Antibacterial and Sterilizing Effect of Benzylpenicillin in Tuberculosis.

The modern chemotherapy era started with Fleming's discovery of benzylpenicillin. He demonstrated that benzylpenicillin did not kill Mycobacterium tuberculosis In this study, we found that >64 mg/liter of static benzylpenicillin concentrations killed 1.16 to 1.43 log10 CFU/ml below starting inoculum of extracellular and intracellular M. tuberculosis over 7 days. When we added the ?-lactamase inhibitor avibactam, benzylpenicillin maximal kill (Emax) of extracellular log-phase-growth M. tuberculosis was 6.80 ± 0.45 log10 CFU/ml at a 50% effective concentration (EC50) of 15.11 ± 2.31 mg/liter, while for intracellular M. tuberculosis it was 2.42 ± 0.14 log10 CFU/ml at an EC50 of 6.70 ± 0.56 mg/liter. The median penicillin (plus avibactam) MIC against South African clinical M. tuberculosis strains (80% either multidrug or extensively drug resistant) was 2 mg/liter. We mimicked human-like benzylpenicillin and avibactam concentration-time profiles in the hollow-fiber model of tuberculosis (HFS-TB). The percent time above the MIC was linked to effect, with an optimal exposure of ?65%. At optimal exposure in the HFS-TB, the bactericidal activity in log-phase-growth M. tuberculosis was 1.44 log10 CFU/ml/day, while 3.28 log10 CFU/ml of intracellular M. tuberculosis was killed over 3 weeks. In an 8-week HFS-TB study of nonreplicating persistent M. tuberculosis, penicillin-avibactam alone and the drug combination of isoniazid, rifampin, and pyrazinamide both killed >7.0 log10 CFU/ml. Monte Carlo simulations of 10,000 preterm infants with disseminated disease identified an optimal dose of 10,000 U/kg (of body weight)/h, while for pregnant women or nonpregnant adults with pulmonary tuberculosis the optimal dose was 25,000 U/kg/h, by continuous intravenous infusion. Penicillin-avibactam should be examined for effect in pregnant women and infants with drug-resistant tuberculosis, to replace injectable ototoxic and teratogenic second-line drugs

Ceftazidime-avibactam has potent sterilizing activity against highly drug-resistant tuberculosis.

There are currently many patients with multidrug-resistant and extensively drug-resistant tuberculosis. Ongoing transmission of the highly drug-resistant strains and high mortality despite treatment remain problematic. The current strategy of drug discovery and development takes up to a decade to bring a new drug to clinical use. We embarked on a strategy to screen all antibiotics in current use and examined them for use in tuberculosis. We found that ceftazidime-avibactam, which is already used in the clinic for multidrug-resistant Gram-negative bacillary infections, markedly killed rapidly growing, intracellular, and semidormant Mycobacterium tuberculosis in the hollow fiber system model. Moreover, multidrug-resistant and extensively drug-resistant clinical isolates demonstrated good ceftazidime-avibactam susceptibility profiles and were inhibited by clinically achievable concentrations. Resistance arose because of mutations in the transpeptidase domain of the penicillin-binding protein PonA1, suggesting that the drug kills M. tuberculosis bacilli via interference with cell wall remodeling. We identified concentrations (exposure targets) for optimal effect in tuberculosis, which we used with susceptibility results in computer-aided clinical trial simulations to identify doses for immediate clinical use as salvage therapy for adults and young children. Moreover, this work provides a roadmap for efficient and timely evaluation of antibiotics and optimization of clinically relevant dosing regimens

Alpha-Tomatine Induces Apoptosis and Inhibits Nuclear Factor-Kappa B Activation on Human Prostatic Adenocarcinoma PC-3 Cells

