Magnetic Resonance Imaging of Macrophage Response to Radiation Therapy.

BACKGROUND: Magnetic resonance imaging (MRI) is a non-invasive imaging modality which, in conjunction with biopsies, provide a qualitative assessment of tumor response to treatment. Intravenous injection of contrast agents such as fluorine (19F) nanoemulsions labels systemic macrophages, which can, then, be tracked in real time with MRI. This method can provide quantifiable insights into the behavior of tumor-associated macrophages (TAMs) in the tumor microenvironment and macrophage recruitment during therapy. METHODS: Female mice received mammary fat pad injections of murine breast or colon cancer cell lines. The mice then received an intravenous 19F nanoemulsion injection, followed by a baseline 19F MRI. For each cancer model, half of the mice then received 8 Gy of localized radiation therapy (RT), while others remained untreated. The mice were monitored for two weeks for tumor growth and 9F signal using MRI. RESULTS: Across both cohorts, the RT-treated groups presented significant tumor growth reduction or arrest, contrary to the untreated groups. Similarly, the fluorine signal in treated groups increased significantly as early as four days post therapy. The fluorine signal change correlated to tumor volumes irrespective of time. CONCLUSION: These results demonstrate the potential of 19F MRI to non-invasively track macrophages during radiation therapy and its prognostic value with regard to tumor growth.

Learning to Love Computers: Useful Cinema and the Mediation of American Computing, 1958-62.

Cinema has long been used to mediate new technologies as contentious as the atomic bomb, yet historians of technology have largely overlooked mediation processes. This article argues that media are integral to the historical definition, negotiation, and spread of new technologies by demonstrating useful cinema's significance for the social shaping of mainframe computing. When the 1950s' adoption of computers triggered a wave of automation anxiety among working Americans, powerful institutional actors turned to educational, industrial, and documentary films to reshape American public opinion. Films tailored by IBM, the U.S. Navy, and CBS helped quell crises from software labor shortages to the existential threat of pushbutton weapons. Once distributed among educational film channels, however, these films reached increasingly large audiences, spreading and generalizing computerization's narrative inevitability. By tracing films instead of hardware, this article demonstrates the importance of the media-historical approach to studying the social shaping of technology.

Molecular interactions and inhibition of the SARS-CoV-2 main protease by a thiadiazolidinone derivative.

We report molecular interactions and inhibition of the main protease (MPro ) of SARS-CoV-2, a key enzyme involved in the viral life cycle. By using a thiadiazolidinone (TDZD) derivative as a chemical probe, we explore the conformational dynamics of MPro via docking protocols and molecular dynamics simulations in all-atom detail. We reveal the local and global dynamics of MPro in the presence of this inhibitor and confirm the inhibition of the enzyme with an IC50 value of 1.39 ± 0.22 µM, which is comparable to other known inhibitors of this enzyme.

The Path to Progress Preclinical Studies of Age-Related Neurodegenerative Diseases: A Perspective on Rodent and hiPSC-Derived Models.

Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most prevalent age-related neurodegenerative diseases, and currently no effective clinical treatments exist for either, despite decades of clinical trials. The failure to translate preclinical findings into effective treatments is indicative of a problem in the current evaluation pipeline for potential therapeutics. At present, there are no useful animal models for AD and PD research that reflect the entire biology of the diseases, specifically, the more common non-Mendelian forms. Whereas the field continues to seek suitable rodent models for investigating potential therapeutics for these diseases, rodent models have still been used primarily for preclinical studies. Here, we advocate for a paradigm shift toward the application of human-induced pluripotent stem cell (hiPSC)-derived systems for PD and AD modeling and the development of improved human-based models in a dish for drug discovery and preclinical assessment of therapeutic targets.

Fermentation-pyrolysis of fibre waste from a paper recycling mill for the production of fuel products.

A range of energy fuels (ethanol, char, oil/wax and gas) was produced from fibre waste contaminated with plastic through the application of a fermentation-pyrolysis route. The fibre component was first converted to ethanol by simultaneous saccharification and fermentation (SSF), achieving an ethanol concentration of 39.8 g/L. The residue, enriched in lignin and plastics, was subjected to fast pyrolysis at temperatures between 350 and 550 °C. A wax product with a higher heating value (HHV) higher than 28 MJ/kg was obtained for temperatures higher than 450 °C, while values lower than 15 MJ/kg were observed for the oils produced from the untreated waste stream. Pyrolysis at 550 °C produced a wax with an HHV as high as 32.1 MJ/kg, where 51.8% of the energy content of the fermentation residue was transferred. The attractive energy contents of the pyrolysis products were enabled by oxygen removal from the feedstock during fermentation to ethanol.

