Search

The land cover across the HKH region is changing at an accelerated rate due to the rapid economic growth and population pressures that are impacting the long-term sustainability of ecosystems.

Autologous, CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplantation is a promising strategy for achieving HIV remission. However, only a fraction of HSPCs can be editedex vivoto provide protection against infection prior to autologous transplantation. The optimal transplantation conditions for achieving viral control in the absence of suppressive antiretroviral therapy (ART) are still unknown. We analyzed data from SHIV-1157ipd3N4-infected juvenile pig-tailed macaques that underwent autologous HSPC transplantation with and without CCR5 gene editing. We developed a mathematical model that recapitulates reconstitution of T cell subset counts and SHIV plasma viral loads in control and transplanted macaques. The model predicts that viral control can be obtained following ART treatment interruption (ATI) when: 1) levels of transplanted HSPCs are at least 10-fold higher than residual endogenous HSPCs after total body irradiation and 2) the fraction of protected HSPCs in the transplant achieves a threshold (73%-90%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, then spontaneous viral control is projected to occur immediately. Our results support strategies that 1) increase stem cell dose, 2) enhance potency of conditioning regimen, 3) elevate fraction of gene modified SHIV-resistant cells, 4) extend periods between HSPC transplantation and ATI with tracking of CD4+CCR5-cell recovery and / or 5) augment anti-SHIV immunity to achieve sustained SHIV remission.One Sentence SummaryAutologous transplantation of ΔCCR5 HSPCs may induce post-ATI SHIV control when the gene-edited cell dose is sufficient to overcome SHIV immunity loss.

Covellite-phase CuS and carrollite-phase CuCo

Declining populations of Zizania palustris L. (northern wildrice, or wildrice) during the last century drives the demand for new and innovative techniques to support monitoring of this culturally and ecologically significant crop wild relative. We trained three wildrice detection models in R and Google Earth Engine using data from annual aquatic vegetation surveys in northern Minnesota. Three different training datasets, varying in the definition of wildrice presence, were combined with Landsat 8 Operational Land Imager (OLI) and Sentinel-1 C-band synthetic aperture radar (SAR) imagery to map wildrice in 2015 using random forests. Spectral predictors were derived from phenologically important time periods of emergence (June–July) and peak harvest (August–September). The range of the Vertical Vertical (VV) polarization between the two time periods was consistently the top predictor. Model outputs were evaluated using both point and area-based validation (polygon). While all models performed well in the point validation with percent correctly classified ranging from 83.8% to 91.1%, we found polygon validation necessary to comprehensively assess wildrice detection accuracy. Our practical approach highlights a variety of applications that can be applied to guide field excursions and estimate the extent of occurrence at landscape scales. Further testing and validation of the methods we present may support multiyear monitoring which is foundational for the preservation of wildrice for future generations.

Masks are a vital tool for limiting SARS-CoV-2 spread in the population. Here we utilize a mathematical model to assess the impact of masking on transmission within individual transmission pairs and at the population level. Our model quantitatively links mask efficacy to reductions in viral load and subsequent transmission risk. Our results reinforce that the use of masks by both a potential transmitter and exposed person substantially reduces the probability of successful transmission, even if masks only lower exposure viral load by ~50%. Slight increases in masking relative to current levels would reduce the reproductive number substantially below 1, particularly if implemented comprehensively in potential super-spreader environments. Our model predicts that moderately efficacious masks that reduce transmission risk by 50% will lower exposure viral load 10-fold among people who do get infected, potentially limiting infection severity. Because peak viral load tends to occur pre-symptomatically, we also identify that antiviral therapy targeting symptomatic individuals is unlikely to impact transmission risk. Instead, antiviral therapy is only effective for this indication as post-exposure prophylaxis, specifically if given to ~50% of newly infected people within 3 days of an exposure. These results highlight the primacy of masking relative to other biomedical interventions under consideration for limiting the extent of the COVID-19 pandemic prior to widespread implementation of a vaccine.

SARS-CoV-2 is difficult to contain because many transmissions occur during the pre-symptomatic phase of infection. Moreover, in contrast to influenza, while most SARS-CoV-2 infected people do not transmit the virus to anybody, a small percentage secondarily infect large numbers of people. We designed mathematical models of SARS-CoV-2 and influenza which link observed viral shedding patterns with key epidemiologic features of each virus, including distributions of the number of secondary cases attributed to each infected person (individual R0) and the duration between symptom onset in the transmitter and secondarily infected person (serial interval). We identify that people with SARS-CoV-2 or influenza infections are usually contagious for fewer than one day congruent with peak viral load several days after infection, and that transmission is unlikely below a certain viral load. SARS-CoV-2 super-spreader events with over 10 secondary infections occur when an infected person is briefly shedding at a very high viral load and has a high concurrent number of exposed contacts. The higher predisposition of SARS-CoV-2 towards super-spreading events is not due to its 1–2 additional weeks of viral shedding relative to influenza. Rather, a person infected with SARS-CoV-2 exposes more people within equivalent physical contact networks than a person infected with influenza, likely due to aerosolization of virus. Our results support policies that limit crowd size in indoor spaces and provide viral load benchmarks for infection control and therapeutic interventions intended to prevent secondary transmission., One Sentence Summary: We developed a coupled within-host and between-host mathematical model to identify viral shedding levels required for transmission of SARS-CoV-2 and influenza, and to explain why super-spreading events occur more commonly during SARS-CoV-2 infection.

In HIV prevention trials, precise identification of infection time is critical to quantify drug efficacy but difficult to estimate as trials may have relatively sparse visit schedules. The last negative visit does not guarantee a boundary on infection time because viral nucleic acid is not present in the blood during early infection. Here, we developed a framework that combines stochastic and deterministic within-host mathematical modeling of viral dynamics accounting for the early unobservable viral load phase until it reaches a high chronic set point. The infection time estimation is based on a population non-linear mixed effects (pNLME) framework that includes the with-in host modeling. We applied this framework to viral load data from the RV217 trial and found a parsimonious model capable of recapitulating the viral loads. When adding the stochastic and deterministic portion of the best model, the estimated infection time for the RV217 data had an average of 2 weeks between infecting exposure and first positive. We assessed the sensitivity of the infection time estimation by conducting in silico studies with varying viral load sampling schemes before and after infection. pNLME accurately estimates infection times for a daily sampling scheme and is fairly robust to sparser schemes. For a monthly sampling scheme before and after first positive bias increases to -7 days. For pragmatic trial design, we found sampling weekly before and monthly after first positive allows accurate pNLME estimation. Our estimates can be used in parallel with other approaches that rely on viral sequencing, and because the model is mechanistic, it is primed for future application to infection timing for specific interventions.