BACKGROUND: Alpha-tomatine (α-tomatine) is the major saponin in tomato (Lycopersicon esculentum). This study investigates the chemopreventive potential of α-tomatine on androgen-independent human prostatic adenocarcinoma PC-3 cells. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of highly aggressive human prostate cancer PC-3 cells with α-tomatine resulted in a concentration-dependent inhibition of cell growth with a half-maximal efficient concentration (EC(50)) value of 1.67±0.3 µM. It is also less cytotoxic to normal human liver WRL-68 cells and normal human prostate RWPE-1 cells. Assessment of real-time growth kinetics by cell impedance-based Real-Time Cell Analyzer (RTCA) showed that α-tomatine exhibited its cytotoxic effects against PC-3 cells as early as an hour after treatment. The inhibitory effect of α-tomatine on PC-3 cancer cell growth was mainly due to induction of apoptosis as evidenced by positive Annexin V staining and decreased in mitochondrial membrane potential but increased in nuclear condensation, polarization of F-actin, cell membrane permeability and cytochrome c expressions. Results also showed that α-tomatine induced activation of caspase-3, -8 and -9, suggesting that both intrinsic and extrinsic apoptosis pathways are involved. Furthermore, nuclear factor-kappa B (NF-κB) nuclear translocation was inhibited, which in turn resulted in significant decreased in NF-κB/p50 and NF-κB/p65 in the nuclear fraction of the treated cells compared to the control untreated cells. These results provide further insights into the molecular mechanism of the anti-proliferative actions of α-tomatine. CONCLUSION/SIGNIFICANCE: α-tomatine induces apoptosis and inhibits NF-κB activation on prostate cancer cells. These results suggest that α-tomatine may be beneficial for protection against prostate cancer development and progression

In Vitro and In Vivo Anti-Angiogenic Activities of Panduratin A

Targeting angiogenesis has emerged as an attractive and promising strategy in anti-cancer therapeutic development. The present study investigates the anti-angiogenic potential of Panduratin A (PA), a natural chalcone isolated from Boesenbergia rotunda by using both in vitro and in vivo assays.PA exerted selective cytotoxicity on human umbilical vein endothelial cells (HUVECs) with IC(50) value of 6.91 ± 0.85 µM when compared to human normal fibroblast and normal liver epithelial cells. Assessment of the growth kinetics by cell impedance-based Real-Time Cell Analyzer showed that PA induced both cytotoxic and cytostatic effects on HUVECs, depending on the concentration used. Results also showed that PA suppressed VEGF-induced survival and proliferation of HUVECs. Furthermore, endothelial cell migration, invasion, and morphogenesis or tube formation demonstrated significant time- and dose-dependent inhibition by PA. PA also suppressed matrix metalloproteinase-2 (MMP-2) secretion and attenuated its activation to intermediate and active MMP-2. In addition, PA suppressed F-actin stress fiber formation to prevent migration of the endothelial cells. More importantly, anti-angiogenic potential of PA was also evidenced in two in vivo models. PA inhibited neo-vessels formation in murine Matrigel plugs, and angiogenesis in zebrafish embryos.Taken together, our study demonstrated the distinctive anti-angiogenic properties of PA, both in vitro and in vivo. This report thus reveals another biological activity of PA in addition to its reported anti-inflammatory and anti-cancer activities, suggestive of PA's potential for development as an anti-angiogenic agent for cancer therapy

Roadmap on energy harvesting materials

Ambient energy harvesting has great potential to contribute to sustainable development and address growing environmental challenges. Converting waste energy from energy-intensive processes and systems (e.g. combustion engines and furnaces) is crucial to reducing their environmental impact and achieving net-zero emissions. Compact energy harvesters will also be key to powering the exponentially growing smart devices ecosystem that is part of the Internet of Things, thus enabling futuristic applications that can improve our quality of life (e.g. smart homes, smart cities, smart manufacturing, and smart healthcare). To achieve these goals, innovative materials are needed to efficiently convert ambient energy into electricity through various physical mechanisms, such as the photovoltaic effect, thermoelectricity, piezoelectricity, triboelectricity, and radiofrequency wireless power transfer. By bringing together the perspectives of experts in various types of energy harvesting materials, this Roadmap provides extensive insights into recent advances and present challenges in the field. Additionally, the Roadmap analyses the key performance metrics of these technologies in relation to their ultimate energy conversion limits. Building on these insights, the Roadmap outlines promising directions for future research to fully harness the potential of energy harvesting materials for green energy anytime, anywhere