The TOC159 null mutant of Arabidopsis thaliana is impaired in the accumulation of plastid lipids and phosphatidylcholine.

We used electrospray ionization tandem mass spectrometry to profile glycerolipids in the TOC159 null mutant of Arabidopsis, which is referred to as plastid protein import 2, or ppi2. The goal was to evaluate the impact of a defective atToc159 receptor in the accumulation of plastid lipids. The ppi2 mutant is severely impaired in the accumulation of monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and phosphatidylglycerol (PG), which are major components of the thylakoid membranes. Major molecular species of MGDG and DGDG are drastically decreased, which is consistent with our previous findings of decreased levels of hexadecatrienoic and linolenic acids. Under normal growth conditions, the ppi2 mutant accumulated significantly lower levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI). In the cold-acclimated mutant, the amounts of PE and PI were similar to the wildtype level, which indicates that the ER pathway of lipid synthesis was functional in the mutant. The cold-acclimated ppi2 mutant accumulated increased amounts of phosphatidic acid (PA), which was mirrored by an increase in phospholipase Dα (PLDα) transcript levels. These data suggest that PLDα activity contributed to the accumulation of cold-induced PA in the ppi2 mutant. The accumulation of major molecular species in PA indicates that cold-induced PA originated from the degradation of both plastidial and extraplastidial lipids. Compared with the wildtype, the ppi2 mutant had a low double bond index and high acyl chain length, which is indicative of decreased membrane fluidity. Taken together, these data indicate that a defective atToc159 receptor severely impaired the plastid pathway of lipid synthesis, which negatively affected the synthesis and/or accumulation of PC.

An Improved Protocol for the Production of Lentiviral Vectors.

Lentiviral vectors are an ideal gene-delivery system for large gene-editing tools, such as the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system, due to their high packaging capacity and broad tropism. Here, we present a calcium phosphate-based protocol for lentiviral production and concentration for in vitro and in vivo use. This revised procedure has been optimized to ensure high viral titers and transduction efficiency and is scalable to meet specific production needs.

Improved predictability of peak periphyton in rivers using site-specific accrual periods and long-term water quality datasets.

Prevention of excessive periphyton standing crop (quantified as chlorophyll a) is among primary objectives for river management. Defensible instream nutrient criteria to achieve periphyton chlorophyll a targets at the site scale require robust predictive models. Such models have proved elusive because peak chlorophyll a depends on multiple factors in addition to nutrients. A key predictor may be accrual period, which depends on river flow variability and the flow magnitudes (effective flows, EF) at which periphyton biomass removal is initiated. In this study we used a seven-year dataset from 44 gravel-bed river sites in the Manawatu-Whanganui region, New Zealand, to explore the relative importance of accrual period, nutrients, and other variables in explaining peak chlorophyll a, using a regression approach. We also assessed the effect of combining data from multiple years. Previous empirical studies have used a universal flow metric (3 × median flow) to define accrual period (Da3). We calculated site-specific EF, which varied from 2 × to 15 × median flow. Accrual period based on EF (DaEF) outperformed Da3 in models. However, in the study region, more variance in chlorophyll a was explained by conductivity (EC) and dissolved inorganic nitrogen (DIN) than by DaEF. The best models derived from multi-year datasets included EC, DIN and DaEF as predictors and accounted for up to 82% of the variance in peak chlorophyll a. Models from annual data were weaker and more variable in strength and predictors. The models indicated that EC and DaEF should be considered when setting DIN criteria for periphyton outcomes in the study region. The principles we used in developing the models may have broad relevance to the management of periphyton in other regions.

Hippocampal CA2 Organizes CA1 Slow and Fast γ Oscillations during Novel Social and Object Interaction.

