Nitrogen and sulfur co-doped Ti3C2Tx MXenes for high-rate lithium-ion batteries.

The electrification of heavy-duty transport and aviation urgently requires new strategies to develop high-rate lithium-ion batteries (LIBs) whose performance fundamentally relies on electrode materials. However, commercially available graphite anodes still suffer from slow kinetics of lithium-ion diffusion and severe safety concerns of lithium plating when achieving the high-rate use goal. Herein, taking Ti3C2Tx as an example, it is demonstrated that N and S co-doping in Ti3C2Tx results in a high-rate MXene anode for LIBs. Nitrogen doping not only flattens the MXene layers and expands the interlayer spacing but also increases the Ti valence state change ability. As evidenced by density functional theory calculations, the diffusion barriers of S-containing Ti3C2Tx MXenes are lower than those of the S-free counterpart, suggesting that S plays an essential role in achieving high-rate performance. Therefore, the N and S co-doped Ti3C2Tx anode in LIBs exhibited excellent performance with a reversible capacity of 113.8 mA h g-1 at a rate of 3C and ∼89% capacity retention after 1000 charge/discharge cycles. The high capacity is attributed to the change in the oxidation states of both Ti and O elements, and the tiny volume change within ∼0.6% upon the stable charging/discharging process accounts for the good capacity retention. When paired up with a LiFe0.5Mn0.5PO4 cathode, the full cell delivers a reversible capacity of 134 mA h g-1 after 1000 cycles at a high rate of 1C. The demonstration of N and S co-doped Ti3C2Tx MXenes in this work may offer a feasible approach for high-rate intercalation anode materials.

Enhanced Pitting Corrosion Resistance of Nanostructured AISI 304 Stainless Steel via Pipe Inner Surface Grinding Treatment.

By means of a pipe's inner surface grinding, a single-phase nanostructured austenite was formed on the surface of an AISI 304 stainless steel. The electrochemical corrosion behavior was compared with a coarse-grained counterpart of identical surface roughness. Experimental results show that the nanostructured austenite shows a higher pitting potential and a wider passivation interval than those of its coarse-grained counterpart. The enhanced corrosion resistance was attributed to the fast diffusion of Cr within the nanostructure and, hence, the formation of a thicker passive film to efficiently protect the surface against the ion attack. This work provides insights into a simple processing method to improve the surface strength and pitting resistance of stainless steel.

Patterning of Wafer-Scale MXene Films for High-Performance Image Sensor Arrays.

As a rapidly growing family of 2D transition metal carbides and nitrides, MXenes are recognized as promising materials for the development of future electronics and optoelectronics. So far, the reported patterning methods for MXene films lack efficiency, resolution, and compatibility, resulting in limited device integration and performance. Here, a high-performance MXene image sensor array fabricated by a wafer-scale combination patterning method of an MXene film is reported. This method combines MXene centrifugation, spin-coating, photolithography, and dry-etching and is highly compatible with mainstream semiconductor processing, with a resolution up to 2 µm, which is at least 100 times higher than other large-area patterning methods reported previously. As a result, a high-density integrated array of 1024-pixel Ti3 C2 Tx /Si photodetectors with a detectivity of 7.73 × 1014 Jones and a light-dark current ratio (Ilight /Idark ) of 6.22 × 106 , which is the ultrahigh value among all reported MXene-based photodetectors, is fabricated. This patterning technique paves a way for large-scale high-performance MXetronics compatible with mainstream semiconductor processes.

Diastereoselective Synthesis of 2'-Dihalopyrimidine Ribonucleoside Inhibitors of Hepatitis C Virus Replication.

We present a newly developed synthetic route to 2-bromo-2-fluoro ribolactone based on our published 2-chloro-2-fluoro ribolactone synthesis. Stereoselective fluorination is key to controlling the 2-diastereoselectivity. We also report a substantially improved glycosylation reaction with both the 2-bromo-2-fluoro and 2-chloro-2-fluoro sugars. These improvements allowed us to prepare 2'-dihalo nucleosides 13 and 14 in an overall 15-20% yield.

