Innovative ochre processing and tool use in China 40,000 years ago.

Homo sapiens was present in northern Asia by around 40,000 years ago, having replaced archaic populations across Eurasia after episodes of earlier population expansions and interbreeding1-4. Cultural adaptations of the last Neanderthals, the Denisovans and the incoming populations of H. sapiens into Asia remain unknown1,5-7. Here we describe Xiamabei, a well-preserved, approximately 40,000-year-old archaeological site in northern China, which includes the earliest known ochre-processing feature in east Asia, a distinctive miniaturized lithic assemblage with bladelet-like tools bearing traces of hafting, and a bone tool. The cultural assembly of traits at Xiamabei is unique for Eastern Asia and does not correspond with those found at other archaeological site assemblages inhabited by archaic populations or those generally associated with the expansion of H. sapiens, such as the Initial Upper Palaeolithic8-10. The record of northern Asia supports a process of technological innovations and cultural diversification emerging in a period of hominin hybridization and admixture2,3,6,11.

Casuattimines A-N, fourteen new Lycopodium alkaloids from Lycopodiastrum casuarinoides with Cav3.1 channel inhibitory activity.

Two new dimeric Lycopodium alkaloids, casuattimines A and B (1 and 2), along with twelve previously undescribed Lycopodium alkaloids, casuattimines C-N (3-14), and eight known Lycopodium alkaloids, were isolated from Lycopodiastrum casuarinoides. Casuattimines A and B (1 and 2) are the first two ether-linked Lycopodium alkaloid dimers. Casuattimines C and D (3 and 4) are unique Lycopodium alkaloids characterized by a long fatty acid chain. Structural elucidation was achieved through HRESIMS, NMR, and electronic circular dichroism (ECD) calculations. In addition, the absolute configurations of compounds 7, 13, and 14 were determined by single crystal X-ray diffraction. Compounds 1, 2, and 4 demonstrated notable Cav3.1 channel inhibitory activities presenting IC50 values of 10.75 ± 1.02 µM, 9.33 ± 0.79 µM, and 7.14 ± 0.86 µM, respectively. The dynamics of compound 4 against the Cav3.1 channel and preliminary structure-activity relationships of these active Lycopodium alkaloids were also discussed.

Discovery of α-Obscurine Derivatives as Novel Cav3.1 Calcium Channel Blockers.

Voltage-gated calcium channels (VGCCs), particularly T-type calcium channels (TTCCs), are crucial for various physiological processes and have been implicated in pain, epilepsy, and cancer. Despite the clinical trials of TTCC blockers like Z944 and MK8998, none are currently available on the market. This study investigates the efficacy of Lycopodium alkaloids, particularly as natural product-based TTCC blockers. We synthesized eighteen derivatives from α-obscurine, a lycodine-type alkaloid, and identified five derivatives with significant Cav3.1 blockade activity. The most potent derivative, compound 7, exhibited an IC50 value of 0.19±0.03 µM and was further analyzed through molecular docking, revealing key interactions with Cav3.1. These findings provide a foundation for the structural optimization of Cav3.1 calcium channel blockers and present compound 7 as a promising lead compound for drug development and a tool for chemical biology research.

Lycopodium Alkaloids from Huperzia goebelii.

One new fawcettimine-type Lycopodium alkaloid, hupertimine F (1), together with five known (2-6) Lycopodium alkaloids were isolated from Huperzia goebelii. The structure of 1 was elucidated by 1D and 2D NMR spectra, HRESIMS, and X-ray diffraction. Structurally, 1 represents the fourth example of Lycopodium alkaloids characterized by a 5/5/5/5/6 pentacyclic ring system with a 1-aza-7-oxabicyclo[2.2.1]heptane moiety. These known compounds 2, 3, 5, and 6 were isolated from H. goebelii for the first time. Compounds 1-6 were evaluated for acetylcholinesterase, butyrylcholinesterase and monoamine oxidase B inhibitory activities in vitro.

Lycocasine A, a Lycopodium Alkaloid from Lycopodiastrum casuarinoides and Its Acid-Sensing Ion Channel 1a Inhibitory Activity.

A novel Lycopodium alkaloid, lycocasine A (1), and seven known Lycopodium alkaloids (2-8), were isolated from Lycopodiastrum casuarinoides. Their structures were determined through NMR, HRESIMS, and X-ray diffraction analysis. Compound 1 features an unprecedented 5/6/6 tricyclic skeleton, highlighted by a 5-aza-tricyclic[6,3,1,02,6]dodecane motif. In bioactivity assays, compound 1 demonstrated weak inhibitory activity against acid-sensing ion channel 1a.

