Cytotoxicity in the Age of Nano: The Role of Fourth Period Transition Metal Oxide Nanoparticle Physicochemical Properties

A clear understanding of physicochemical factors governing nanoparticle toxicity is still in its infancy. We used a systematic approach to delineate physicochemical properties of nanoparticles that govern cytotoxicity. The cytotoxicity of fourth period metal oxide nanoparticles (NPs): TiO2, Cr2O3, Mn2O3, Fe2O3, NiO, CuO, and ZnO increases with the atomic number of the transition metal oxide. This trend was not cell-type specific, as observed in non-transformed human lung cells (BEAS-2B) and human bronchoalveolar carcinoma-derived cells (A549). Addition of NPs to the cell culture medium did not significantly alter pH. Physiochemical properties were assessed to discover the determinants of cytotoxicity: (1) point-of-zero charge (PZC) (i.e., isoelectric point) described the surface charge of NPs in cytosolic and lysosomal compartments; (2) relative number of available binding sites on the NP surface quantified by X-ray photoelectron spectroscopy was used to estimate the probability of biomolecular interactions on the particle surface; (3) band-gap energy measurements to predict electron abstraction from NPs which might lead to oxidative stress and subsequent cell death; and (4) ion dissolution. Our results indicate that cytotoxicity is a function of particle surface charge, the relative number of available surface binding sites, and metal ion dissolution from NPs. These findings provide a physicochemical basis for both risk assessment and the design of safer nanomaterials

The conundrum of increased burden of end-stage renal disease in Asians

The conundrum of increased burden of end-stage renal disease in Asians.BackgroundFew cohort studies have examined the risk of end-stage renal disease (ESRD) among Asians compared with whites and blacks.MethodsTo compare the incidence of ESRD in Asians, whites, and blacks in Northern California, we examined sociodemographic and clinical data on 299,168 adults who underwent a screening health checkup at Kaiser Permanente between 1964 and 1985. Incident cases of ESRD were ascertained by matching patient identifiers with the nationally comprehensive United States Renal Data System ESRD registry.ResultsOverall, 1346 cases of ESRD occurred during 7,837,310 person-years of follow-up. The age-adjusted rate of ESRD (per 100,000 person-years) was 14.0 [95% confidence interval (CI) 10.5-18.5] among Asians, 7.9 (95% CI 6.5-9.5) among whites, and 43.4 (95% CI 36.6-51.4)] among blacks. Controlling for age, gender, educational attainment, diabetes, prior myocardial infarction, serum creatinine, systolic and diastolic blood pressure, proteinuria, hematuria, cigarette smoking, serum total cholesterol, and body mass index increased the risk of ESRD in Asians relative to whites from 1.69 to 2.08 (95% CI 1.61-2.67). By contrast, adjustment for the same covariates decreased the risk of ESRD in blacks relative to whites from 5.30 to 3.28 (95% CI 2.91-3.69).ConclusionFactors contributing to the excess ESRD risk in Asians relative to whites extend beyond usually considered sociodemographic and comorbidity disparities. Strategies aimed at examining novel risk factors for kidney disease and efforts to increase awareness of kidney disease among Asians may reduce ESRD incidence in this high-risk group

Research-based versus clinical serum creatinine measurements and the association of acute kidney injury with subsequent kidney function: findings from the Chronic Renal Insufficiency Cohort study.