Understanding charge storage in Nb2CTx MXene as an anode material for lithium ion batteries.

MXenes represent an emerging family of two-dimensional materials of transition metal carbides/carbonitrides terminated with functional groups like -O, -OH, and -F on the chemically active surface of MX slabs. As a member of the family, Nb2CTx exhibits superior lithium storage capacity over most of the other MXenes as anode materials in lithium-ion batteries (LIBs). However, an in-depth understanding of the charge storage mechanism is still lacking so far. Here, through combining complementary experiments and density functional theory calculations, we provide insights into the (de)lithiation process. Specifically, Nb2CTx with dominant -O functional groups stores charge as a result of changes in the oxidation states of both transition metals Nb and O, which is supported by Bader charge analysis showing a significant change in the oxidation states of Nb and O upon lithiation. As monitored by ex situ X-ray diffraction, the interlayer spacing of Nb2CTx changes slightly upon lithium ion (de)intercalation, corresponding to a volume change of only 2.3% with a near zero-strain feature. By coupling with a LiFePO4/C cathode, the full cell presents superior rate capability and cycling stability as well. The insights into the charge storage mechanism of Nb2CTx in this work provide useful guidance for the rational design of MXene-based anode materials for high-performance LIBs.

Fabrication of Low Roughness Gradient Nanostructured Inner Surface on an AISI 304 Stainless Steel Pipe via Ultra-Sonic Rolling Treatment (USRT).

Gradient nanostructure (GNS) has drawn great attention, owing to the unique deformation and properties that are superior to nanostructure with uniform scale. GNS is commonly fabricated via surface plastic deformation with small tips (of balls or shots) so as to produce high deformation to refine the coarse grains, but unfortunately it suffers from the deterioration of surface quality which is hard to guarantee the reliable service. Although there are mirror-finishing techniques that can greatly enhance the surface quality, the induced slight deformation is commonly unable to produce GNS of reasonable thickness. Here, we propose a method to fabricate a GNS surface layer with a substantially enhanced surface quality via ultra-sonic rolling treatment (USRT), namely, surface rolling with a roller vibrated at a frequency of 20,000 Hz. It is found that 4-pass USRT is able to produce 20-30 µm thick GNS on AISI 304 stainless steel pipe inner surface, wherein the surface quality is enhanced by one order of magnitude from the starting Ra = 3.92 µm to 0.19 µm. Processing by a roller with a high-frequency vibration is necessary for both good surface quality and the effective accumulation of heavy deformation on the surface. The flattening mechanism as well as the microstructural evolution from millimeter- to nanometer-scale for AISI 304 stainless steel is discussed.

Intracellular metabolism and potential cardiotoxicity of a ß-D-2'-C-methyl-2,6-diaminopurine ribonucleoside phosphoramidate that inhibits hepatitis C virus replication.

ß-D-2'-C-Methyl-2,6-diaminopurine ribonucleoside (2'-C-Me-DAPN) phosphoramidate prodrug (DAPN-PD) is a selective hepatitis C virus inhibitor that is metabolized intracellularly into two active metabolites: 2'-C-Methyl-DAPN triphosphate (2'-C-Me-DAPN-TP) and 2'-C-methyl-guanosine 5'-triphosphate (2'-C-Me-GTP). BMS-986094 and IDX-184 are also bioconverted to 2'-C-Me-GTP. A phase IIb clinical trial with BMS-986094 was abruptly halted due to adverse cardiac and renal effects. Herein, we developed an efficient large scale synthesis of DAPN-PD and determined intracellular pharmacology of DAPN-PD in comparison with BMS-986094 and IDX-184, versus Huh-7, HepG2 and interspecies primary hepatocytes and human cardiomyocytes. Imaging data of drug treated human cardiomyocytes was found to be most useful in determining toxicity potential as no obvious beating rate change was observed for IDX-184 up to 50 µM up at 48 h. However, with BMS-986094 and DAPN-PD at 10 µM changes to both beat rate and rhythm were noted.