Satellite remote sensing plays an important role in the monitoring of surface water for historical analysis and near real-time applications. Due to its cloud penetrating capability, many studies have focused on providing efficient and high quality methods for surface water mapping using Synthetic Aperture Radar (SAR). However, few studies have explored the effects of SAR pre-processing steps used and the subsequent results as inputs into surface water mapping algorithms. This study leverages the Google Earth Engine to compare two unsupervised histogram-based thresholding surface water mapping algorithms utilizing two distinct pre-processed Sentinel-1 SAR datasets, specifically one with and one without terrain correction. The resulting surface water maps from the four different collections were validated with user-interpreted samples from high-resolution Planet Scope data. It was found that the overall accuracy from the four collections ranged from 92% to 95% with Cohen’s Kappa coefficients ranging from 0.7999 to 0.8427. The thresholding algorithm that samples a histogram based on water edge information performed best with a maximum accuracy of 95%. While the accuracies varied between methods it was found that there is no statistical significant difference between the errors of the different collections. Furthermore, the surface water maps generated from the terrain corrected data resulted in a intersection over union metrics of 95.8%–96.4%, showing greater spatial agreement, as compared to 92.3%–93.1% intersection over union using the non-terrain corrected data. Overall, it was found that algorithms using terrain correction yield higher overall accuracy and yielded a greater spatial agreement between methods. However, differences between the approaches presented in this paper were not found to be significant suggesting both methods are valid for generating accurate surface water maps. High accuracy surface water maps are critical to disaster planning and response efforts, thus results from this study can help inform SAR data users on the pre-processing steps needed and its effects as inputs on algorithms for surface water mapping applications.

Heterojunctions between p-type cuprous oxide (Cu2O) and suitable n-type layers stand out as some of the best performing and abundant oxide photoabsorbers currently available for the generation of hydrogen with photoelectrochemical cells or conversion of solar energy to electricity. In this contribution, we used drift-diffusion semiconductor modeling to investigate the mechanism governing the charge transport in TiO2/Ga2O3/Cu2O and TiO2/Al:ZnO/Cu2O heterojunctions. The simulated photovoltage 0.9 V for TiO2/Ga2O3/Cu2O agrees well with the measured value of 1.0 V and the governing mechanism is identified to be thermionic emission of electrons across the Ga2O3/TiO2 interface. By modeling an optimized increase in Ga2O3 donor concentration, a photovoltage improvement of only 0.1 V is achievable, whereas further optimizing the electron affinity of Ga2O3 may lead to more significant improvement approaching 0.7 V. The optimized electron affinity of Ga2O3 enabled a simulated photovoltage of 1.6 V, close to the theoretical limit for Cu2O with a 2.17 eV bandgap energy. Additionally, we find that simulations can reproduce the measured photovoltage of TiO2/Al:ZnO/Cu2O only when an interface recombination layer at the Al:ZnO/Cu2O interface is included in the model. Our findings enable detailed understanding of the charge transport mechanism in Cu2O heterojunctions and offer various design directions for further photovoltage improvement.

Floods and water-related disasters impact local populations across many regions in Southeast Asia during the annual monsoon season. Satellite remote sensing serves as a critical resource for generating flood maps used in disaster efforts to evaluate flood extent and monitor recovery in remote and isolated regions where information is limited. However, these data are retrieved by multiple sensors, have varying latencies, spatial, temporal, and radiometric resolutions, are distributed in different formats, and require different processing methods making it difficult for end-users to use the data. SERVIR-Mekong has developed a near real-time flood service, HYDRAFloods, in partnership with Myanmar’s Department of Disaster Management that leverages Google Earth Engine and cloud computing to generate automated multi-sensor flood maps using the most recent imagery available of affected areas. The HYDRAFloods application increases the spatiotemporal monitoring of hydrologic events across large areas by leveraging optical, SAR, and microwave remote sensing data to generate flood water extent maps. Beta testing of HYDRFloods conducted during the 2019 Southeast Asia monsoon season emphasized the importance of multi-sensor observations as frequent cloud cover limited useable imagery for flood event monitoring. Given HYDRAFloods’ multi-sensor approach, cloud-based resources offer a means to consolidate and streamline the process of accessing, processing, and visualizing flood maps in a more cost effective and computationally efficient way. The HYDRAFlood’s cloud-based approach enables a consistent, automated methodology for generating flood extent maps that are made available through a single, tailored, mapviewer that has been customized based on end-user feedback, allowing users to switch their focus to using data for disaster response.

SUMMARYAlthough there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and constitute clinical correlates of recovery from infection. To examine the human neutralizing antibody response to HBV in elite neutralizers we screened 144 individuals. The top individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection, but selected for resistance mutations in mice with established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. The co-crystal structure of one of the bNAbs with a peptide epitope containing residues frequently mutated in human immune escape variants revealed a loop anchored by oppositely charged residues. The structure provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.

ispartof: MATERIALS TODAY CHEMISTRY vol:23 status: published

Schistosomiasis is of public health importance to an estimated one billion people in 79 countries. A vaccine is urgently needed. Here, we report the results of four independent, double-blind studies of an Sm-p80-based vaccine in baboons. The vaccine exhibited potent prophylactic efficacy against transmission of Schistosoma mansoni infection and was associated with significantly less egg-induced pathology, compared with unvaccinated control animals. Specifically, the vaccine resulted in a 93.45% reduction of pathology-producing female worms and significantly resolved the major clinical manifestations of hepatic/intestinal schistosomiasis by reducing the tissue egg-load by 89.95%. A 35-fold decrease in fecal egg excretion in vaccinated animals, combined with an 81.51% reduction in hatching of eggs into the snail-infective stage (miracidia), demonstrates the parasite transmission-blocking potential of the vaccine. Substantially higher Sm-p80 expression in female worms and Sm-p80-specific antibodies in vaccinated baboons appear to play an important role in vaccine-mediated protection. Preliminary analyses of RNA sequencing revealed distinct molecular signatures of vaccine-induced effects in baboon immune effector cells. This study provides comprehensive evidence for the effectiveness of an Sm-p80-based vaccine for schistosomiasis.