Background:Observational studies relying on clinically obtained data have shown that acute kidney injury (AKI) is linked to accelerated chronic kidney disease (CKD) progression. However, prior reports lacked uniform collection of important confounders such as proteinuria and pre-AKI kidney function trajectory, and may be susceptible to ascertainment bias, as patients may be more likely to undergo kidney function testing after AKI. Methods:We studied 444 adults with CKD who participated in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study and were concurrent members of a large integrated healthcare delivery system. We estimated glomerular filtration rate (eGFR) trajectories using serum creatinine measurements from (i) the CRIC research protocol (yearly) and (ii) routine clinical care. We used linear mixed effects models to evaluate the associations of AKI with acute absolute change in eGFR and post-AKI eGFR slope, and explored whether these varied by source of creatinine results. Models were adjusted for demographic characteristics, diabetes status and albuminuria. Results:During median follow-up of 8.5 years, mean rate of eGFR loss was -0.31 mL/min/1.73 m2/year overall, and 73 individuals experienced AKI (55% Stage 1). A significant interaction existed between AKI and source of serum creatinine for acute absolute change in eGFR level after discharge; in contrast, AKI was independently associated with a faster rate of eGFR decline (mean additional loss of -0.67 mL/min/1.73 m2/year), which was not impacted by source of serum creatinine. Conclusions:AKI is independently associated with subsequent steeper eGFR decline regardless of the serum creatinine source used, but the strength of association is smaller than observed in prior studies after taking into account key confounders such as pre-AKI eGFR slope and albuminuria

Maintaining Structural Stability of Poly(lactic acid): Effects of Multifunctional Epoxy based Reactive Oligomers

In order to reduce the effects of hydrolytic degradation and to maintain sufficient viscosity during processing of biomass based poly(l-lactic acid) (PLLA), various epoxy functional reactive oligomers have been characterized and incorporated into the degraded fragments as chain extenders. The molecular weight of PLLA increased with the increase in functionality of the reactive oligomers. No further increase in molecular weight was observed for oligomers with functionality of greater than five. Under our experimental conditions, no gelation was found even when the highest functionality reactive oligomers were used. This is attributed to the preferential reaction of the carboxylic acid versus the negligible reactivity of the hydroxyl groups, present at the two ends of the degraded PLLA chains, with the epoxy groups. The study provides a clear understanding of the degradation and chain extension reaction of poly(lactic acid) (PLA) with epoxy functional reactive oligomers. It is also shown that a higher functionality and concentration of the reactive oligomers is needed, to bring about a sufficient increase in the molecular weight and hence the hydrolytic stability in circumstances when PLA chains suffer significant degradation during processing

WTC2005-64310 TRIBOCHEMICAL REACTIONS AT THE WATER-LUBRICATED SILICON NITRIDE INTERFACE: GEL FORMATION MECHANISM

ABSTRACT Silicon-based ceramics such as silicon nitride can be very effectively lubricated by water under certain conditions (1-3). After a wear-in period a condition of very low friction coefficient (<0.01) can be achieved for average contact pressures of 40 MPa and lower. Tomizawa & Fischer (1) proposed a chemomechanical polishing mechanism to reduce surface roughness enabling the onset of hydrodynamic lubrication by water. We suggest that there is an additional soft hydrated silica gel layer adhering to the rubbing surfaces that provides a deformable protective film to enable effective hydrodynamic lubrication of water and protect the surfaces from occasional asperity contacts. The existence of such films was indicated by the nanomechanical data performed on worn surfaces. EXPERIMENTAL PROCEDURES Ball-on-three-flat (BTF) wear tests were conducted using a gold-coated ball pot to prevent interference from steel contacting the fluid and initiate unwanted tribochemical reactions. Tests were conducted at 600 rpm (0.23 m/s) and 5 kg applied load using silicon nitride specimens and water lubricant. These conditions are sufficient to produce mean Hertzian contact pressures of greater than 0.9 GPa at the beginning of the test, prior to any wear. Water with different pH was used as lubricant and time to achieve tribochemical lubrication (induction time) was measured as well as the wear scar diameter after fixed time periods. The presence of films within the contacting surfaces was observed optically and with AFM. The nanomechanical properties of the films were measured using a Hysitron Triboscope. RESULTS Ball-on-three-flat wear tests (600 rpm, 5 kg) indicated effective lubrication could be achieved in 150 seconds using de-ionized water with neutral pH Figure 1 Water-lubricated silicon nitride BTF test at pH 7 At the beginning of the test, the friction coefficient is quite high: 0.4 to 0.5. It stays high until about 150 seconds into the test when it suddenly drops down to below 0.01 indicating a sudden change in lubrication mechanism has occurred. Mean pressure at the end of the test is approximately 40 MPa. Water taken from the test leaves a silicon-containing residue after evaporation (from dissolved silica) indicating that tribochemical reactions are taking place in the rubbing contact to create very smooth surfaces: Tests conducted using water at pH 1.8 achieved very rapid effective lubrication as shown i