The changing epidemiology of syndactyly in Chinese newborns: a nationwide surveillance-based study.

BACKGROUND: Little is known about the epidemiologic features of syndactyly (SD) in Chinese newborns. METHODS: Using 2007-2019 data from the Chinese Birth Defects Monitoring Network, we conducted a prevalence analysis on overall, isolated and associated syndactyly according to birth year, maternal age, maternal residence, geographic region and infant sex, with special interests in time trends, perinatal outcomes and clinical phenotypes. RESULTS: A total of 13,611 SD cases were identified among 24,157,719 births in the study period, yielding the prevalence of 5.63, 4.66 and 0.97 per 10,000 for overall, isolated, and associated SD, respectively. The prevalence of each type of SD exhibited an upward trend over the period. The prevalence of overall SD varied significantly by maternal residence (urban vs. rural, 6.69/10,000 vs. 4.35/10,000), maternal age (< 20 years, 5.43/10,000; 20-24 years, 5.03/10,000; 25-29 year, 5.65/10,000; 30-34 years, 6.07/10,000; ≥ 35 years, 5.76/10,000), geographic region (central, 5.07/10,000; east, 6.75/10,000; west, 5.12/10,000), and infant sex (male vs. female, 6.28/10,000 vs. 4.86/10,000). Newborns with associated SD were more likely to be born prematurely (29.2% vs. 10.6%) or with low birthweight (30.5% vs.9.8%) than those with isolated SD. The bilaterally, and unilaterally affected cases accounted for 18.4% and 76.7%, respectively. The feet were more frequently involved (64.3%) in those bilaterally affected cases, while right side preference (right vs left: 53.8% vs 46.2%) and upper limbs preference (hand vs foot: 50.8% vs 48.0%) were found in unilateral cases. CONCLUSIONS: The prevalence of syndactyly in China is on the rise and notably higher than that in other Asian and European countries, highlighting the importance of investigating the etiology, epidemiology, and clinical implications of this condition in the Chinese population.

[Two new prenylated 2-arylbenzofurans from roots of Artocarpus heterophyllus and their anti-respiratory burst activities].

Two prenylated 2-arylbenzofurans were isolated from roots of Artocarpus heterophyllus, with a combination of various chromatographic approaches, including ODS, MCI, Sephadex LH-20, and semipreparative high performance liquid chromatography(HPLC). They were identified as 5-[6-hydroxy-4-methoxy-5,7-bis(3-methylbut-2-enyl)benzofuran-2-yl]-1,3-benzenediol(1) and 5-[2H,9H-2,2,9,9-tetramethyl-furo[2,3-f]pyrano[2,3-h][1]benzopyran-6-yl]-1,3-benzenediol(2) with spectroscopic methods, such as HR-ESI-MS, IR, 1D NMR, and 2D NMR, and named artoheterins B(1) and C(2), respectively. The anti-respiratory burst activities of the two compounds were evaluated with rat polymorphonuclear neutrophils(PMNs) stimulated by phorbol 12-myristate 13-acetate(PMA). The results showed that 1 and 2 exhibited significant inhibitory effect on respiratory burst of PMNs with IC_(50) values of 0.27 and 1.53 µmol·L~(-1), respectively.

Synthesis of Metal-Free Chiral Covalent Organic Framework for Visible-Light-Mediated Enantioselective Photooxidation in Water.

Although chiral covalent organic frameworks (CCOFs) presence grows in thermal asymmetric catalysis, their application in equally important asymmetric photocatalysis has yet to begin. Herein, we first report a propargylamine-linked and quaternary ammonium bromide decorated porphyrin-CCOF which can highly promote visible-light-driven enantioselective photooxidation of sulfides to sulfoxides in water and in air. This methodology has also been applied to the synthesis of (R)-modafinil, a wakefulness-promoting medication used for the treatment of excessive sleepiness. This research might open a new way for the application of CCOFs in asymmetric photocatalysis.

Design, synthesis, and anti-influenza A virus activity evaluation of novel indole containing derivatives of triazole.

We designed and synthesized 18 substituted indole derivatives containing a triazole scaffold as novel anti-influenza A virus candidates using a bio-isosteric and scaffold-hopping strategy from the lead compound 4-32-2. Most of the target compounds (eg: 6, 7a, 7d, 7f-j, 7l, 7m, 7o, 7q) exhibited potent anti-influenza A virus activity and low cytotoxicity in vitro. In particular, 7a exhibited the most potent anti-IAV activity (IC50: 1.34 ± 0.13 µM) with low cytotoxicity (CC50: > 100 µM), and high selectivity index (SI: > 74.63), which provides a new chemical scaffold for the development of novel anti-IAV drug.