Background:Most infants with congenital Cytomegalovirus (CMV) infection are born to seropositive women as a result of maternal CMV nonprimary infection (reinfection or reactivation). Although infected children are known to transmit CMV to their seronegative mothers, the frequency and magnitude of no

Although large research efforts have been devoted to photoelectrochemical (PEC) water splitting in the past several decades, the lack of efficient, stable and Earth-abundant photoelectrodes remains a bottleneck for practical application. Here, we report a photocathode with a coaxial nanowire structure implementing a Cu2O/Ga2O3-buried p–n junction that achieves efficient light harvesting across the whole visible region to over 600 nm, reaching an external quantum yield for hydrogen generation close to 80%. With a photocurrent onset over +1 V against the reversible hydrogen electrode and a photocurrent density of ~10 mA cm−2 at 0 V versus the reversible hydrogen electrode, our electrode constitutes the best oxide photocathode for catalytic generation of hydrogen from sunlight known today. Conformal coating via atomic-layer deposition of a TiO2 protection layer enables stable operation exceeding 100 h. Using NiMo as the hydrogen evolution catalyst, an all Earth-abundant Cu2O photocathode was achieved with stable operation in a weak alkaline electrolyte. To show the practical impact of this photocathode, we constructed an all-oxide unassisted solar water splitting tandem device using state-of-the-art BiVO4 as the photoanode, achieving ~3% solar-to-hydrogen conversion efficiency. The generation of hydrogen fuel from water and visible light requires photoelectrodes that are inexpensive, stable and highly active. Now, Luo, Gratzel and co-workers report Cu2O photocathodes that reach these goals. Incorporation into an unassisted solar water splitting device gives ~3% solar-to-hydrogen conversion efficiency.

In situ cancer vaccines are under active clinical investigation, given their reported ability to eradicate both local and disseminated malignancies. Intratumoral vaccine administration is thought to activate a T cell-mediated immune response, which begins in the treated tumor and cascades systemically. In this study, we describe a PET tracer (64Cu-DOTA-AbOX40) that enabled noninvasive and longitudinal imaging of OX40, a cell-surface marker of T cell activation. We report the spatiotemporal dynamics of T cell activation following in situ vaccination with CpG oligodeoxynucleotide in a dual tumor-bearing mouse model. We demonstrate that OX40 imaging was able to predict tumor responses on day 9 after treatment on the basis of tumor tracer uptake on day 2, with greater accuracy than both anatomical and blood-based measurements. These studies provide key insights into global T cell activation following local CpG treatment and indicate that 64Cu-DOTA-AbOX40 is a promising candidate for monitoring clinical cancer immunotherapy strategies.

Low-temperature planar organic–inorganic lead halide perovskite solar cells have been at the center of attraction as power conversion efficiencies go beyond 20%. Here, we investigate Nb doping of SnO2 deposited by a low-cost, scalable chemical bath deposition (CBD) method. We study the effects of doping on compositional, structural, morphological, and device performance when these layers are employed as electron-selective layers (ESLs) in planar-structured PSCs. We use doping concentrations of 0, 1, 5, and 10 mol % Nb to Sn in solution. The ESLs were characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, atomic force microscopy, and ultraviolet–visible spectroscopy. ESLs with an optimum 5 mol % Nb doping yielded, on average, an improvement of all the device photovoltaic parameters with a champion power conversion efficiency of 20.5% (20.1% stabilized).

BACKGROUND & AIMS Pancreatic ductal adenocarcinoma (PDA) patients have not yet benefitted from the revolution in cancer immunotherapy due in large part to a dominantly immunosuppressive tumor microenvironment (TME). MEK inhibition combined with autophagy inhibition leads to transient tumor responses in some PDA patients. We examined the functional effects of combined MEK and autophagy inhibition on the PDA immune microenvironment and the efficacy of synergizing the combined inhibition of MEK and autophagy with CD40 agonism against PDA using immunocompetent model systems. METHODS We implanted immunologically "cold" murine PDA cells orthotopically in WT C57BL/6J mice. We administered combinations of inhibitors of MEK1/2, inhibitors of autophagy and CD40 agonism and measured anticancer efficacy and immune sequel using mass cytometry (CyTOF) and CODEX multiplexed immunofluorescence imaging analysis to characterize the TME. We also used human and mouse PDA cell lines and human macrophages in vitro, to perform functional assays to elucidate the cellular effects induced by the treatments. RESULTS We find that co-inhibition of MEK (using cobimetinib, COBI) and autophagy (using mefloquine, MFQ), but not either treatment alone, activates the STING/Type I Interferon pathway in tumor cells which in turn activates paracrine tumor associated macrophages (TAMs) toward an immunogenic M1-like phenotype. This switch is further augmented by a CD40 agonism (aCD40). Triple therapy (COBI+MFQ+aCD40) achieved cytotoxic T cell activation in an immunologically "cold" mouse PDA model, leading to enhanced anti-tumor immunity. CONCLUSIONS MEK and autophagy co-inhibition coupled with CD40 agonism invokes immuno-repolarization and is an attractive therapeutic approach for PDA immunotherapy development.

Cu2S has been regarded as a promising solar energy conversion material because of its favorable visible light absorption and earth abundance. Here, we present an indirect preparation method via a solution-processed ion exchange reaction to synthesize stoichiometric Cu2S films with high photoactivity. In addition, we developed a chemical bath deposition method to fabricate CdS buffer layers on Cu2S by adding a reducing agent in the precursor solution, avoiding oxidation of Cu2S. After being coated with the TiO2 protection layer and the RuOx hydrogen evolution catalyst, the Cu2S photoelectrode delivers a photocurrent density of 7.0 mA cm–2 at −0.3 V vs RHE and an onset potential of 0.48 V vs RHE under AM 1.5G simulated sunlight illumination for solar driven water reduction. To our knowledge, this is the first time that Cu2S has been used for solar hydrogen evolution with encouraging performance, which will stimulate further studies on Cu-based photocathodes.

Cost and resource efficiency of Laser Beam Melting (LBM) highly depend on powder recycling procedures. Non-solidified powder can be sieved and reused in subsequent build cycles. However, due to quality concerns, powder recycling is not commonly practiced. One effect, which can impair the powder quality, lies in the formation and insertion of spatter particles during the melting process. In this paper, spatter particles emerging during LBM of AlSi10Mg are characterized regarding geometric (size, morphology), chemical (alloy composition, oxygen content, oxide layer thickness) properties as well as mass. Spatter particles are collected during the process using two isolation methods. Three types of spatter particles can be differentiated by their formation mechanism. It is found that spatter particles can differ significantly in oxide layer thickness and particle size. A significant share of spatter particles can be segregated by sieving. However, a certain fraction of the spatter particles will be included in the recycled powder.

