benign tumors and 1412 malignant tumors). Our meta-analysis showed that ADC values measured through DW-MRI were higher in benign breast tumors compared with malignant breast tumors, and this difference was statistically significant. In addition, the ADC values in the normal breast tissues were markedly higher than the benign breast tumors, which were also at a statistically significant level. Consistent with these observations, the ADC values in the normal breast tissues were significantly higher when compared with the values found in the malignant breast tumors. CONCLUSIONS: Our data strongly support the conclusion that the ADC value measured through DW-MRI is an important radiographic index for differential diagnosis of benign and malignant breast tumors and is critical to our assessment of the internal structure of tumors.

Value of magnetic resonance imaging radiomics features in predicting histologic grade of invasive ductal carcinoma of the breast.

BACKGROUND: Breast cancer has the second highest mortality rate of all cancers and occurs mainly in women. OBJECTIVE: To investigate the relationship between magnetic resonance imaging (MRI) radiomics features and histological grade of invasive ductal carcinoma (IDC) of the breast and to evaluate its diagnostic efficacy. METHODS: The two conventional MRI quantitative indicators, i.e. the apparent diffusion coefficient (ADC) and the initial enhancement rate, were collected from 112 patients with breast cancer. The breast cancer lesions were manually segmented in dynamic contrast-enhanced MRI (DCE-MRI) and ADC images, the differences in radiomics features between Grades I, II and III IDCs were compared and the diagnostic efficacy was evaluated. RESULTS: The ADC values (0.77 ± 0.22 vs 0.91 ± 0.22 vs 0.92 ± 0.20, F= 4.204, p< 0.01), as well as the B_sum_variance (188.51 ± 67.803 vs 265.37 ± 77.86 vs 263.74 ± 82.58, F= 6.040, p< 0.01), L_energy (0.03 ± 0.02 vs 0.13 ± 0.11 vs 0.12 ± 0.14, F= 7.118, p< 0.01) and L_sum_average (0.78 ± 0.32 vs 16.34 ± 4.23 vs 015.45 ± 3.74, F= 21.860, p< 0.001) values of patients with Grade III IDC were significantly lower than those of patients with Grades I and II IDC. The B_uniform (0.15 ± 0.12 vs 0.11 ± 0.04 vs 0.12 ± 0.03, F= 3.797, p< 0.01) and L_SRE (0.85 ± 0.07 vs 0.78 ± 0.03 vs 0.79 ± 0.32, F= 3.024, p< 0.01) values of patients with Grade III IDC were significantly higher than those of patients with Grades I and II IDC. All differences were statistically significant (p< 0.05). The ADC radiomics signature model had a higher area-under-the-curve value in identifying different grades of IDC than the ADC value model and the DCE radiomics signature model (0.869 vs 0.711 vs 0.682). The accuracy (0.812 vs 0.647 vs 0.710), specificity (0.731 vs 0.435 vs 0.342), positive predictive value (0.815 vs 0.663 vs 0.669) and negative predictive value (0.753 vs 0.570 vs 0.718) of the ADC radiomics signature model were all significantly better than the ADC value model and the DCE radiomics signature model. CONCLUSION: ADC values and breast MRI radiomics signatures are significant in identifying the histological grades of IDC, with the ADC radiomics signatures having greater value.

3D printing of interferon γ-preconditioned NSC-derived exosomes/collagen/chitosan biological scaffolds for neurological recovery after TBI.

The reconstruction of neural function and recovery of chronic damage following traumatic brain injury (TBI) remain significant clinical challenges. Exosomes derived from neural stem cells (NSCs) offer various benefits in TBI treatment. Numerous studies confirmed that appropriate preconditioning methods enhanced the targeted efficacy of exosome therapy. Interferon-gamma (IFN-γ) possesses immunomodulatory capabilities and is widely involved in neurological disorders. In this study, IFN-γ was employed for preconditioning NSCs to enhance the efficacy of exosome (IFN-Exo, IE) for TBI. miRNA sequencing revealed the potential of IFN-Exo in promoting neural differentiation and modulating inflammatory responses. Through low-temperature 3D printing, IFN-Exo was combined with collagen/chitosan (3D-CC-IE) to preserve the biological activity of the exosome. The delivery of exosomes via biomaterial scaffolds benefited the retention and therapeutic potential of exosomes, ensuring that they could exert long-term effects at the injury site. The 3D-CC-IE scaffold exhibited excellent biocompatibility and mechanical properties. Subsequently, 3D-CC-IE scaffold significantly improved impaired motor and cognitive functions after TBI in rat. Histological results showed that 3D-CC-IE scaffold markedly facilitated the reconstruction of damaged neural tissue and promoted endogenous neurogenesis. Further mechanistic validation suggested that IFN-Exo alleviated neuroinflammation by modulating the MAPK/mTOR signaling pathway. In summary, the results of this study indicated that 3D-CC-IE scaffold engaged in long-term pathophysiological processes, fostering neural function recovery after TBI, offering a promising regenerative therapy avenue.

Defective feedback regulation of NF-kappaB underlies Sjogren's syndrome in mice with mutated kappaB enhancers of the IkappaBalpha promoter.