Silver-Rich Hybrid Framework Iodide Based on [Ag8I6]2+ Clusters Displays Low-Temperature Dual Emission and Luminescence Thermochromism.

Cluster-based framework metal iodides have diverse structures and excellent luminescence properties, and show promising applications in sensing and solid-state lighting. However, the design and synthesis of these materials remain great challenges because excess I- ions introduced into the synthesis systems decrease the condensation degree of M-I units. In this work, a new strategy is developed to control the condensation behavior of Ag-I units, and a new silver-rich cluster-based framework iodide [DabcoAg8I6(SPh)2]n (1) (Dabco = 1,4-diazabicyclo [2.2.2] octane) has been synthesized under solvothermal conditions in the presence of silver thiophenolate (AgSPh)n. Compound 1 features a three-dimensional (3-D) cluster-based framework with a pillared layer structure composed of cationic [Ag8I6]2+ clusters bridged by SPh- and Dabco, and displays low-temperature dual emission and luminescence thermochromism.

Spiroligustolides A and B: Two pairs of enantiomeric spiro-orthoester-containing phthalide dimers as Cav3.1 calcium channel inhibitors from Ligusticum Chuanxiong Hort.

Two pairs of unprecedented enantiomeric phthalide dimers, spiroligustolides A (1a/1b) and B (2a/2b), featuring a unique spiroorthoster linkage between two monomeric units to form a 5/6/5/6/6-fused ring system, were isolated from the roots of Ligusticum chuanxiong. The structures and relative configurations of 1 and 2 were determined by HR-ESI-MS, IR, and NMR spectroscopic data, coupled with single-crystal X-ray diffraction analysis, and the absolute configurations of 1a, 1b, 2a, and 2b were established by comparing the experimental and calculated electronic circular dichroism (ECD) data. Plausible biosynthetic pathway for 1 and 2 was proposed. Moreover, compounds 1, 1b, and 2b showed remarkable inhibitory activities on Cav3.1 calcium channel with IC50 values of 8.34, 7.08, and 8.60 µM, respectively.

Rhabdomyolysis-associated acute kidney injury: clinical characteristics and intensive care unit transfer analysis.

BACKGROUND: Information on rhabdomyolysis-associated acute kidney injury (AKI) in the emergency department or general ward is limited. AIM: To assess the risk factors, outcomes and clinical correlates with intensive care unit (ICU) transfer of patients with rhabdomyolysis-associated AKI. METHODS: Patients with rhabdomyolysis were divided into the rhabdomyolysis-associated AKI group and the rhabdomyolysis without AKI group. Inhospital outcomes, including ICU transfer, mortality, length of stay, daily cost and renal recovery were analysed. Multivariate regression analysis was performed to identify the association between rhabdomyolysis-associated AKI and ICU transfer. RESULTS: Among 149 patients with rhabdomyolysis, 68 (45.6%) developed AKI. Age and urine protein were important risk factors for incidence of rhabdomyolysis-associated AKI. Patients with rhabdomyolysis-associated AKI had higher levels of undergoing dialysis (19.1% vs 2.5%; P < 0.01), all-cause mortality (13.2% vs 1.2%; P < 0.01), cost of hospitalisation (10.8 1000 yuan, IQR (5.5, 3.5) vs 5.9 1000 yuan, IQR 5.9 (3.6, 9.9); P = 0.03), as well as longer length of hospital stay (8.0 days (5.0, 14.0)) versus (6.0 days (4.0, 11.0); P = 0.02). Additionally, the percentage of patients with AKI who transferred to ICU was higher than patients without AKI (33.8% vs 12.3%; P < 0.002) and rhabdomyolysis-associated AKI was an independent risk factor for ICU transfer (adjusted odds ratio = 2.58; 95% confidence interval, 1.12-6.8, P = 0.03). CONCLUSION: Rhabdomyolysis-associated AKI was common in the emergency department or general ward and led to more severe outcomes. It was also associated with an increased risk of ICU transfer.

A Ferrocene-Functionalized Covalent Organic Framework for Enhancing Chemodynamic Therapy via Redox Dyshomeostasis.