The most limiting factor for the commercialization of perovskite solar cells is the lack of long-term stability under operating conditions. To examine the intrinsic stability of the perovskite film, we investigated the chemical and electronic properties of methylammonium lead triiodide (CH3NH3PbI3) perovskite by in situ X-ray photoelectron spectroscopy (XPS). In particular, XPS data were collected under dark conditions, at applied voltage, under illumination, at open circuit, and under operating conditions. In addition, operation in ambient air atmosphere was analysed by XPS. It was observed that the chemical properties of methylammonium lead triiodide change upon illumination under open-circuit condition by formation of metallic lead species and then by conversion into PbI2 due to evaporation of the organic compounds. These changes, however, can be restricted by applying an extraction voltage to the device contacts that will extract the photogenerated charges from the absorber. As these results were obtained in vacuum, i.e., in an inert atmosphere, experiments prove that the photogenerated charge carriers intrinsically induce changes in chemical and electronic properties if they are not extracted from the absorber. By illuminating CH3NH3PbI3 in ambient air, the metallic lead species react with oxygen and form lead oxides and lead complexes, which passivate the film and remove the in-gap states.

Background Asymptomatic carotid artery stenosis (ACS) has a low risk of stroke. To achieve an advantage over noninterventional best medical treatment (BMT), carotid endarterectomy (CEA) or carotid artery stenting (CAS) must be performed with the lowest possible risk of stroke. Therefore, an analysis of risk-elevating factors is essential. Grade of ipsilateral and contralateral stenosis as well as plaque morphology are known risk factors in ACS. Methods The randomized, controlled, multicenter SPACE-2 trial had to be stopped prematurely after recruiting 513 patients. 203 patients were randomized to CEA, 197 to CAS, and 113 to BMT. Within one year, risk factors such as grade of stenosis and plaque morphology were analyzed. Results Grade of contralateral stenosis (GCS) was higher in patients with any stroke (50%ECST vs. 20%ECST; p=0.012). Echolucent plaque morphology was associated with any stroke on the day of intervention (OR 5.23; p=0.041). In the periprocedural period, any stroke was correlated with GCS in the CEA group (70%ECST vs. 20%ECST; p=0.026) and with echolucent plaque morphology in the CAS group (6% vs. 1%; p=0.048). In multivariate analysis, occlusion of the contralateral carotid artery (CCO) was associated with risk of any stroke (OR 7.00; p=0.006), without heterogeneity between CEA and CAS. Conclusion In patients with asymptomatic carotid artery stenosis, GCS, CCO, as well as echolucent plaque morphology were associated with a higher risk of cerebrovascular events. The risk of stroke in the periprocedural period was increased by GCS in CEA and by echolucent plaque in CAS. Due to small sample size, results must be interpreted carefully.

Background Approximately 70% of all breast cancers express the estrogen receptor, and are regulated by estrogen. While the ovaries are the primary source of estrogen in premenopausal women, most breast cancer is diagnosed following menopause, when systemic levels of this hormone decline. Estrogen production from androgen precursors is catalyzed by the aromatase enzyme. Although aromatase expression and local estrogen production in breast adipose tissue have been implicated in the development of primary breast cancer, the source of estrogen involved in the regulation of estrogen receptor-positive (ER+) metastatic breast cancer progression is less clear. Methods Bone is the most common distant site of breast cancer metastasis, particularly for ER+ breast cancers. We employed a co-culture model using trabecular bone tissues obtained from total hip replacement (THR) surgery specimens to study ER+ and estrogen receptor-negative (ER-) breast cancer cells within the human bone microenvironment. Luciferase-expressing ER+ (MCF-7, T-47D, ZR-75) and ER- (SK-BR-3, MDA-MB-231, MCF-10A) breast cancer cells were cultured directly on bone tissue fragments or in bone tissue-conditioned media, and monitored over time with bioluminescence imaging (BLI). Bone tissue-conditioned media were generated in the presence vs. absence of aromatase inhibitors, and testosterone. Bone tissue fragments were analyzed for aromatase expression by immunohistochemistry. Results ER+ breast cancer cells were preferentially sustained in co-cultures with bone tissues and bone tissue-conditioned media relative to ER- cells. Bone fragments analyzed by immunohistochemistry revealed expression of the aromatase enzyme. Bone tissue-conditioned media generated in the presence of testosterone had increased estrogen levels and heightened capacity to stimulate ER+ breast cancer cell proliferation. Pretreatment of cultured bone tissues with aromatase inhibitors, which inhibited estrogen production, reduced the capacity of conditioned media to stimulate ER+ cell proliferation. Conclusions These results suggest that a local estrogen signaling axis regulates ER+ breast cancer cell viability and proliferation within the bone metastatic niche, and that aromatase inhibitors modulate this axis. Although endocrine therapies are highly effective in the treatment of ER+ breast cancer, resistance to these treatments reduces their efficacy. Characterization of estrogen signaling networks within the bone microenvironment will identify new strategies for combating metastatic progression and endocrine resistance. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0910-x) contains supplementary material, which is available to authorized users.

Methylammonium-tin-iodide (MASnxI3, 0.9 ≤ x ≤ 1.1) systems were prepared by precipitation process in aqueous solutions. The “as prepared” MASnxI3 systems exhibited a tetragonal crystalline phase (space group I4cm) with polyhedral crystallites (length 50–400 µm). The as prepared samples were annealed at T = 150 °C for t = 8 h under nitrogen and synthetic air. Under nitrogen, the CH3NH3SnxI3 systems adopt nearly-cubic tetragonal structure (space group P4mm) with crystallites of 2–4 µm length whereas a degradation process with formation of non-crystalline phases occurred in air. The differential thermal analysis (DTA) profile in nitrogen revealed events at T = 247 °C, T = 297 °C (decomposition of CH3NH3SnxI3 systems into methylamine (CH3NH2), hydroiodic acid (HI) and SnI2), and in the range T = 342–373 °C (melting of SnI2) respectively. The thermal profile in air showed endothermic events at T = 139 °C and T = 259 °C with additional events at onset temperatures of T = 337 °C and T = 423 °C respectively which correspond to the formation of Sn(IV)-O binds and to the decomposition of methylamine. Static thermogravimetry analysis (TG), performed at T = 85 °C and T = 150 °C for t = 2 h, revealed a linear weight loss as a function of the time. The optical absorption spectra displayed absorbance edges in near infrared range, at 1107.0 nm (x = 0.9), 1098.6 nm (x = 1.0) and 1073.2 nm (x = 1.1) respectively.

