Primary cilium participates in radiation-induced bystander effects through TGF-ß1 signaling.

Many studies have indicated that tumor growth factor-beta (TGF-ß) signaling mediates radiation-induced bystander effects (RIBEs). The primary cilium (PC) coordinates several signaling pathways including TGF-ß signaling to regulate diverse cellular processes. But whether the PC participates in TGF-ß induced RIBEs remains unclear. The cellular levels of TGF-ß1 were detected by western blot analysis and the secretion of TGF-ß1 was measured by ELISA kit. The ciliogenesis was altered by CytoD treatment, STIL siRNA transfection, IFT88 siRNA transfection, or KIF3a siRNA transfection, separately, and was detected by western blot analysis and immunofluorescence staining. G0 /G1 phase cells were arrested by serum starvation and S phase cells were induced by double thymidine block. The TGF-ß1 signaling was interfered by LY2109761, a TGF-ß receptor 1 (TßR1) inhibitor, or TGF-ß1 neutral antibody. The DNA damages were induced by TGF-ß1 or radiated conditional medium (RCM) from irradiated cells and were reflected by p21 expression, 53BP1 foci, and γH2AX foci. Compared with unirradiated control, both A549 and Beas-2B cells expressed and secreted more TGF-ß1 after carbon ion beam or X-ray irradiation. RCM collected from irradiated cells or TGF-ß1 treatment caused an increase of DNA damage in cocultured unirradiated Beas-2B cells while blockage of TGF-ß signaling by TßR1 inhibitor or TGF-ß1 neutral antibody alleviates this phenomenon. IFT88 siRNA or KIF3a siRNA impaired PC formation resulted in an aggravated DNA damage in bystander cells, while elevated PC formation by CytoD or STIL siRNA resulted in a decrease of DNA damage. Furthermore, TGF-ß1 induced more DNA damages in S phases cells which showed lower PC formation rate and less DNA damages in G0 /G1 phase cells which showed higher PC formation rate. This study demonstrates the particular role of primary cilia during RCM induced DNA damages through TGF-ß1 signaling restriction and thereby provides a functional link between primary cilia and RIBEs.

Synthesis of Alkylated Polyfluorobenzenes through Decarboxylative Giese Addition of Aliphatic N-Hydroxyphthalimide Esters with Polyfluorostyrene.

Polyfluoroaromatic compounds play crucial roles in medicinal and material science. However, the synthesis of alkylated polyfluoroarenes has been relatively underdeveloped. In this study, we devised a novel decarboxylative coupling reaction between aliphatic N-hydroxyphthalimide esters and polyfluorostyrene, leveraging the photochemical activity of electron donor-acceptor (EDA) complexes. This method offers simple reaction conditions, a broad substrate scope, and excellent functional group tolerance. Furthermore, we have demonstrated the practicality of this protocol through late-stage polyfluoroaryl modification of biologically active molecules using readily available carboxylic acids as starting materials, thus providing an important supplement to the current toolbox for accessing alkylated polyfluoroaryl motifs.

A retrospective study comprising 228 cases of pediatric scalp and skull lesions.

BACKGROUND: Most neurosurgery presentations in children present with a mass that may be scalp and skull lesions, including neoplastic and congenital malformed structural lesions, respectively. Clinicians should make early diagnoses and identify cases requiring surgical intervention promptly to help achieve a better prognosis. METHOD: This study retrospectively reviewed studies on children's scalp and skull lesions within a pediatric medical center's department of neurosurgery. The detailed clinical information and pathological types of these cases were scrutinized. RESULT: A total of 228 children's scalp and skull lesions with clinical information and identified histopathology types were summarized. The most common scalp and skull lesions were benign dermoid cysts; malignant types were rare but can occur in children. CONCLUSION: Based on the combined clinical symptoms and image information, children's scalp and skull lesions should be diagnosed early. Malignant scalp and skull lesions/other special cases should be treated seriously.

[Investigation and clarification of traditional measuring units of Tibetan medicine].

