Reaction of the mononuclear Ni(II) thiolate complexes [Ni(L)]hydrogenase ͉ iron ͉ nickel ͉ thiolates ͉ density functional theory calculations H ydrogenases catalyze the reversible oxidation of molecular hydrogen and play a vital role in anaerobic metabolisms of a wide variety of microorganisms (1, 2).[NiFe]hydrogenases are particularly interesting because of their heterobinuclear active site and have been studied extensively (3-12). Thiolate-bridged heterobimetallic Ni-Fe complexes, therefore, have also received considerable attention because of their importance as structural, spectroscopic, and functional models for the active site of the enzyme (13-15). The structure of the oxidized inactive form of [NiFe]hydrogenase in Desulfovibrio gigas has been determined by x-ray crystallography (4, 5) and confirms an unusual heterobimetallic Ni-Fe core incorporating two terminal thiolates and two bridging thiolates at the Ni ion, with the bridging thiolates binding to a Fe(CN) 2 (CO) fragment with a Ni-Fe separation of 2.9 Å (Fig. 1). The vast majority of low-molecular-weight mimics have sought to model these structural patterns and this Ni-Fe separation (13-15).Of particular interest to us was the reported x-ray absorption study of [NiFe]hydrogenase from Chromatium vinosum that estimated the Ni-Fe separation as 2.5-2.6 Å in the reduced and active Ni-SI form of the enzyme (16). This finding was further supported by theoretical (17) and mechanistic (18, 19) studies that suggest a shorter Ni-Fe separation (2.5 Å) in the active form of the enzyme compared with that observed in the structure of its oxidized, inactive form (2.9 Å) (4). Furthermore, recent crystal structure determinations of [NiFe]hydrogenases from Desulfovibrio vulgaris Miyazaki F (8) and D. gigas (11) also exhibit shorter Ni-Fe separations (2.55 and 2.53 Å, respectively), while Cramer and coworkers (20) have identified spin-state changes brought about by stereochemical distortion and͞or addition of further ligands at the active site. We therefore were challenged to synthesize low-molecular-weight heterobinuclear Ni-Fe complexes that would mimic not only the short Ni-Fe distance of the Ni-SI, Ni-C, and related reduced centers, but also to model the proposed stereochemical distortions and spin-state changes at the Ni center on binding to Fe fragment(s). Materials and MethodsAll operations were carried out at room temperature under a pure argon atmosphere by using standard Schlenk techniques. [Ni(pdt) (dppe)] (21, 22) and [Fe(CO) 3 (BDA)] (23) (pdt, propanedithiolate; dppe, 1,2-diphenylphosphinoethane; BDA, benzylidene acetone) were prepared by methods described in the literature. Fe 2 (CO) 9 and Fe 3 (CO) 12 were purchased from Aldrich and used as received. All solvents were dried and distilled before use. CH 2 Cl 2 was distilled from CaH 2 and benzene from Na͞benzophenone ketyl under argon. All calculations on complex 3 were carried out with the program ORCA (24). The functional for the geometry optimization was BP86 (25,26), and the basis set was TZVP on lig...

Circulating tumor DNA (ctDNA) is a promising noninvasive biomarker for the early diagnosis of cancers. However, it is challenging for accurate and sensitive detection of pico-to-femtomolar serum concentration of ctDNA, especially in the presence of its analogues that produce strong background noise. Herein, a DNA-rN1-DNA-mediated surface-enhanced Raman scattering frequency shift assay is developed, which enables sensitive detection of ctDNA with one single base pair mutation (KARS G12D mutation) from the normal ones (KARS G12D normal) of lung cancer. This sensing platform features in both the designed hairpin DNA-rN1-DNA probe for specific ctDNA recognition and the employed RNase HII enzyme that specifically hydrolyzes the DNA-rN1-DNA/ctDNA hybrid and thus allows ctDNA recycling in the system to realize signal amplification. The detection system shows sub-femtomolar-level sensitivity in the phosphate-buffered saline solution and is demonstrated to function well in both fetal bovine serum and human physiological media. In particular, the sensitive assay of ctDNA in serum samples from lung cancer patients is achieved, suggesting its high potential applications in clinical settings for early diagnosis and prognosis of lung cancer.