A key goal in hippocampal research is to understand how neuronal activity is generated and organized across hippocampal subregions to enable memory formation and retrieval. Neuronal activity in CA2 is regulated by spatial and social investigation as well as by novelty (Mankin et al., 2015; Alexander et al., 2016), and CA2 activity controls population oscillatory activity in the slow γ and ripple ranges within hippocampus (Kay et al., 2016; Oliva et al., 2016; Boehringer et al., 2017; Alexander et al., 2018). CA2 neurons are also required for social recognition memory (Stevenson and Caldwell, 2012; Hitti and Siegelbaum, 2014; Smith et al., 2016). Because CA1 exhibits layer-specific organization (Scheffer-Teixeira et al., 2012; Lasztóczi and Klausberger, 2014, 2016) reflective of its inputs (Fernández-Ruiz et al., 2012; Schomburg et al., 2014), and because CA2 activity controls CA1 slow γ (Alexander et al., 2018), we hypothesized that silencing CA2 would affect CA1 slow γ in a layer-specific manner during investigation of a novel social stimulus. While recording from CA1, we leveraged molecular tools to selectively target and inhibit CA2 pyramidal cells using inhibitory DREADDs while subject mice investigated novel animals or objects. We found that CA2 inhibition reduced slow γ power during investigation of a novel animal and fast γ power during both novel object and animal investigation in a manner reflective of the CA2 axonal projection zones within CA1. Our results suggest that CA2 contributes to CA1 slow and fast γ oscillations in a stimulus-specific manner.

Fully implantable neural recording and stimulation interfaces: Peripheral nerve interface applications.

BACKGROUND: Peripheral nerve interfacing has many applications ranging from investigation of neural signals to therapeutic intervention for varied diseases. This need has driven technological advancements in the field of electrode arrays and wireless systems for in-vivo electrophysiological experiments. Hence we present our fully implantable, programmable miniaturized wireless stimulation and recording devices. NEW METHOD: The method consists of technological advancements enabling implantable wireless recording up to 128 channels with a sampling rate of 50Khz and stimulation up to ±4 mA from 15 independent channels. The novelty of the technique consists of induction charging cages which enables freely moving small animals to undergo continuous electrophysiological and behavioral studies without any impediments. The biocompatible hermetic packaging technology for implantable capsules ensures stability for long-term chronic studies. RESULTS: Electromyographs wirelessly recorded from leg muscles of a macaque and a rat using implantable technology are presented during different behavioral task studies. The device's simultaneous stimulation and recording capabilities are reported when interfaced with the vagus and pelvic nerves. COMPARISON WITH EXISTING METHOD(S): The wireless interfacing technology has a large number of recording and stimulating channels without compromising on the signal quality due to sampling rates or stimulating current output capabilities. The induction charging technology along with transceiver and software interface allows experiments on multiple animals to be carried out simultaneously. CONCLUSIONS: This customizable technology using wireless power transmission, reduced battery size, and miniaturized electronics has paved way for a robust, fully implantable, hermetic neural interface system enabling the study of bioelectronic medical therapies.

CA2 neuronal activity controls hippocampal low gamma and ripple oscillations.

Hippocampal oscillations arise from coordinated activity among distinct populations of neurons and are associated with cognitive functions. Much progress has been made toward identifying the contribution of specific neuronal populations in hippocampal oscillations, but less is known about the role of hippocampal area CA2, which is thought to support social memory. Furthermore, the little evidence on the role of CA2 in oscillations has yielded conflicting conclusions. Therefore, we sought to identify the contribution of CA2 to oscillations using a controlled experimental system. We used excitatory and inhibitory DREADDs to manipulate CA2 neuronal activity and studied resulting hippocampal-prefrontal cortical network oscillations. We found that modification of CA2 activity bidirectionally regulated hippocampal and prefrontal cortical low-gamma oscillations and inversely modulated hippocampal ripple oscillations in mice. These findings support a role for CA2 in low-gamma generation and ripple modulation within the hippocampus and underscore the importance of CA2 in extrahippocampal oscillations.

Entrapped Sediments as a Source of Phosphorus in Epilithic Cyanobacterial Proliferations in Low Nutrient Rivers.