Novel influenza polymerase PB2 inhibitors for the treatment of influenza A infection.

Exploration of the chemical space of known influenza polymerase PB2 inhibitor Pimodivir, was performed by our group. We synthesized and identified compounds 16a and 16b, two novel thienopyrimidine derivatives displaying anti-influenza A activity in the single digit nanomolar range in cell culture. Binding of these unique compounds in the influenza polymerase PB2 pocket was also determined using molecular modeling.

Discovery of a Series of 2'-α-Fluoro,2'-ß-bromo-ribonucleosides and Their Phosphoramidate Prodrugs as Potent Pan-Genotypic Inhibitors of Hepatitis C Virus.

Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of ß-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 µM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.

Maximizing Specific Loss Power for Magnetic Hyperthermia by Hard-Soft Mixed Ferrites.

Maximized specific loss power and intrinsic loss power approaching theoretical limits for alternating-current (AC) magnetic-field heating of nanoparticles are reported. This is achieved by engineering the effective magnetic anisotropy barrier of nanoparticles via alloying of hard and soft ferrites. 22 nm Co0.03 Mn0.28 Fe2.7 O4 /SiO2 nanoparticles reach a specific loss power value of 3417 W g-1metal at a field of 33 kA m-1 and 380 kHz. Biocompatible Zn0.3 Fe2.7 O4 /SiO2 nanoparticles achieve specific loss power of 500 W g-1metal and intrinsic loss power of 26.8 nHm2 kg-1 at field parameters of 7 kA m-1 and 380 kHz, below the clinical safety limit. Magnetic bone cement achieves heating adequate for bone tumor hyperthermia, incorporating an ultralow dosage of just 1 wt% of nanoparticles. In cellular hyperthermia experiments, these nanoparticles demonstrate high cell death rate at low field parameters. Zn0.3 Fe2.7 O4 /SiO2 nanoparticles show cell viabilities above 97% at concentrations up to 500 µg mL-1 within 48 h, suggesting toxicity lower than that of magnetite.

A Fine Grain, High Mn Steel with Excellent Cryogenic Temperature Properties and Corresponding Constitutive Behaviour.

A Fe-34.5 wt % Mn-0.04 wt % C ultra-high Mn steel with a fully recrystallised fine-grained structure was produced by cold rolling and subsequent annealing. The steel exhibited excellent cryogenic temperature properties with enhanced work hardening rate, high tensile strength, and high uniform elongation. In order to capture the unique mechanical behaviour, a constitutive model within finite strain plasticity framework based on Hill-type yield function was established with standard Armstrong-Frederick type isotropic hardening. In particular, the evolution of isotropic hardening was determined by the content of martensite; thus, a relationship between model parameters and martensite content is built explicitly.

Nucleotide Substrate Specificity of Anti-Hepatitis C Virus Nucleoside Analogs for Human Mitochondrial RNA Polymerase.

Nucleoside analog inhibitors (NAIs) are an important class of antiviral agents. Although highly effective, some NAIs with activity against hepatitis C virus (HCV) can cause toxicity, presumably due to off-target inhibition of host mitochondrial RNA polymerase (POLRMT). The in vitro nucleotide substrate specificity of POLRMT was studied in order to explore structure-activity relationships that can facilitate the identification of nontoxic NAIs. These findings have important implications for the development of all anti-RNA virus NAIs.

Biochemical Characterization of the Active Anti-Hepatitis C Virus Metabolites of 2,6-Diaminopurine Ribonucleoside Prodrug Compared to Sofosbuvir and BMS-986094.