Chemodynamic therapy (CDT), which induces cell death by decomposing high levels of H2 O2 in tumor cells into highly toxic ·OH, is recognized as a promising antineoplastic approach. However, current CDT approaches are often restricted by the highly controlled and upregulated cellular antioxidant defense. To enhance ·OH-induced cellular damage by CDT, a covalent organic framework (COF)-based, ferrocene (Fc)- and glutathione peroxidase 4 (GPX4) inhibitor-loaded nanodrug, RSL3@COF-Fc (2b), is fabricated. The obtained 2b not only promotes in situ Fenton-like reactions to trigger ·OH production in cells, but also attenuates the repair mechanisms under oxidative stress via irreversible covalent GPX4 inhibition. As a result, these two approaches synergistically result in massive lipid peroxide accumulation, subsequent cell damage, and ultimately ferroptosis, while not being limited by intracellular glutathione. It is believed that this research provides a paradigm for enhancing reactive oxygen species-mediated oncotherapy through redox dyshomeostasis and may provide new insights for developing COF-based nanomedicine.

Monoterpene Indole Alkaloids with Cav3.1 T-Type Calcium Channel Inhibitory Activity from Catharanthus roseus.

Catharanthus roseus is a well-known traditional herbal medicine for the treatment of cancer, hypertension, scald, and sore in China. Phytochemical investigation on the twigs and leaves of this species led to the isolation of two new monoterpene indole alkaloids, catharanosines A (1) and B (2), and six known analogues (3-8). Structures of 1 and 2 were established by 1H-, 13C- and 2D-NMR, and HREIMS data. The absolute configuration of 1 was confirmed by single-crystal X-ray diffraction analysis. Compound 2 represented an unprecedented aspidosperma-type alkaloid with a 2-piperidinyl moiety at C-10. Compounds 6-8 exhibited remarkable Cav3.1 low voltage-gated calcium channel (LVGCC) inhibitory activity with IC50 values of 11.83 ± 1.02, 14.3 ± 1.20, and 14.54 ± 0.99 µM, respectively.

Covalent Organic Frameworks (COFs) for Cancer Therapeutics.

As newly emerged crystalline porous materials, covalent organic frameworks (COFs) possess fascinating structures and some specific features such as modularity, crystallinity, porosity, stability, versatility, and biocompatibility. Besides adsorption/separation, sensing, catalysis, and energy applications, COFs have recently shown a promise in biomedical applications. This contribution provides an overview of the recent developments of COF-based medicines in cancer therapeutics, including drug delivery, photodynamic therapy (PDT), photothermal therapy (PTT), and combined therapy. Furthermore, the major challenges and developing trends in this field are also discussed. These recent developments are summarized and discussed to help encourage further contributions in this emerging and promising field.

A Glycosylated Covalent Organic Framework Equipped with BODIPY and CaCO3 for Synergistic Tumor Therapy.

Ca2+ , a ubiquitous but nuanced modulator of cellular physiology, is meticulously controlled intracellularly. However, intracellular Ca2+ regulation, such as mitochondrial Ca2+ buffering capacity, can be disrupted by 1 O2 . Thus, the intracellular Ca2+ overload, which is recognized as one of the important cell pro-death factors, can be logically achieved by the synergism of 1 O2 with exogenous Ca2+ delivery. Reported herein is a nanoscale covalent organic framework (NCOF)-based nanoagent, namely CaCO3 @COF-BODIPY-2I@GAG (4), which is embedded with CaCO3 nanoparticle (NP) and surface-decorated with BODIPY-2I as photosensitizer (PS) and glycosaminoglycan (GAG) targeting agent for CD44 receptors on digestive tract tumor cells. Under illumination, the light-triggered 1 O2 not only kills the tumor cells directly, but also leads to their mitochondrial dysfunction and Ca2+ overload. An enhanced antitumor efficiency is achieved via photodynamic therapy (PDT) and Ca2+ overload synergistic therapy.

UiO-68-PT MOF-Based Sensor and Its Mixed Matrix Membrane for Detection of HClO in Water.

As an important type of reactive oxygen species (ROS), hypochloric acid (HClO) is closely linked with our daily life, and its convenient and rapid detection is very significant and imperative. Fluorescent and visual probes are being recognized as powerful and convenient tools for detection of ROS in the environment and living organisms by visualizing and imaging. In this contribution, a new metal-organic framework-based fluorescent probe UiO-68-PT, which was generated from a phenthiazine-decorated benzimidazole bridging dicarboxyl ligand and ZrCl4 under solvothermal conditions via in situ one-pot approach, is reported. The obtained UiO-68-PT features a unique HClO and Vitamin C-triggered reversible redox process, which is accompanied by both visual and fluorescence changes. Therefore, it can be a highly sensitive, specific, and reusable sensor to detect HClO species in water via both visual and fluorogenic observation (turn-on). Furthermore, its mixed membrane material (MMM) was fabricated by the combination of UiO-68-PT and poly(vinyl alcohol), and the obtained hydrophilic MMM can be used as a reversible colorimetric card for visual detection of the HClO in aqueous solution.