Formation, photoluminescence and charge storage characteristics of Au nanocrystals embedded in amorphous Al2O3 matrix

A method to fabricate Au nanocrystals embedded in amorphous Al2O3 matrix has been developed. The formation of spherically shaped Au nanocrystals has been observed using high-resolution transmission electron microscopy (HRTEM). The Au nanocrystals size distribution is narrow and the average diameters are approximately 5 nm. The photoluminescence and charge storage characteristics of Au nanocrystals embedded in amorphous Al2O3 matrix were investigated. A relatively intense visible photoluminescence was exhibited in the small Au nanocrystals. Good performances in terms of large memory window were also observed

Effects of Ti/Co and Co/Ti systems on the germanosilicidation of poly-Si capped poly-Si1−xGex substrate

Ti/Co and Co/Ti bilayered systems were used for the formation of Co germanosilicide on polysilicon buffered poly-Si1−xGex (x=0.2, 0.3) gate stacks. In both cases, substantial Ge was found to segregate to the grain boundaries at the surface of the polycrystalline silicide (i.e., CoSiGe) films, resulting in a substantial degradation in the sheet resistance and a poor quality of the silicide films. It is shown that Ge is probably being expelled from the poly-SiGe grain and segregates to the grain boundaries during the annealing process, leading to the undesirable sheet resistance and poor film morphology observed from the Co germanosilicide films

Textured Ni(Pt) germanosilicide formation on a condensed Si1-xGex/Si substrate

A study of Ni and Ni(Pt) germanosilicidation on a condensed Si1−xGex/Si substrate was performed. The partial relaxation of the condensed SiGe layer resulted in an improvement in the morphological stability of the germanosilicide through the alleviation of compressive stress. Pt alloying to the Ni film resulted in highly textured Ni(Pt) germanosilicide grains, particularly in the (002) orientation, due to the reduction in the interfacial energy caused by the presence of Pt alloy. Pt atoms diffuse slowly and result in a variation in lattice parameters in the Ni(Pt)SiGe grain as a function of depth. Nevertheless, Pt alloying has increased the morphological stability of the NiPtSiGe film.Published versio

Biomimetic processing of bioactive interface on silicon substrates

To facilitate the implantation of silicon-based devices in vivo, the presence of a biocompatible and bioactive coating is noted to be an essential factor. The objective of this present work is therefore to explore a relatively simple and low cost process to induce the formation of bioactive apatite on silicon. The formation of apatite on silicon was carried out by a biomimetic approach on two orientations of silicon wafer, namely (100) and (111). The samples are functionalized by chemical etching, followed by incubation in a simulated body fluid. Scanning electron microscopy, energy dispersive X-ray analysis, X-ray diffraction analysis, and X-ray photoelectron spectroscopy were carried out. It was found that the growth of apatite is dependent on the orientation of the silicon wafer. Cell culturing experiment further verified the biological performance of the apatite-coated silicon samples

Alternative resistive switching mechanism based on migration of charged counter-ions within conductive polymers

In this paper, an alternative bi-stable resistive switching mechanism for non-volatile organic memory applications is reported. The memory device is formed from a sandwiched structure of Au/polyaniline:poly(4-styrenesulfonic acid) (PANI:PSSH)/ITO and operates via the migration of negatively charged counter-ions (PSS−) within the polymer composite. The electro-statically bonded PSS− within the polymer film segregates at the polymer’s interface upon electrical biasing, serving to disrupt current conduction pathways through the polymer by influencing the resonance state of the conducting main chain. By relocation of this PSS− layer at the polymer interface, electrical conductivity was modulated and an electrical bi-stable device was achieved. The resistive ratio between the ON/OFF states of the device is about 2–3 orders of magnitude, both of which can be read out for up to 500 times with negligible degradation