WTC2005-64310 TRIBOCHEMICAL REACTIONS AT THE WATER-LUBRICATED SILICON NITRIDE INTERFACE: GEL FORMATION MECHANISM

ABSTRACT Silicon-based ceramics such as silicon nitride can be very effectively lubricated by water under certain conditions (1-3). After a wear-in period a condition of very low friction coefficient (<0.01) can be achieved for average contact pressures of 40 MPa and lower. Tomizawa & Fischer (1) proposed a chemomechanical polishing mechanism to reduce surface roughness enabling the onset of hydrodynamic lubrication by water. We suggest that there is an additional soft hydrated silica gel layer adhering to the rubbing surfaces that provides a deformable protective film to enable effective hydrodynamic lubrication of water and protect the surfaces from occasional asperity contacts. The existence of such films was indicated by the nanomechanical data performed on worn surfaces. EXPERIMENTAL PROCEDURES Ball-on-three-flat (BTF) wear tests were conducted using a gold-coated ball pot to prevent interference from steel contacting the fluid and initiate unwanted tribochemical reactions. Tests were conducted at 600 rpm (0.23 m/s) and 5 kg applied load using silicon nitride specimens and water lubricant. These conditions are sufficient to produce mean Hertzian contact pressures of greater than 0.9 GPa at the beginning of the test, prior to any wear. Water with different pH was used as lubricant and time to achieve tribochemical lubrication (induction time) was measured as well as the wear scar diameter after fixed time periods. The presence of films within the contacting surfaces was observed optically and with AFM. The nanomechanical properties of the films were measured using a Hysitron Triboscope. RESULTS Ball-on-three-flat wear tests (600 rpm, 5 kg) indicated effective lubrication could be achieved in 150 seconds using de-ionized water with neutral pH Figure 1 Water-lubricated silicon nitride BTF test at pH 7 At the beginning of the test, the friction coefficient is quite high: 0.4 to 0.5. It stays high until about 150 seconds into the test when it suddenly drops down to below 0.01 indicating a sudden change in lubrication mechanism has occurred. Mean pressure at the end of the test is approximately 40 MPa. Water taken from the test leaves a silicon-containing residue after evaporation (from dissolved silica) indicating that tribochemical reactions are taking place in the rubbing contact to create very smooth surfaces: Tests conducted using water at pH 1.8 achieved very rapid effective lubrication as shown i

Maximal Spontaneous Photon Emission and Energy Loss from Free Electrons

Free electron radiation such as Cerenkov, Smith--Purcell, and transition radiation can be greatly affected by structured optical environments, as has been demonstrated in a variety of polaritonic, photonic-crystal, and metamaterial systems. However, the amount of radiation that can ultimately be extracted from free electrons near an arbitrary material structure has remained elusive. Here we derive a fundamental upper limit to the spontaneous photon emission and energy loss of free electrons, regardless of geometry, which illuminates the effects of material properties and electron velocities. We obtain experimental evidence for our theory with quantitative measurements of Smith--Purcell radiation. Our framework allows us to make two predictions. One is a new regime of radiation operation---at subwavelength separations, slower (nonrelativistic) electrons can achieve stronger radiation than fast (relativistic) electrons. The second is a divergence of the emission probability in the limit of lossless materials. We further reveal that such divergences can be approached by coupling free electrons to photonic bound states in the continuum (BICs). Our findings suggest that compact and efficient free-electron radiation sources from microwaves to the soft X-ray regime may be achievable without requiring ultrahigh accelerating voltages.Comment: 7 pages, 4 figure

Mycolactone-dependent depletion of endothelial cell thrombomodulin is strongly associated with fibrin deposition in Buruli ulcer lesions

A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin's substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells' ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone's effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tisischemia could contribute to the development of the tissue necrosis seen in BU lesions