Feedback regulation of transcription factor NF-kappaB by its inhibitor IkappaBalpha plays an essential role in control of NF-kappaB activity. To understand the biological significance of IkappaBalpha-mediated feedback regulation of NF-kappaB, we generated mice harboring mutated kappaB enhancers in the promoter of the IkappaBalpha gene (IkappaBalpha(M/M)) to inhibit NF-kappaB-regulated IkappaBalpha expression. Here, we report that these mutant mice are defective in NF-kappaB-induced expression of IkappaBalpha. This defective feedback regulation of NF-kappaB by IkappaBalpha not only altered activity of NF-kappaB, but also the expression of NF-kappaB-regulated genes. As a result, IkappaBalpha(M/M), the homozygous knock-in mice with mutated kappaB enhancers in the IkappaBalpha promoter, acquire shorten life span, hypersensitivity to septic shock, abnormal T-cell development and activation, and Sjögren's Syndrome. These findings therefore demonstrate that the IkappaBalpha-mediated feedback regulation of NF-kappaB has an essential role in controlling T-cell development and functions, provide mechanistic insight into the development of Sjögren's Syndrome, and suggest the potential of NF-kappaB signaling as a therapeutic target for Sjögren's Syndrome and other autoimmune diseases.

Late-stage functionalization of 5-nitrofurans derivatives and their antibacterial activities.

Structure modification of drugs is a reliable way to optimize lead compounds, among which the most striking and direct method is late-stage functionalization (LSF). Here, we employed the Cu-catalyzed C-H LSF to modify 5-nitrofuran drugs. A series of modifications have been carried out including hydroxylation, methylation, azidination, cyanation, arylation, etc. Antibacterial activities of all compounds in vitro were measured. The results showed that compound 1 and compound 18 were the most active among all compounds. Meanwhile, the cell cytotoxicity assays of potent compounds 1, 3, 4, 5 & 18 and the parent drug FZD were conducted.

Copper catalyzed Shono-type oxidation of proline residues in peptide.

Since the initial report in 1975, the Shono oxidation has become a powerful tool to functionalize the α position of amines, including proline derivatives, by electrochemical oxidation. However, the application of electrochemical Shono oxidations is restricted to the preparation of simple building blocks and homogeneous Shono-type oxidation of proline derivatives remains challenging. The late-stage functionalization at proline residues embedded within peptides is highly important as substitutions about the proline ring are known to affect biological and pharmacological activities. Here, we show that homogenous copper-catalyzed oxidation conditions complement the Shono oxidation and this general protocol can be applied to a series of formal C-C coupling reactions with a variety of nucleophiles using a one-pot procedure. This protocol shows good tolerance toward 19 proteinogenic amino acids and was used to functionalize several representative bioactive peptides, including captopril, enalapril, Smac, and endomorphin-2. Last, peptide cyclization can also be achieved by using an appropriately positioned side-chain hydroxyl moiety.

Population Genetics of Oncomelania hupensis Snails from New-Emerging Snail Habitats in a Currently Schistosoma japonicum Non-Endemic Area.

Schistosomiasis is still one of the most significant neglected tropical diseases worldwide, and China is endemic for Schistosoma japonicum. With its great achievement in schistosomiasis control, the government of China has set the goal to eliminate the parasitic disease at the country level by 2030. However, one major challenge is the remaining huge areas of habitats for the intermediate host Oncomelania hupensis. This is further exacerbated by an increasing number of new emerging snail habitats reported each year. Therefore, population genetics on snails in such areas will be useful in evaluation of snail control effect and/or dispersal. We then sampled snails from new emerging habitats in Taicang of Jiangsu, China, a currently S. japonicum non-endemic area from 2014 to 2017, and performed population genetic analyses based on nine microsatellites. Results showed that all snail populations had low genetic diversity, and most genetic variations originated from within snail populations. The estimated effective population size for the 2015 population was infinitive. All snails could be separated into two clusters, and further DIYABC analysis revealed that both the 2016 and the 2017 populations may derive from the 2015, indicating that the 2017 population must have been missed in the field survey performed in 2016. These findings may have implications in development of more practical guidelines for snail monitoring and control.

Resonant energy transfer assisted by off-diagonal coupling.

Dynamics of resonant energy transfer of a single excitation in a molecular dimer system are studied in the simultaneous presence of diagonal and off-diagonal exciton-phonon coupling. It is found that, at given temperatures, the off-diagonal coupling can enhance both the coherence of the resonant energy transfer and the net quantity of energy transferred from an initially excited monomer to the other. Also studied is the dynamics of entanglement between the dimer system and the phonon bath as measured by the von Neumann entanglement entropy, and the inter-monomer entanglement dynamics for the excitonic system.

Waterproofing performance of polypropylene - concrete wall of underground silo under combined compressive stress and water pressure.

Safe, economical and high-quality storage of huge amount of grain for a longer duration under COVID-19 is a challenge and underground storage is a good alternative due to stable temperature, less cooling consumption and better pest control effect. However, the underground silo has very high requirement of waterproof and the performance of underground silo under combined compression and water pressure was rarely studied. In this study, a new composite structure, polypropylene - concrete wall (PPCW) for underground silo was proposed. Total three PPCWs with different size were manufactured to test the waterproofing features under joint effect of compression and hydropower of water. The strains, lateral displacement and cracking conditions of PPCWs were investigated. According to the experimental results, the PP board and concrete presented very good performance of interaction working under compression. The maximum water pressure of the specimens with stud spacing of 250mm increased by about 15.7% compared with that of the specimens with stud spacing of 350mm. The welding and strength of PP board has the greatest influence on the ultimate performance of PPCW. Based on the empirical coefficient method of concrete flat-slab and tested results, a new modified method was proposed to predict the bending moment at mid-span of PPCW by using an adjustment coefficient, R m . Considering this experimental case only, the adopting a R m = 0.64 could control the relative errors between test and analysis under 15.6%.