We provided an ultrasensitive sensing strategy for microRNA detection by first employing branched DNA. With the aid of microcontact printing, we realized the multiplex sensing of different kinds of liver cancer biomarkers: microRNA and protein simultaneously. Delicately designed branched DNA included multiple complementary sticky ends as probe to microRNA capture and the double-stranded rigid branched core to increase the active sticky-ends distance and expose more DNA probes for sensitivity. The branched DNA enables 2 orders of magnitude increase in sensitivity for microRNA detection over single-stranded DNA. The limit of detection reaches as low as 10 attomolar (S/N = 3) for miR-223 and 10–12 M for α-fetoprotein. In addition, this system shows high selectivity and appropriate reproducibility (the relative standard deviation is less than 20%) in physiological media. Serum samples are tested and the results of α-fetoprotein are in good agreement with the current gold-standard method, electrochemiluminescence immunoassay analyzer. The results suggest the reliability of this approach in physiological media and show high potential in the sensing of low abundant microRNA in serum, especially for early diagnosis of primary liver cancers.

As a main element in the hard metal industry, cobalt is one of the major components of human metal implants. Cobalt-containing implants, especially joint prostheses used for artificial joint replacement, can be corroded due to the complex physiological environment in vivo, producing a large number of nanoscale cobalt particles (Cobalt Nanoparticles, CoNPs). These CoNPs can be first accumulated around the implant to cause adverse local reactions and then enter into the blood vessels followed by reaching the liver, heart, brain, kidney, and other organs through systematic circulation, which leads to multi-system toxicity symptoms. To ensure the long-term existence of cobalt-containing implants in the body, it is urgently required to find out a safe and effective detoxification drug. Herein, we have demonstrated that CoNPs could induce the ferroptosis-like cell death through the enhancement of intracellular reactive oxygen species (ROS) level, cytoplasmic Fe2+ level, lipid peroxidation, and consumption of reduced glutathione (GSH) as well as inhibition of glutathione peroxidase 4 (GPX4) activity. Importantly, α-lipoic acid (ALA), a natural antioxidant with the capability to scavenge free radicals and chelate toxic metals, was found to efficiently alleviate the adverse effects of CoNPs. The present study illustrates a new mechanism of CoNPs mediated by ferroptosis-like cytotoxicity and discloses an effective method for the detoxification of CoNPs by employing the natural antioxidant of ALA, providing a basis for further in vivo detoxification study.

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Blood analyses for rare-earth element (REE)-high background regions in South Jiangxi show that the population averages of many of the biochemical indices deviate markedly from normal values in the normal region. These deviations are thought to be caused by prolonged intake of REE through food chains in view of that the toxicity of other harmful metals such as Pb and Cd can be neglected because of their insignificant amounts in the environment. In comparison with the normal region, blood biochemical indices abnormal in the REE-high regions are manifested as low total serum protein (TSP), albumin, beta-globulin, glutamic pyruvic transitanase, serium triglycerides, and immunoglobulin, but high cholesterol. These deviations may be related to the REE concentration and composition of food chains, and are sex dependent. Certain blood indices (such as TSP) of different age groups in the LREE-high region indicate that the influence of REE on males is a one-way irreversible process, whereas females show a strong ability of restoration.

Auditory brainstem electric response (ABR) and somatosensory evoked potential (SEP) of 21 subjects (41 ears) among villagers in a rare earth element (REE) area in Gan County, Jiangxi, China, were studied. No difference in ABR between the subjects from the REE area and the control group was noted. However, the conduction detected by SEP from the median nerve to the thalamus (P15) was shortened (P < 0.05), especially to the first-grade primary somatosensory responsive region (S1) (P < 0.01) and the amplitude of S1 decreased (P < 0.05), indicating that REE was difficult to accumulate in the brainstem, but it was susceptible to cerebral cortex, thus causing sub-clinical damage. This condition was confirmed in the animal experiment. It was suggested that the toxicity through long-term intake of small doses of REE might not be negligible, and the hazard of REE environments should be investigated.

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