Prime Focus Spectrograph - Subaru's future -

The Prime Focus Spectrograph (PFS) of the Subaru Measurement of Images and Redshifts (SuMIRe) project has been endorsed by Japanese community as one of the main future instruments of the Subaru 8.2-meter telescope at Mauna Kea, Hawaii. This optical/near-infrared multi-fiber spectrograph targets cosmology with galaxy surveys, Galactic archaeology, and studies of galaxy/AGN evolution. Taking advantage of Subaru's wide field of view, which is further extended with the recently completed Wide Field Corrector, PFS will enable us to carry out multi-fiber spectroscopy of 2400 targets within 1.3 degree diameter. A microlens is attached at each fiber entrance for F-ratio transformation into a larger one so that difficulties of spectrograph design are eased. Fibers are accurately placed onto target positions by positioners, each of which consists of two stages of piezo-electric rotary motors, through iterations by using back-illuminated fiber position measurements with a wide-field metrology camera. Fibers then carry light to a set of four identical fast-Schmidt spectrographs with three color arms each: the wavelength ranges from 0.38 {\mu}m to 1.3 {\mu}m will be simultaneously observed with an average resolving power of 3000. Before and during the era of extremely large telescopes, PFS will provide the unique capability of obtaining spectra of 2400 cosmological/astrophysical targets simultaneously with an 8-10 meter class telescope. The PFS collaboration, led by IPMU, consists of USP/LNA in Brazil, Caltech/JPL, Princeton, & JHU in USA, LAM in France, ASIAA in Taiwan, and NAOJ/Subaru.Comment: 13 pages, 11 figures, submitted to "Ground-based and Airborne Instrumentation for Astronomy IV, Ian S. McLean, Suzanne K. Ramsay, Hideki Takami, Editors, Proc. SPIE 8446 (2012)

Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2) : 12-month results from a randomised, double-masked, phase 3 trial

Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth.GATHER2 is a randomised, double-masked, sham-controlled, 24-month, phase 3 trial across 205 retina clinics, research hospitals, and academic institutions globally. To be eligible, patients had to be aged 50 years or older with non-centrepoint-involving geographic atrophy and best corrected visual acuity between 20/25 and 20/320 in the study eye. Eligible patients were randomly assigned (1:1) to monthly avacincaptad pegol 2 mg administered as a 100 μL intravitreal injection or sham for the first 12 months. Randomisation was performed using an interactive response technology system with stratification by factors known to be of prognostic importance in age-related macular degeneration. Patients, investigators, study centre staff, sponsor personnel, and data analysts were masked to treatment allocation. The primary endpoint was geographic atrophy lesion size measured by fundus autofluorescence at baseline, month 6, and month 12. Efficacy and safety analyses were done in the modified intention-to-treat and safety populations, respectively. This trial is registered with ClinicalTrials.gov, NCT04435366.Between June 22, 2020, and July 23, 2021, 1422 patients were screened for eligibility, of whom 448 were enrolled and randomly assigned to avacincaptad pegol 2 mg (n=225) or sham (n=223). One patient in the sham group did not receive study treatment and was excluded from analyses. There were 154 (68%) female patients and 71 (32%) male patients in the avacincaptad pegol 2 mg group, and 156 (70%) female patients and 66 (30%) male patients in the sham group. From baseline to month 12, the mean rate of square-root-transformed geographic atrophy area growth was 0·336 mm/year (SE 0·032) with avacincaptad pegol 2 mg and 0·392 mm/year (0·033) with sham, a difference in growth of 0·056 mm/year (95% CI 0·016-0·096; p=0·0064), representing a 14% difference between the avacincaptad pegol 2 mg group and the sham group. Ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) in the sham group. There were no endophthalmitis, intraocular inflammation, or ischaemic optic neuropathy events over 12 months. To month 12, macular neovascularisation in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and nine (4%) in the sham group, with exudative macular neovascularisation occurring in 11 (5%) in the avacincaptad pegol 2 mg group and seven (3%) in the sham group.Monthly avacincaptad pegol 2 mg was well tolerated and showed significantly slower geographic atrophy growth over 12 months than sham treatment, suggesting that avacincaptad pegol might slow disease progression and potentially change the trajectory of disease for patients with geographic atrophy.Iveric Bio, An Astellas Company