Quantity is the key factor to ensure the safety and effectiveness of medicines. It is very important to study and determine the traditional measuring units and their quantity values of Tibetan medicine. Based on the literature records of Tibetan medicine and combined with modern experimental verification and investigation research, this study determined the reference, name, and conversion rate of traditional measuring units of Tibetan medicine. Meanwhile, through large sample sampling and repeated quantification of refe-rence of basic units, its weight and volume were clarified. The modern SI volume and weight unit values corresponding to the traditional volume and weight units of Tibetan medicine were deduced, and the correctness, reliability, and practicability of these determination results were demonstrated. This study also put forward some specific suggestions and reference values for formulating the standards of measuring units of weight and volume of Tibetan medicine. It is of great significance in guiding the processing, production, and clinical treatment of Tibetan medicine, and promoting the standardization and standardized development of Tibetan medicine.

Saponins and their derivatives: Potential candidates to alleviate anthracycline-induced cardiotoxicity and multidrug resistance.

Anthracyclines (ANTs) continue to play an irreplaceable role in oncology treatment. However, the clinical application of ANTs has been limited. In the first place, ANTs can cause dose-dependent cardiotoxicity such as arrhythmia, cardiomyopathy, and congestive heart failure. In the second place, the development of multidrug resistance (MDR) leads to their chemotherapeutic failure. Oncology cardiologists are urgently searching for agents that can both protect the heart and reverse MDR without compromising the antitumor effects of ANTs. Based on in vivo and in vitro data, we found that natural compounds, including saponins, may be active agents for other both natural and chemical compounds in the inhibition of anthracycline-induced cardiotoxicity (AIC) and the reversal of MDR. In this review, we summarize the work of previous researchers, describe the mechanisms of AIC and MDR, and focus on revealing the pharmacological effects and potential molecular targets of saponins and their derivatives in the inhibition of AIC and the reversal of MDR, aiming to encourage future research and clinical trials.

Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E.

The annotinolides are one of the most recent additions to the Lycopodium family of alkaloids, with its members possessing challenging, caged structures that include a [3.2.1]-bicyclic core bearing six contiguous stereocenters, including four that are fully substituted. Herein, we document a concise and stereoselective route that achieves the first total syntheses of three of its members: annotinolides C, D, and E. Key operations include a gold(I)-catalyzed Conia-ene reaction that fashions much of the main core in a single operation, as well as a number of other challenging and chemoselective transformations to generate the remaining elements. Moreover, efforts utilizing the natural products themselves, seeking adjustments in their oxidation states and the rearrangement of individual ring systems, shed light on their potential biogenesis with some outcomes counter to those originally proposed. Finally, formal enantioenriched syntheses of the target molecules are also presented.

Predicting asymptomatic neurosyphilis using peripheral blood indicators.

BACKGROUND: The high misdiagnosis rate of asymptomatic neurosyphilis (ANS) has long challenged infectious disease clinicians. We aim to develop a model for diagnosing ANS in asymptomatic syphilis (AS) patients without CSF indicators. RESULTS: 277 AS patients with HIV-negative and underwent lumbar puncture were enrolled in this horizontal study.The area under the curve for predicting ANS by CSF leukocytes and protein was 0.643 and 0.675 [95% CI, 0.583-0.699VS.0.616-0.729]. Through LRM, the AUC increased to 0.806 [95% CI, 0.732-0.832], and the Youden's index was 0.430. If the score is ≤ 0.159, ANS can be excluded with a predictive value of 92.9%; we can identify ANS while the score is over 0.819, with a predictive value of 91.7% and a specificity of 99.25%. This study showed that the LRM can diagnose ANS in AS patients effectively. CONCLUSION: Given a large number of misdiagnosis ANS patients and CSF results' insufficiency, the model is more practical. Our research will help clinicians track suspected syphilis, especially those who cannot accept the CSF test.

Asymmetric Total Synthesis of Pre-schisanartanin C.

Pre-schisanartanin C belongs to the family of Schisandra nortriterpenoids with potent antihepatitis, antitumor, and anti-HIV activities. This paper presents the enantioselective total synthesis of pre-schisanartanin C (1). An important step in the total synthesis of 1 is gold-catalyzed intramolecular cyclopropanation of a 1,8-enyne substrate bearing a secondary ester group at the propargylic position to prepare a bicyclo[6.1.0]nonane core. Additional highlights include (i) an asymmetric Diels-Alder reaction to install the initial C5 stereogenic center of 1 and (ii) a sequential Pd-catalyzed Stille coupling, regio- and stereoselective Sharpless asymmetric dihydroxylation, and a subsequent intramolecular lactonization to construct the side chain of 1. The developed chemistry paves the way for the total syntheses of other family members bearing highly rigid bicyclo[6.1.0]nonane cores.