Ribonucleoside analog inhibitors (rNAI) target the hepatitis C virus (HCV) RNA-dependent RNA polymerase nonstructural protein 5B (NS5B) and cause RNA chain termination. Here, we expand our studies on ß-d-2'-C-methyl-2,6-diaminopurine-ribonucleotide (DAPN) phosphoramidate prodrug 1 (PD1) as a novel investigational inhibitor of HCV. DAPN-PD1 is metabolized intracellularly into two distinct bioactive nucleoside triphosphate (TP) analogs. The first metabolite, 2'-C-methyl-GTP, is a well-characterized inhibitor of NS5B polymerase, whereas the second metabolite, 2'-C-methyl-DAPN-TP, behaves as an adenosine base analog. In vitro assays suggest that both metabolites are inhibitors of NS5B-mediated RNA polymerization. Additional factors, such as rNAI-TP incorporation efficiencies, intracellular rNAI-TP levels, and competition with natural ribonucleotides, were examined in order to further characterize the potential role of each nucleotide metabolite in vivo Finally, we found that although both 2'-C-methyl-GTP and 2'-C-methyl-DAPN-TP were weak substrates for human mitochondrial RNA (mtRNA) polymerase (POLRMT) in vitro, DAPN-PD1 did not cause off-target inhibition of mtRNA transcription in Huh-7 cells. In contrast, administration of BMS-986094, which also generates 2'-C-methyl-GTP and previously has been associated with toxicity in humans, caused detectable inhibition of mtRNA transcription. Metabolism of BMS-986094 in Huh-7 cells leads to 87-fold higher levels of intracellular 2'-C-methyl-GTP than DAPN-PD1. Collectively, our data characterize DAPN-PD1 as a novel and potent antiviral agent that combines the delivery of two active metabolites.

Synthesis and Evaluation of 2,6-Modified Purine 2'-C-Methyl Ribonucleosides as Inhibitors of HCV Replication.

A variety of 2,6-modified purine 2'-C-methylribonucleosides and their phosphoramidate prodrugs were synthesized and evaluated for inhibition of HCV RNA replication in Huh-7 cells and for cytotoxicity in various cell lines. Cellular pharmacology and HCV polymerase incorporation studies on the most potent and selective compound are reported.

Realizing chemical codoping in TiO2.

We demonstrate experimentally a chemical codoping approach that would simultaneously narrow the band gap and control the band edge positions of TiO2 semiconductors. It is shown that a sequential doping scheme with nitrogen (N) leading the way, followed by phosphorus (P), is crucial for the incorporation of both N and P into the anion sites. Various characterization techniques confirm the formation of the N-P bonds, and as a consequence of chemical codoping, the band gap of TiO2 is reduced from 3.2 eV to 1.8 eV. The realization of chemical codoping could be an important step forward in improving the general performance of electronic and optoelectronic materials and devices.

ß-D-2'-C-Methyl-2,6-diaminopurine Ribonucleoside Phosphoramidates are Potent and Selective Inhibitors of Hepatitis C Virus (HCV) and Are Bioconverted Intracellularly to Bioactive 2,6-Diaminopurine and Guanosine 5'-Triphosphate Forms.

The conversion of selected ß-D-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2'-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2'-C-Me-DAPN-TP and 2'-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2'-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 µM. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.

Asymmetric binding to NS5A by daclatasvir (BMS-790052) and analogs suggests two novel modes of HCV inhibition.

Symmetric, dimeric daclatasvir (BMS-790052) is the clinical lead for a class of picomolar inhibitors of HCV replication. While specific, resistance-bearing mutations at positions 31 and 93 of domain I strongly suggest the viral NS5A as target, structural mechanism(s) for the drugs' activities and resistance remains unclear. Several previous models suggested symmetric binding modes relative to the homodimeric target; however, none can fully explain SAR details for this class. We present semiautomated workflows to model potential receptor conformations for docking. Surprisingly, ranking docked hits with our library-derived 3D-pharmacophore revealed two distinct asymmetric binding modes, at a conserved poly-proline region between 31 and 93, consistent with SAR. Interfering with protein-protein interactions at this membrane interface can explain potent inhibition of replication-complex formation, resistance, effects on lipid droplet distribution, and virion release. These detailed interaction models and proposed mechanisms of action will allow structure-based design of new NS5A directed compounds with higher barriers to HCV resistance.