Characterization and Identification of Prenylated Flavonoids from Artocarpus heterophyllus Lam. Roots by Quadrupole Time-Of-Flight and Linear Trap Quadrupole Orbitrap Mass Spectrometry.

In this study, a combination of quadrupole time-of-flight mass spectrometry (Q-TOF-MS) and linear trap quadrupole orbitrap mass spectrometry (LTQ-Orbitrap-MS) was performed to investigate the fragmentation behaviors of prenylated flavonoids (PFs) from Artocarpus plants. Fifteen PFs were selected as the model molecules and divided into five types (groups A-E) according to their structural characteristics in terms of the position and existing form of prenyl substitution in the flavone skeleton. The LTQ-Orbitrap-MSn spectra of the [M - H]- ions for these compounds provided a wealth of structural information on the five different types of compounds. The main fragmentation pathways of group A were the ortho effect and retro Diels-Alder (RDA), and common losses of C4H10, CO, and CO2. The compounds in group B easily lose C6H12, forming a stable structure of a 1,4-dienyl group, unlike those in group A. The fragmentation pathway for group C is characterized by obvious 1,4A-, 1,4B- cracking of the C ring. The diagnostic fragmentation for group D is obvious RDA cracking of the C ring and the successive loss of CH3 and H2O in the LTQ-Orbitrap-MSn spectra. Fragmentation with successive loss of CO or CO2, ·CH3, and CH4 in the LTQ-Orbitrap-MSn spectra formed the characteristics of group E. The summarized fragmentation rules were successfully exploited to identify PFs from Artocarpus heterophyllus, a well-known Artocarpus plant, which led to the identification of a total of 47 PFs in this plant.

Efficacy and safety of using premedication with simethicone/Pronase during upper gastrointestinal endoscopy examination with sedation: A single center, prospective, single blinded, randomized controlled trial.

BACKGROUND AND AIM: To investigate the efficacy and safety of premedication with simethicone/Pronase during esophagogastroduodenoscopy (EGD) with sedation. METHODS: Six hundred and ten patients were randomly allocated to two groups based on type of premedication given. Premedication used in the control group was 10 mL lidocaine hydrochloride mucilage (LHM, N = 314) and premedication used in the intervention group was 80 mL simethicone/Pronase solution plus 10 mL lidocaine hydrochloride mucilage (SP/LHM, N = 296). EGD was done under sedation. Visibility scores, number of mucosal areas that needed cleansing, water consumption for cleansing, time taken for examination, diminutive lesions, pathological diagnosis, patients' gag reflex and oxygenation (pulse oximetry) were recorded. RESULTS: SP/LHM has significantly lower total visibility score than LHM (7.978 ± 1.526 vs 6.348 ± 1.097, P < 0.01). During the procedure, number of intragastric areas that needed cleansing and amount of water consumed were significantly less in the SP/LHM than in the LHM group (P < 0.01). In SP/LHM (P = 0.01), endoscopy procedure duration was significantly longer. Although there was no significant difference in rate of detection of diminutive lesions between LHM and SP/LHM, the endoscopist carried out more biopsies in SP/LHM. This led to a higher rate of diagnosis of atrophic gastritis (P = 0.014) and intestinal metaplasia (P = 0.024). There was no significant difference in gag reflex (P = 0.604) and oxygenation during the endoscopy procedure for either group of patients. CONCLUSION: Routine use of premedication with simethicone/Pronase should be recommended during EGD with sedation.

Postoperative functional status in patients with supratentorial superficial low-grade glioma.

BACKGROUND: We investigated the functional status of adult supratentorial superficial low-grade glioma (ASS-LGG) after surgery and analyzed its relevant factors to guide the therapeutic strategy and improve the life quality of these patients. METHODS: Clinical materials from January 2008 to December 2010 in 104 adults with ASS-LGG were analyzed retrospectively. The follow-up period ranged from 6 months to 1.5 years. The logistic regression was used to evaluate the preoperative and postoperative variation of functional status in patients to disclose the relevant factors affecting postoperative functional status, such as age, gender, the duration of symptom, size and location of the tumor, hemisphere, resection degree, and tumor pathologic grade and preoperative Karnofsky performance status (Pre-KPS). RESULTS: Four out of nine candidate factors are related to the postoperative functional status. They are age less than 40 years, the size of tumor less than 5 cm in diameter, tumor located in the right hemisphere, and limited resection of tumor in the eloquent area. CONCLUSIONS: It seems more meaningful to evaluate the functional status of the patients with ASS-LGG on the basis of these clinical features, involving age, tumor size, location, and extent of resection.