Total Synthesis of the Caged Indole Alkaloid Arboridinine Enabled by aza-Prins and Metal-Mediated Cyclizations.

Although alkaloid natural products possess incredible diversity when considered broadly, certain domains are sometimes shared by several members, even from different sub-collections. Such homology can point to potential synthetic strategies. Herein, we highlight how such an analysis of the natural product arboridinine pinpointed two key elements of structural similarity that suggested the value of a metal-mediated 6-endo-dig cyclization to fashion its tetracyclic indolenine core, as well as the need to develop what could be considered a reversed polarity aza-Prins cyclization to deliver its tertiary allylic alcohol and final cage structure. The power of the latter design element is highlighted by several failures in achieving similar functional group patterning through more traditional aza-Prins and Mannich cyclization strategies. Overall, these operations fueled an inaugural 13-step racemic synthesis of the target; exploration of varied solutions for the enantioselective preparation of a key 7-membered indole-containing piece afforded a 16-step formal asymmetric solution.

Total Syntheses of Scaparvins B, C, and D Enabled by a Key C-H Functionalization.

The clerodane diterpene family possesses an impressive range of bioactivities and high synthetic challenge due to their unique amalgamation of rings, stereocenters, and oxygenation. Herein, we disclose the first total syntheses of three members, scaparvins B, C, and D, through a route fueled by several chemoselective and carefully orchestrated steps. One such operation is a tailored late-stage C-H functionalization converting a carboxylic acid into a lactone through the oxidation of a tertiary C-H bond under conditions that minimize epoxidation of an alkene. This step, among others, afforded critical functionality to complete the targets. In addition, use of an appropriate chiral catalyst with a Rawal diene renders the sequence enantioselective.

The Central Hinge Link Truncation of the Antimicrobial Peptide Fowlicidin-3 Enhances Its Cell Selectivity without Antibacterial Activity Loss.

Antimicrobial peptides (AMPs) have been paid considerable attention because of their broad-spectrum antimicrobial activity and a reduced possibility of the development of bacterial drug resistance. Fowlicidin-3 (Fow-3) is an identified type of chicken cathelicidin AMP that has exhibited considerable antimicrobial activity and cytotoxicity. To reduce cell toxicity and improve cell selectivity, several truncated peptides of fowlicidin-3, Fow-3(1-15), Fow-3(1-19), Fow-3(1-15-20-27), and Fow-3(20-27), were synthesized. Our results indicated that neither the N- nor C-terminal segment alone [Fow-3(1-15), Fow-3(1-19), Fow-3(20-27)] was sufficient to confer antibacterial activity. However, Fow-3(1-19) with the inclusion of the central hinge link (-AGIN-) retained substantial cell toxicity, which other analogs lost. Fow-3(1-15-20-27) displayed potent antimicrobial activity for a wide range of Gram-negative and Gram-positive bacteria and no obvious hemolytic activity or cytotoxicity. The central link region was shown to be critically important in the function of cell toxicity but was not relevant to antibacterial activity. Fow-3(1-15-20-27) maintained antibacterial activity in the presence of physiological concentrations of salts. The results from fluorescence spectroscopy, scanning electron microcopy, and transmission electron microcopy showed that Fow-3(1-15-20-27) as well as fowlicidin-3 killed bacterial cells by increasing membrane permeability and damaging the membrane envelope integrity. Fow-3(1-15-20-27) could be a promising antimicrobial agent for clinical application.

CuO nanoparticle interaction with human epithelial cells: cellular uptake, location, export, and genotoxicity.

The toxicity of CuO nanoparticles (NPs) to human lung epithelial (A549) cells was investigated in this study. CuO NPs (10-100 mg/L) had significant toxicity to A549 cells, whereas CuO bulk particles (BPs) showed much lower toxicity (24 h IC(50), 58 and 15 mg/L for CuO BPs and NPs, respectively). Transmission electron microscopic analysis demonstrated CuO NP entry into A549 cells and organelles, including lysosomes, mitochondria, and nucleus. Endocytosis was the primary pathway of CuO NPs uptake. CuO NPs (15 mg/L) induced mitochondrial depolarization, possibly mediated by reactive oxygen species (ROS) generation. Intracellular CuO NPs first generate ROS, which subsequently induces the expression of p38 and p53 and ultimately causes DNA damage (Comet assay). We confirm for the first time that the primary cytotoxic response is oxidative stress rather than DNA damage. A fraction of the CuO NPs was exported to the extracellular environment. In this study, centrifugal ultrafiltration tubes were successfully employed to determine the dissolved Cu(2+) from CuO NPs in the cell medium. Dissolved Cu(2+) ions contributed less than half of the total toxicity caused by CuO NPs, including ROS generation and DNA damage. This study provided useful data for understanding transport and toxicity of metal oxide NPs in human cells.