Room temperature ferromagnetic (Fe1-xCox)3BO5 nanorods.

Cobalt-doped ferroferriborate ((Fe1-xCox)3BO5) nanorods (NRs) are synthesized by a one-pot high-temperature organic-solution-phase method. The aspect ratios of the NRs are tuned by the heating rate. These NRs form via anisotropic growth along twin boundaries of the multiply twinned nuclei. Magnetic properties are dramatically modified by Co substitutional doping, changing from antiferromagnetic order at low temperatures to ferromagnetic above room temperature, with a greatly enhanced magnetic ordering temperature. These anisotropic ferromagnetic NRs with a high ordering temperature may provide a new platform for understanding nanomagnetism and for magnetic applications.

Chutes and ladders in hepatitis C nucleoside drug development.

Chutes and Ladders is an exciting up-and-down-again game in which players race to be the first to the top of the board. Along the way, they will find ladders to help them advance, and chutes that will cause them to move backwards. The development of nucleoside analogs for clinical treatment of hepatitis C presents a similar scenario in which taking shortcuts may help quickly advance a program, but there is always a tremendous risk of being sent backwards as one competes for the finish line. In recent years the treatment options for chronic hepatitis C virus (HCV) infection have expand due to the development of a replicon based in vitro evaluation system, allowing for the identification of multiple drugable viral targets along with a concerted and substantial drug discovery effort. Three major drug targets have reached clinical study for chronic HCV infection: the NS3/4A serine protease, the large phosphoprotein NS5A, and the NS5B RNA-dependent RNA polymerase. Recently, two oral HCV protease inhibitors were approved by the FDA and were the first direct acting anti-HCV agents to result from the substantial research in this area. There are currently many new chemical entities from several different target classes that are being evaluated worldwide in clinical trials for their effectiveness at achieving a sustained virologic response (SVR) (Pham et al., 2004; Radkowski et al., 2005). Clearly the goal is to develop therapies leading to a cure that are safe, widely accessible and available, and effective against all HCV genotypes (GT), and all stages of the disease. Nucleoside analogs that target the HCV NS5B polymerase that have reached human clinical trials is the focus of this review as they have demonstrated significant advantages in the clinic with broader activity against the various HCV GT and a higher barrier to the development of resistant viruses when compared to all other classes of HCV inhibitors.

Adenosine Dioxolane Nucleoside Phosphoramidates as Antiviral Agents for Human Immunodeficiency and Hepatitis B Viruses.

There are currently six nucleoside reverse transcriptase inhibitors (NRTI) that are FDA approved for human clinical use and these remain the backbone of current HIV therapy. In order for these NRTIs to be effective they need to be phosphorylated consecutively by cellular kinases to their triphosphate forms. Herein, we report the synthesis of C-6 modified (-)-ß-D-(2R,4R)-1,3-dioxolane adenosine nucleosides and their nucleotides including our novel phosphoramidate prodrug technology. We have introduced a side chain moiety on the phenol portion of the phosphoramidate to reduce the toxicity potential. The synthesized phosphoramidates displayed up to a 3,600-fold greater potency versus HIV-1 when compared to their corresponding parent nucleoside and were up to 300-fold more potent versus HBV. No cytotoxicity was observed up to 100 µM in the various cell systems tested, except for compound 17 and 18 which displayed a CC50 of 7.3 and 12 µM respectively in Huh-7 cells. The improved and significant dual antiviral activity of these novel phosphoramidate nucleosides was partially explained by the increased intracellular formation of the adenosine dioxolane triphosphate.