B lymphocytes are a key pathologic feature of multiple sclerosis (MS) and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to noninvasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here, we evaluated 64Cu-rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using PET. Methods: To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of myelin oligodendrocyte glycoprotein fragment1-125 emulsified in complete Freund adjuvant. Control mice received complete Freund adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19 h after 64Cu-rituximab administration. Mice were perfused and sacrificed after the final PET scan, and radioactivity in dissected tissues was measured with a γ-counter. CNS tissues from these mice were immunostained to quantify B cells or were further analyzed via digital autoradiography. Results: Lumbar spinal cord PET signal was significantly higher in EAE mice than in controls at all evaluated time points (e.g., 1 h after injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 percentage injected dose [%ID]/g, P < 0.05). 64Cu-rituximab PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice, compared with 1.25 ± 0.08 and 2.24 ± 0.11 %ID/g for controls (P < 0.05 for all regions except striatum and thalamus at 1 h after injection). Similarly, ex vivo biodistribution results revealed notably higher 64Cu-rituximab uptake in the brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increased 64Cu-rituximab uptake in CNS tissues corresponded with elevated B cells. Conclusion: B cells can be detected in the CNS of EAE mice using 64Cu-rituximab PET. Results from these studies warrant further investigation of 64Cu-rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell-targeted therapeutics en route to the clinic.

Nanoparticle delivery systems are known to enhance the immune response to soluble antigens (Ags) and are thus a promising tool for the development of new vaccines. Our laboratory has engineered two different nanoparticulate systems in which Ag is either encapsulated within the core of polymersomes (PSs) or decorated onto the surface of nanoparticles (NPs). Previous studies showed that PSs are better at enhancing CD4 T cells and antibody titers, while NPs preferentially augment cytotoxic CD8 T cells. Herein, we demonstrate that the differential activation of T cell immunity reflects differences in the modes of intracellular trafficking and distinct biodistribution of the Ag in lymphoid organs, which are both driven by the properties of each nanocarrier. Furthermore, we found that Ags within PSs promoted better CD4 T cell activation and induced a higher frequency of CD4 T follicular helper (Tfh) cells. These differences correlated with changes in the frequency of germinal center B cells and plasma cell formation, which reflects the previously observed antibody titers. Our results show that PSs are a promising vector for the delivery of Ags for B cell vaccine development. This study demonstrates that nanocarrier design has a large impact on the quality of the induced adaptive immune response. (C) 2017 Published by Elsevier Ltd.

Photoelectrochemical (PEC) cells based on an interfacial electric field formed at a semiconductor–electrolyte junction aim to achieve solar-driven water electrolysis at low cost and with low complexity. When targeting real devices with competitive efficiencies, one must critically understand the photovoltage demands on each photoabsorber as they relate to its band gap and its role in a tandem device. Now four decades after the first observations of PEC phenomena, device photovoltages remain below their target values for the most widely-studied materials, although innovative approaches have shown encouraging progress. This brief review summarizes the most recent advances in understanding and improving PEC device photovoltages.

Background New strategies are needed to reduce the incidence of malaria, and promising approaches include the development of vaccines and monoclonal antibodies (mAbs) that target the circumsporozoite protein (CSP). To select the best candidates and speed development, it is essential to standardize preclinical assays to measure the potency of such interventions in animal models. Methods Two assay configurations were studied using transgenic Plasmodium berghei expressing Plasmodium falciparum full-length circumsporozoite protein. The assays measured (1) reduction in parasite infection of the liver (liver burden) following an intravenous (i.v) administration of sporozoites and (2) protection from parasitaemia following mosquito bite challenge. Two human CSP mAbs, AB311 and AB317, were compared for their ability to inhibit infection. Multiple independent experiments were conducted to define assay variability and resultant impact on the ability to discriminate differences in mAb functional activity. Results Overall, the assays produced highly consistent results in that all individual experiments showed greater functional activity for AB317 compared to AB311 as calculated by the dose required for 50% inhibition (ID50) as well as the serum concentration required for 50% inhibition (IC50). The data were then used to model experimental designs with adequate statistical power to rigorously screen, compare, and rank order novel anti-CSP mAbs. Conclusion The results indicate that in vivo assays described here can provide reliable information for comparing the functional activity of mAbs. The results also provide guidance regarding selection of the appropriate experimental design, dose selection, and group sizes.

Human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) infections are common in early childhood. In a prospective Ugandan birth cohort study, most infants acquired HHV-6 (24/31, 77%) and CMV (20/30, 67%) during follow-up. To assess the transmission risk, we modeled a dose&ndash, response relationship between infant HHV-6 and CMV infections and weekly oral viral shedding by mothers and all other (&ldquo, secondary&rdquo, ) children in the home. Oral viral loads that were shed by mothers and secondary children were significantly associated with HHV-6 but not CMV transmission. While secondary children had higher and more frequent HHV-6 shedding than their mothers, they had a lower per-exposure transmission risk, suggesting that transmission to maternal contacts may be more efficient. HHV-6 transmission was relatively inefficient, occurring after &lt, 25% of all weekly exposures. Although HHV-6 transmission often occurs following repeated, low dose exposures, we found a non-linear dose&ndash, response relationship in which infection risk markedly increases when exposures reached a threshold of &gt, 5 log10 DNA copies/mL. The lack of association between oral CMV shedding and transmission is consistent with breastfeeding being the dominant route of infant infection for that virus. These affirm saliva as the route of HHV-6 transmission and provide benchmarks for developing strategies to reduce the risk of infection and its related morbidity.

The ongoing Antibody Mediated Prevention (AMP) trials will uncover whether passive infusion of the broadly neutralizing antibody (bNAb) VRC01 can protect against HIV acquisition. Previous statistical simulations indicate these trials may be partially protective. In that case, it will be crucial to identify the mechanism of breakthrough infections. To that end, we developed a mathematical modeling framework to simulate the AMP trials and infer the breakthrough mechanisms using measurable trial outcomes. This framework combines viral dynamics with antibody pharmacokinetics and pharmacodynamics, and will be generally applicable to forthcoming bNAb prevention trials. We fit our model to human viral load data (RV217). Then, we incorporated VRC01 neutralization using serum pharmacokinetics (HVTN 104) and in vitro pharmacodynamics (LANL CATNAP database). We systematically explored trial outcomes by reducing in vivo potency and varying the distribution of sensitivity to VRC01 in circulating strains. We found trial outcomes could be used in a clinical trial regression model (CTRM) to reveal whether partially protective trials were caused by large fractions of VRC01-resistant (IC50>50 μg/mL) circulating strains or rather a global reduction in VRC01 potency against all strains. The former mechanism suggests the need to enhance neutralizing antibody breadth; the latter suggests the need to enhance VRC01 delivery and/or in vivo binding. We will apply the clinical trial regression model to data from the completed trials to help optimize future approaches for passive delivery of anti-HIV neutralizing antibodies., Author summary Infusions of broadly neutralizing antibodies are currently being tested as a novel HIV prevention modality. To help interpret the results of these antibody mediated prevention (AMP) studies we developed a mathematical modeling framework. The approach combines antibody potency and drug levels with models of HIV viral dynamics, which will be generally applicable to future studies. Through simulating these clinical trials, we found trial outcomes can be used in combination to infer whether breakthrough infections are caused by large fractions of antibody-resistant circulating strains or some reduction in potency against all strains. This distinction helps to focus future trials on enhancing neutralizing antibody breadth or antibody delivery and/or in vivo binding.