Proliferations of the benthic mat-forming cyanobacteria Phormidium have been reported in rivers worldwide. Phormidium commonly produces natural toxins which pose a health risk to animal and humans. Recent field studies in New Zealand identified that sites with Phormidium proliferations consistently have low concentrations of water column dissolved reactive phosphorus (DRP). Unlike other river periphyton, Phormidium mats are thick and cohesive, with water and fine sediment trapped in a mucilaginous matrix. We hypothesized that daytime photosynthetic activity would elevate pH inside the mats, and/or night time respiration would reduce dissolved oxygen. Either condition could be sufficient to facilitate desorption of phosphates from sediment incorporated within mats, thus allowing Phormidium to utilize it for growth. Using microelectrodes, optodes and pulse amplitude modulation fluorometry we demonstrated that photosynthetic activity results in elevated pH (>9) during daytime, and that night-time respiration causes oxygen depletion (<4 mg L-1) within mats. Water trapped within the mucilaginous Phormidium mat matrix had on average 320-fold higher DRP concentrations than bulk river water and this, together with elevated concentrations of elements, including iron, suggest phosphorus release from entrapped sediment. Sequential extraction of phosphorus from trapped sediment was used to investigate the role of sediment at sites on the Mangatainoka River (New Zealand) with and without Phormidium proliferations. Deposition of fine sediment (<63 µm) was significantly higher at the site with the most extensive proliferations and concentrations of biological available phosphorus were two- to four- fold higher. Collectively these results provide evidence that fine sediment can provide a source of phosphorus to support Phormidium growth and proliferation.

Efficient photoelectrochemical water oxidation over cobalt-phosphate (Co-Pi) catalyst modified BiVO4/1D-WO3 heterojunction electrodes.

We report the design, synthesis and photoelectrochemical characterization of cobalt phosphate (Co-Pi) oxygen evolution catalyst modified heterojunction photoelectrodes consisting of one-dimensional WO3 nanorods (1D-WO3) and highly porous BiVO4 layers. The 1D-WO3 nanorods were prepared by the decomposition of the tetrabutylammonium decatungstate precursor in the presence of poly(ethylene glycol) as a binding agent. The porous BiVO4 layers were spray deposited using a surfactant assisted metal-organic decomposition method. The Co-Pi oxygen evolution catalyst was deposited onto the BiVO4/1D-WO3/FTO heterojunction electrode using a photoassisted electrodeposition method. The Co-Pi catalyst modified heterojunction electrodes exhibited a sustained enhancement in the photocurrent compared to the unmodified BiVO4/1D-WO3/FTO heterojunction electrodes. The improved photoelectrochemical properties profited from the enhanced charge carrier separation achieved through the integration of highly porous BiVO4 layers on top of 1D-WO3 nanorods and from the superior kinetics due to the presence of the Co-Pi oxygen evolution catalyst on top of BiVO4/1D-WO3/FTO heterojunction electrodes.

BiVO(4)/CuWO(4) heterojunction photoanodes for efficient solar driven water oxidation.

BiVO(4)/CuWO(4) heterojunction electrodes were prepared using spray deposition of a highly porous bismuth vanadate film onto the surface of an electrodeposited three dimensional network connected copper tungstate. Bilayer BiVO(4)/CuWO(4)/fluorine doped tin oxide glass (FTO) electrodes demonstrated higher photocurrent magnitudes than either with BiVO(4)/FTO or CuWO(4)/FTO electrodes in 1.0 M Na(2)SO(4) electrolyte buffered at pH 7. The photocurrent is enhanced by the formation of the heterojunction that aids charge carrier collection brought about by the band edge offsets. When the pH 7 buffered electrolytes contained 1.0 M bicarbonate is employed instead of 1.0 M sulfate, the charge transfer resistance was decreased. This led to nearly 1.8 times the photocurrent density at 1.0 V vs. Ag/AgCl. The photocurrent was stable over 24 hours in bicarbonate electrolyte.

Light induced water oxidation on cobalt-phosphate (Co-Pi) catalyst modified semi-transparent, porous SiO2-BiVO4 electrodes.

A facile and simple procedure for the synthesis of semi-transparent and porous SiO2-BiVO4 electrodes is reported. The method involves a surfactant assisted metal-organic decomposition at 500 °C. An earth abundant oxygen evolution catalyst (OEC), cobalt phosphate (Co-Pi), has been used to modify the SiO2-BiVO4 electrode by electrodeposition (ED) and photoassisted electrodeposition (PED) methods. Modified electrodes by these two methods have been examined for light induced water oxidation and compared to the unmodified SiO2-BiVO4 electrodes by various photoelectrochemical techniques. The PED method was a more effective method of OEC preparation than the ED method as evidenced by an increased photocurrent magnitude during photocurrent-potential (I-V) characterizations. Electrode surfaces catalyzed by PED exhibited a very large cathodic shift (∼420 mV) in the onset potential for water oxidation. The chopped-light I-V measurements performed at different intervals over 24-hour extended testing under illumination and applied bias conditions show a fair photostability for PED Co-Pi modified SiO2-BiVO4.