Chk1 Inhibition Hinders the Restoration of H3.1K56 and H3.3K56 Acetylation and Reprograms Gene Transcription After DNA Damage Repair.

H3K56 acetylation (H3K56Ac) was reported to play a critical role in chromatin assembly; thus, H3K56ac participates in the regulation of DNA replication, cell cycle progression, DNA repair, and transcriptional activation. To investigate the influence of DNA damage regulators on the acetylation of histone H3 and gene transcription, U2OS cells expressing SNAP-labeled H3.1 or SNAP-labeled H3.3 were treated with ATM, ATR, or a Chk1 inhibitor after ultraviolet (UV) radiation. The levels of H3.1K56ac, H3.3K56ac, and other H3 site-specific acetylation were checked at different time points until 24 h after UV radiation. The difference in gene transcription levels was also examined by mRNA sequencing. The results identified Chk1 as an important regulator of histone H3K56 acetylation in the restoration of both H3.1K56ac and H3.3K56ac. Moreover, compromising Chk1 activity via chemical inhibitors suppresses gene transcription after UV radiation. The study suggests a previously unknown role of Chk1 in regulating H3K56 and some other site-specific H3 acetylation and in reprograming gene transcription during DNA damage repair.

Bioaccumulation of mercury along continuous fauna trophic levels in the Yellow River Estuary and adjacent sea indicated by nitrogen stable isotopes.

Mercury (Hg), and its organic forms, are some of the most hazardous elements, with strong toxicity, persistence, and biological accumulation in marine organisms. Hg accumulation in continuous trophic levels (TL) in marine food chains remains unclear. In this study, individual invertebrate and fish samples collected from the Yellow River Estuary adjacent sea were grouped into continuous TL ranges, and the bioaccumulations of total Hg (THg) and methylmercury (MeHg) were analyzed. The trophic magnification factor in invertebrates and fish was 1.40 and 1.72 for THg, and 2.56 and 2.17 for MeHg, indicating that both THg and MeHg were significantly biomagnified with increasing TL in both invertebrates and fish through trophic transfer. To evaluate the health risk of seafood consumption, the target hazard quotient (THQ) was calculated. Increasing THQ values indicated that the health risks of invertebrate and fish consumption in humans, especially children, were both elevated with increasing TL. THQ values > 1 indicated that consumption of invertebrates at a TL above 4.0 and fish above 4.5 may pose a relatively higher risk for children. Therefore, the consumption of both individual invertebrates and fish at high trophic positions may present greater health risk, especially in young children.

MiR-663a Inhibits Radiation-Induced Epithelium-to-Mesenchymal Transition by Targeting TGF-ß1.

Objective: miR-663a has been reported to be downregulated by X-ray irradiation and participates in radiation-induced bystander effect via TGF-ß1. The goal of this study was to explore the role of miR-663a during radiation-induced Epithelium-to-mesenchymal transition (EMT). Methods: TGF-ß1 or IR was used to induce EMT. After miR-663a transfection, cell migration and cell morphological changes were detected and the expression levels of miR-663a, TGF-ß1, and EMT-related factors were quantified. Results: Enhancement of cell migration and promotion of mesenchymal changes induced by either TGF-ß1 or radiation were suppressed by miR-663a. Furthermore, both X-ray and carbon ion irradiation resulted in the upregulation of TGF-ß1 and downregulation of miR-663a, while the silencing of TGF-ß1 by miR-663a reversed the EMT process after radiation. Conclusion: Our findings demonstrate an EMT-suppressing effect by miR-663a via TGF-ß1 in radiation-induced EMT.

Discovery of ABBV-3373, an Anti-TNF Glucocorticoid Receptor Modulator Immunology Antibody Drug Conjugate.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro. Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

Natural distinction of carbon and nitrogen isotopic niches in common fish species across marine biotopes in the Yellow River estuary.