DNA vectors have been widely used as a priming of poxvirus vaccine in prime/boost regimens. Whether the number of DNA impacts qualitatively or quantitatively the immune response is not fully explored. With the aim to reinforce T-cell responses by optimizing the prime-boost regimen, the multicentric EV03/ANRS VAC20 phase I/II trial, randomized 147 HIV-negative volunteers to either 3xDNA plus 1xNYVAC (weeks 0, 4, 8 plus 24; n = 74) or to 2xDNA plus 2xNYVAC (weeks 0, 4 plus 20, 24; n = 73) groups. T-cell responses (IFN-γ ELISPOT) to at least one peptide pool were higher in the 3xDNA than the 2xDNA groups (91% and 80% of vaccinees) (P = 0.049). In the 3xDNA arm, 26 (37%) recipients developed a broader T-cell response (Env plus at least to one of the Gag, Pol, Nef pools) than in the 2xDNA (15; 22%) arms (primary endpoint; P = 0.047) with a higher magnitude against Env (at week 26) (P, Author summary Development of a safe and effective HIV-1 vaccine would undoubtedly be the best solution for the ultimate control of the worldwide AIDS pandemic. To date, only one large phase III trial (RV144 Thai study) showed a partial and modest protection against HIV infection. This result raised hope in the field and encouraged the development of vaccines or strategies in order to improve vaccine efficacy. Several vaccine strategies designed to elicit broad HIV-specific T cells and/or neutralizing antibodies to prevent HIV-1 transmission are under evaluation. Among diverse candidate vaccines, the safety and immunogenicity of multi-gene DNA-based and Pox-virus derived vaccines have been evaluated in several clinical studies. The present study was designed to optimize the combination of these two vaccines with the aim of determining the optimal number of DNA primes for a poxvirus-based HIV vaccine regimen. We show here that the prime boost combination is highly immunogenic and that the number of DNA primes induces differentially T cell and antibody responses. A better priming of poxvirus-based vaccine regimens for T cells is obtained with 3 DNA injections. Our results contribute and extend data of several preclinical studies pointing out the potential interest of DNA as a prime capable not only of improving immune responses but also of imprinting the long-term responses to boost vaccines.

Covellite phase CuS and carrollite phase CuCo2S4 nano and microstructures were synthesized from tetrachloridometallate based ionic liquid precursors using a novel, facile, and highly controllable hot injection synthesis strategy. The synthesis parameters including reaction time and temperature were first optimized to produce CuS with a well controlled and unique morphology, providing the best electrocatalytic activity toward the oxygen evolution reaction OER . In an extension to this approach, the electrocatalytic activity was further improved by incorporating Co into the CuS synthesis method to yield CuCo2S4 microflowers. Both routes provide high microflower yields of gt;80 wt . The CuCo2S4 microflowers exhibit a superior performance for the OER in alkaline medium compared to CuS. This is demonstrated by a lower onset potential amp; 8764;1.45 V vs RHE 10 mA cm2 , better durability, and higher turnover frequencies compared to bare CuS flowers or commercial Pt C and IrO2 electrodes. Likely, this effect is associated with the presence of Co3 sites on which a better adsorption of reactive species formed during the OER e.g., OH, O, OOH, etc. can be achieved, thus reducing the OER charge transfer resistance, as indicated by X ray photoelectron spectroscopy and electrochemical impedance spectroscopy measurements

International audience; Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.

Radiological imaging is an integral component of cancer care, including diagnosis, staging, and treatment response monitoring. It contains rich information about tumor phenotypes that are governed not only by cancer cell-intrinsic biological processes but also by the tumor microenvironment, such as the composition and function of tumor-infiltrating immune cells. By analyzing the radiological scans using a quantitative radiomics approach, robust relations between specific imaging and molecular phenotypes can be established. Indeed, a number of studies have demonstrated the feasibility of radiogenomics for predicting intrinsic molecular subtypes and gene expression signatures in breast cancer based on MRI. In parallel, promising results have been shown for inferring the amount of tumor-infiltrating lymphocytes, a key factor for the efficacy of cancer immunotherapy, from standard-of-care radiological images. Compared with the biopsy-based approach, radiogenomics offers a unique avenue to profile the molecular makeup of the tumor and immune microenvironment as well as its evolution in a noninvasive and holistic manner through longitudinal imaging scans. Here, we provide a systematic review of the state of the art radiogenomics studies in the era of immunotherapy and discuss emerging paradigms and opportunities in AI and deep learning approaches. These technical advances are expected to transform the radiogenomics field, leading to the discovery of reliable imaging biomarkers. This will pave the way for their clinical translation to guide precision cancer therapy.

Water oxidation is the key kinetic bottleneck of photoelectrochemical devices for fuel synthesis. Despite advances in the identification of intermediates, elucidating the catalytic mechanism of this multi-redox reaction on metal-oxide photoanodes remains a significant experimental and theoretical challenge. Here, we report an experimental analysis of water oxidation kinetics on four widely studied metal oxides, focusing particularly on haematite. We observe that haematite is able to access a reaction mechanism that is third order in surface-hole density, which is assigned to equilibration between three surface holes and M(OH)-O-M(OH) sites. This reaction exhibits low activation energy (E-a approximate to 60meV). Density functional theory is used to determine the energetics of charge accumulation and O-O bond formation on a model haematite (110) surface. The proposed mechanism shows parallels with the function of the oxygen evolving complex of photosystem II, and provides new insights into the mechanism of heterogeneous water oxidation on a metal oxide surface. The oxidation of water remains the kinetic bottleneck of solar-to-fuel synthesis. Now, spectroelectrochemical evidence together with density functional theory calculations show that charge accumulation determines the reaction mechanism on metal-oxide photoanodes. These insights reveal features that are common to the mechanisms of water oxidation carried out by other inorganic and biological systems.