Stable isotope analysis is a universally recognized and efficient method of indicating trophic relationships that is widely applied in research. However, variation in stable isotope ratios may lead to inaccuracies due to the effects of complex environmental conditions. This research compared the carbon and nitrogen isotopic niches of fish communities between diverse biotopes around the Yellow River estuary and adjacent sea areas, with the aim of revealing distinctions in stable isotopic niche metrics, trophic positions, and feeding preferences. Our analysis of the food source contribution indicated that allochthonous sources were considered major energy sources in estuarine areas directly affected by Yellow River-diluted water, while autochthonous benthic and pelagic producers dominated carbon input into the food web in Laizhou Bay and the open water. A significant variation in the fish δ15N characteristic was found within estuarine adjacent regions, so, together with the results from previous studies, we deemed the local high concentration of dissolved inorganic nitrogen as the original trigger of the abnormal δ15N characteristic in fishes via a transport process along food chains. These results provide a new perspective on the natural distinction of carbon and nitrogen isotopic niches. The detailed data reported here enhance our understanding of variations in fish communities in estuarine ecosystems.

P-cresol degradation through Fe(III)-EDDS/H2O2 Fenton-like reaction enhanced by manganese ion: Effect of pH and reaction mechanism.

P-cresol is a highly toxic phenolic pollutant in coal chemical wastewater. The effective removal of p-cresol is of great significance to the ecological environment. In this study, the degradation of p-cresol by the Fe(III)-EDDS/H2O2 Fenton-like reaction modified by Mn2+ was investigated. The results showed that the removal rate of p-cresol could be significantly increased by the addition of Mn2+ under neutral and weakly alkaline conditions (pH 6.5-8.5). Acidic conditions (pH 3.5) were not conducive to the Fenton-like reaction. This is because a neutral or weakly alkaline environment is conducive to Mn2+-EDDS complex formation, which can produce O2·- to accelerate the reduction of Fe(III), and the efficiency of p-cresol degradation through a Fenton-like reaction catalyzed by the Fe(III)-EDDS complex is significantly improved. In addition, the degradation of EDDS through ·OH was reduced by O2·-, which maintained and stabilized the Mn2+-EDDS complex and Fe(III)-EDDS complex. Under neutral conditions, the optimal dosage of Fe(III) is 0.7 mM, and the optimal molar ratios are EDDS/Fe(III) = 1: 1, Mn2+/Fe(III) = 1: 1, and H2O2/Fe(III) = 15: 1. The addition of free radical clearance isopropanol and CHCl3 proved that ·OH was the main active substance in the p-cresol degradation process.

The clinical treatment and outcome of cerebellopontine angle medulloblastoma: a retrospective study of 15 cases.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor arising in the cerebellum or the 4th ventricle. Cerebellopontine angle (CPA) MBs are extremely rare tumors, with few cases previously described. In this study, we sought to describe the clinical characteristics, molecular features and outcomes of CPA MB. We retrospectively reviewed a total of 968 patients who had a histopathological diagnosis of MB at the Beijing Neurosurgical Institute between 2002 and 2016. The demographic characteristics, clinical manifestations and radiological features were retrospectively analyzed. Molecular subgroup was evaluated by the expression profiling array or immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan-Meier analysis. In this study, 15 patients (12 adults and 3 children) with a mean age at diagnosis of 25.1 years (range 4-45 years) were included. CPA MBs represented 1.5% of the total cases of MB (15/968). Two molecular subgroups were identified in CPA MBs: 5 WNT-MBs (33%) and 10 SHH-MBs (67%). CPA WNT-MBs had the extracerebellar growth with the involvement of brainstem (P = 0.002), whereas CPA SHH-MBs predominantly located within the cerebellar hemispheres (P = 0.004). The 5-year OS and PFS rates for CPA MB were 80.0% ± 10.3% and 66.7% ± 12.2%, respectively. Pediatric patients with CPA MBs had worse outcomes than adult patients (OS: P = 0.019, PFS: P = 0.078). In conclusion, CPA MB is extremely rare and consists of two subgroups. Adult patients with CPA MB had a good prognosis. Maximum safe surgical resection combined with adjuvant radiotherapy and chemotherapy can be an effective treatment strategy for this rare tumor.