The large scale quantification of impervious surfaces provides valuable information for urban planning and socioeconomic development. Remote sensing and GIS techniques provide spatial and temporal information of land surfaces and are widely used for modeling impervious surfaces. Traditionally, these surfaces are predicted by computing statistical indices derived from different bands available in remotely sensed data, such as the Landsat and Sentinel series. More recently, researchers have explored classification and regression techniques to model impervious surfaces. However, these modeling efforts are limited due to lack of labeled data for training and evaluation. This in turn requires significant effort for manual labeling of data and visual interpretation of results. In this paper, we train deep learning neural networks using TensorFlow to predict impervious surfaces from Landsat 8 images. We used OpenStreetMap (OSM), a crowd-sourced map of the world with manually interpreted impervious surfaces such as roads and buildings, to programmatically generate large amounts of training and evaluation data, thus overcoming the need for manual labeling. We conducted extensive experimentation to compare the performance of different deep learning neural network architectures, optimization methods, and the set of features used to train the networks. The four model configurations labeled U-Net_SGD_Bands, U-Net_Adam_Bands, U-Net_Adam_Bands+SI, and VGG-19_Adam_Bands+SI resulted in a root mean squared error (RMSE) of 0.1582, 0.1358, 0.1375, and 0.1582 and an accuracy of 90.87%, 92.28%, 92.46%, and 90.11%, respectively, on the test set. The U-Net_Adam_Bands+SI Model, similar to the others mentioned above, is a deep learning neural network that combines Landsat 8 bands with statistical indices. This model performs the best among all four on statistical accuracy and produces qualitatively sharper and brighter predictions of impervious surfaces as compared to the other models.

Clinical trials for HIV prevention can require knowledge of infection times to subsequently determine protective drug levels. Yet, infection timing is difficult when study visits are sparse. Using population nonlinear mixed-effects (pNLME) statistical inference and viral loads from 46 RV217 study participants, we developed a relatively simple HIV primary infection model that achieved an excellent fit to all data. We also discovered that Aptima assay values from the study strongly correlated with viral loads, enabling imputation of very early viral loads for 28/46 participants. Estimated times between infecting exposures and first positives were generally longer than prior estimates (average of two weeks) and were robust to missing viral upslope data. On simulated data, we found that tighter sampling before diagnosis improved estimation more than tighter sampling after diagnosis. Sampling weekly before and monthly after diagnosis was a pragmatic design for good timing accuracy. Our pNLME timing approach is widely applicable to other infections with existing mathematical models. The present model could be used to simulate future HIV trials and may help estimate protective thresholds from the recently completed antibody-mediated prevention trials.

With increased computing power, the horizontal grid-spacing of regional ocean models is decreasing to the point where they can directly simulate lee waves. Although oceanic lee waves can be inherently nonhydrostatic, such as in the abyssal ocean or in the Gulf Stream, regional ocean models are frequently run in hydrostatic mode to avoid the computational expense of solving the nonhydrostatic pressure. However, the effects of the nonhydrostatic pressure and the numerical error on the accuracy of the simulated lee waves is not immediately obvious. To quantify these effects, this paper presents hydrostatic and nonhydrostatic simulations of an idealized lee wave over both linear and nonlinear height and varying length bathymetry utilizing a range of horizontal grid-spacings. We present an analysis of the numerical error arising from the discrete linear, stratified Euler equations to identify the numerically induced physics in lee wave simulations. As expected for the second-order accurate model, the numerical error in the lee wave drag decreases quadratically with respect to horizontal grid refinement, although the error arises from two primary sources. The first is related to discretization of the kinematic bottom boundary condition, which acts to decrease the lee wave drag. The second is related to discretization of the nonhydrostatic pressure, which acts to increase the drag. Together, the results offer a regional ocean modeler several cautionary notes for calculating and interpreting properties of simulated lee waves, namely, that a hydrostatic model can produce the correct form drag due simply to numerical error, and attempting to employ a nonhydrostatic model to correct for this error can require prohibitively fine grid resolution.

Perovskite solar cells (PSCs) are very promising lab-scale technologies to deliver inexpensive solar electricity. Low-temperature, planar PSCs are of particularly interest for large-scale deployment due to their inherent suitability for flexible substrates and potential for silicon/perovskite tandems. So far, planar PSCs have been prone to large current-voltage hysteresis and low stabilized power output due to a number of issues associated with this kind of device configuration. We find that the suppression of the yellow-phase impurity (∂-FAPbI3) present in formamidium-based perovskites, by RbI addition, contributes to low hysteresis, higher charge carrier mobility, long-lived carrier lifetimes and a champion stabilized power output of 20.3% using SnOx as the electron selective contact. We study the effects of these impurities on the transient behavior that defines hysteresis and its relation to ionic movement. In addition, we find that the formation of a RbPbI3 phase does not significantly affect the charge carrier lifetimes and consequently the performance of the devices. This brings new physical insights onto the role of different impurities in perovskite solar cells, which make these materials so remarkable., US Department of Energy, Office of Science, Office of Basic Energy Sciences (award no. DE-SC0001088)

It is well known that cancers exploit immune checkpoints (programmed death 1 receptor (PD-1) and its ligand (PD-L1)) to evade anti-tumor immune responses. Although immune checkpoint (IC) blockade is a promising approach, not all patients respond. Hence, imaging of tumor-infiltrating lymphocytes (TILs) is of high specific interest, as they are known to express PD-1 during activation and subsequent exhaustion in the tumor microenvironment and are thought to be potentially predictive of therapeutic responses to IC blockade. We developed immune-tracers for positron emission tomography (PET) to image hPD-1 status of human peripheral blood mononuclear cells (hPBMCs) adoptively transferred to NOD-scid IL-2Rγnull (NSG) mice (hNSG) bearing A375 human skin melanoma tumors. The anti-PD-1 human antibody (IgG; keytruda) was labeled with either Zr-89 or Cu-64 radiometals to image PD-1-expressing human TILs in vivo. [89Zr] Keytruda (groups = 2; NSG-ctl (control) and hNSG-nblk (non-blocking), n = 3–5, 3.2 ± 0.4 MBq/15–16 μg/200 μl) and [64Cu] Keytruda (groups = 3; NSG-ctl, NSG-blk (blocking), and hNSG-nblk; n = 4, 7.4 ± 0.4 MBq /20-25 μg/200 μl) were administered in mice. PET-CT scans were performed over 1–144 h ([89Zr] Keytruda) and 1–48 h ([64Cu] Keytruda) on mice. hNSG mice exhibited a high tracer uptake in the spleen, lymphoid organs and tumors. At 24 h, human TILs homing into melanoma of hNSG-nblk mice exhibited high signal (mean %ID/g ± SD) of 3.8 ± 0.4 ([89Zr] Keytruda), and 6.4 ± 0.7 ([64Cu] Keytruda), which was 1.5- and 3-fold higher uptake compared to NSG-ctl mice (p = 0.01), respectively. Biodistribution measurements of hNSG-nblk mice performed at 144 h ([89Zr] Keytruda) and 48 h ([64Cu] Keytruda) p.i. revealed tumor to muscle ratios as high as 45- and 12-fold, respectively. Our immunoPET study clearly demonstrates specific imaging of human PD-1-expressing TILs within the tumor and lymphoid tissues. This suggests these anti-human-PD-1 tracers could be clinically translatable to monitor cancer treatment response to IC blockade therapy.

Data regarding the incidence and prevalence of epileptic seizures in Alzheimer's disease show great variability and are clinically underestimated due to their atypical symptomatology. Considering their considerable negative effects on cognition and activities of daily living, epileptic seizures need to be correctly treated. Hypotheses with respect to the pathogenetic mechanisms and associations between Alzheimer's disease and epilepsy are mostly derived from animal experiments. The causal connections are so far insufficiently understood. Data on risk factors are inconsistent due to methodological limitations in studies. Clinical data for these indications show good response to therapy with anticonvulsants and good tolerability in the case of new active substances. When treating epileptic seizures in this patient collective using anticonvulsants, potential adverse effects and possible drug interactions need to be closely monitored.

Der Beitrag behandelt experimentelle Untersuchungen zum Einsatz von keramischen Schneidstoffen für Sägeanwendungen. Im Fokus steht ein Modellversuch, um die Belastungen des unterbrochenen Schnitts, die beim Sägen auftreten, auf Drehverfahren zu übertragen. Die Motivation liegt hierbei in der einfachen Versuchsdurchführung, da wenige Schneiden und Werkzeuge ausreichen, um Aussagen treffen zu können. Als Beispielanwendung kommt Gusseisen als Werkstückwerkstoff zur Anwendung. Subject of this study are the results of an analysis on the potential of ceramic cutting materials for interrupted-cut applications focusing on sawing processes. The applied machining model shall facilitate an accelerated and simplified qualification of the cutting material. Cast iron was used as application for the tests.

Organic semiconductor light absorbers are receiving attention for their potential application in photoelectrochemical (PEC) cells for renewable fuels generation. Key to their advancement is precise control of the interfaces between charge-selective contacts, absorber layers, and electrocatalysts, while maintaining compatibility with an aqueous electrolyte environment. Here we demonstrate a new process for low-temperature atomic layer deposition (ALD) of TiO2 onto a P3HT:PCBM polymer blend surface for stable high-performance organic PEC photocathodes. This ALD TiO2 layer provides three key functions: (1) formation of an electron-selective contact to the polymer to enable photovoltage and photocurrent generation, (2) a robust interface for conducting charge between the photoabsorber and electrocatalyst layers, and (3) a pinhole-free barrier to water penetration, preventing corrosion of the underlying materials. The resulting device based on the architecture CuI/P3HT:PCBM/TiO2/RuOx showed excellent performance and stability during PEC hydrogen-evolution. More broadly, the achievement of ALD film formation on a polymer surface opens doors in the field of functional organic–inorganic electronic interfaces.

Wang et al. show that antibody gene deamination by activation-induced cytidine deaminase (AID) is restricted to a short time window in early G1 as a result of AID’s transient nuclear localization and accessibility of the target sites., Activation-induced cytidine deaminase (AID) converts cytosine into uracil to initiate somatic hypermutation (SHM) and class switch recombination (CSR) of antibody genes. In addition, this enzyme produces DNA lesions at off-target sites that lead to mutations and chromosome translocations. However, AID is mostly cytoplasmic, and how and exactly when it accesses nuclear DNA remains enigmatic. Here, we show that AID is transiently in spatial contact with genomic DNA from the time the nuclear membrane breaks down in prometaphase until early G1, when it is actively exported into the cytoplasm. Consistent with this observation, the immunoglobulin (Igh) gene deamination as measured by uracil accumulation occurs primarily in early G1 after chromosomes decondense. Altering the timing of cell cycle–regulated AID nuclear residence increases DNA damage at off-target sites. Thus, the cell cycle–controlled breakdown and reassembly of the nuclear membrane and the restoration of transcription after mitosis constitute an essential time window for AID-induced deamination, and provide a novel DNA damage mechanism restricted to early G1.

Immune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. Here, we sought to optimize noninvasive immuno-PET imaging of human programmed death-ligand 1 (PD-L1) expression, in a preclinical model, using a small high-affinity engineered protein scaffold (HAC-PD1). Six HAC-PD1 radiotracer variants were developed and used in preclinical imaging and biodistribution studies to assess their ability to detect human PD-L1 expression in vivo. Radiotracer design modifications included chelate, glycosylation, and radiometal. HACA-PD1 was adopted as the naming convention for aglycosylated tracer variants. NOD scid γ-(NSG) mice were inoculated with subcutaneous tumors engineered to either be constitutively positive (CT26 hPD-L1) or be negative (ΔmPD-L1 CT26) for human PD-L1 expression. When the tumors had grown to an average size of 1 cm in diameter, mice were injected with 0.75–2.25 MBq (∼10 μg) of an engineered radiotracer variant and imaged. At 1 h after injection, organs were harvested for biodistribution. Of the practical immuno-PET tracer modifications considered, glycosylation was the most prominent design factor affecting tracer uptake, specificity, and clearance. In imaging studies, aglycosylated 64Cu-NOTA-HACA-PD1 most accurately visualized human PD-L1 expression in vivo. We reasoned that because of the scaffold’s small size (14 kDa), its pharmacokinetics may be suitable for labeling with the short-lived and widely clinically available radiometal 68Ga. At 1 h after injection, 68Ga-NOTA-HACA-PD1 and 68Ga-DOTA-HACA-PD1 exhibited promising target-to-background ratios in ex vivo biodistribution studies (12.3 and 15.2 tumor-to-muscle ratios, respectively). Notably, all HAC-PD1 radiotracer variants enabled much earlier detection of human PD-L1 expression (1 h after injection) than previously reported radiolabeled antibodies (>24 h after injection). This work provides a template for assessing immuno-PET tracer design parameters and supports the translation of small engineered protein radiotracers for imaging human immune checkpoints.