This Review discusses the major advances and changes made over the past 3 years to our understanding of chimeric antigen receptor (CAR) T cell efficacy and safety. Recently, the field has gained ...insight into how various molecular modules of the CAR influence signalling and function. We report on mechanisms of toxicity and resistance as well as novel engineering and pharmaceutical interventions to overcome these challenges. Looking forward, we discuss new targets and indications for CAR T cell therapy expected to reach the clinic in the next 1-2 years. We also consider some new studies that have implications for the future of CAR T cell therapies, including changes to manufacturing, allogeneic products and drug-regulatable CAR T cells.
Manure is the second largest source of greenhouse gas (GHG) emissions from dairy farms. Detailed data for representative manure systems are needed to guide climate change mitigation strategies. This ...study uses surveys sent to WI dairies to identify current farm and manure management practices, collect inventory data on manure handling and energy consumption, compare practices based on farm size, and relate these practices to GHG emissions. Results show that manure systems and management practices vary significantly with farm size. For example, larger farms handle liquid manure and have long term storage while small farms handle solid manure and land-apply daily. Sand separation, solid-liquid separation (SLS), and anaerobic digestion (AD) are implemented only by the surveyed facilities that are large enough to require permitting. Ammonia, biotic, and fossil GHG emissions from archetypes small, large, and permitted facilities are estimated using modeling tools. For this, the most common manure management practices identified by the survey are analyzed. Results (per cow, kg of milk, and ton of manure) show that storing liquid manure for long periods of time without processing contributes the most to GHG emissions. When implementing manure processing, permitted facilities are able to reduce emissions significantly, mostly through AD. Small farms keep their emissions lower than large farms as they mostly handle solid manure and land-apply manure daily. Depending on the practice and farm size, GHG emissions per ton of manure range from 2200 to 12,000 g CO2-eq for collection, 200 to 2400 g CO2-eq for transportation, 16,000 to 84,000 g CO2-eq for storage, and 16,400 to 33,500 g CO2-eq for land-application.
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•Manure management practices at Wisconsin dairies were surveyed and compared.•Farm size influences manure management practices.•GHG and NH3 emissions were quantified for representative practices.•The largest GHG source is application at small farms and storage at large farms.•Anaerobic digestion reduces GHG emissions and injection reduces NH3 emissions.
Lyα emission from galaxies can be utilized to characterize the ionization state in the intergalactic medium (IGM). We report our search for Lyα emission at z > 7 using a comprehensive Keck/MOSFIRE ...near-infrared spectroscopic data set, as part of the Texas Spectroscopic Search for Lyα Emission at the End of Reionization Survey. We analyze data from 10 nights of MOSFIRE observations which together target 72 high-z candidate galaxies in the GOODS-N field, all with deep exposure times of 4.5–19 hr. Utilizing an improved automated emission-line search, we report 10 Lyα emission lines detected (>4σ) at z > 7, significantly increasing the spectroscopically confirmed sample. Our sample includes large equivalent-width (EW) Lyα emitters (>50 Å), and additional tentative Lyα emission lines detected at 3σ–4σ from five additional galaxies. We constrain the Lyα EW distribution at z ~ 7.6, finding a significant drop from z ≲ 6, suggesting an increasing fraction of neutral hydrogen (H I) in the IGM in this epoch. We estimate the Lyα transmission through the IGM (=EW(z)~7.6/EW(z~2–6)) and infer an IGM H I fraction (X(HI)) of 49 (+19,-19)% at z ~ 7.6, which is lower in modest tension (>1σ) with recent measurements at z ~ 7.6. The spatial distribution of the detected Lyα emitters implies the presence of a potential highly ionized region at z ~ 7.55, which hosts four Lyα emitters within a ∼40 cMpc spatial separation. The prominence of this ionized region in our data set could explain our lower inferred value of X(HI), though our analysis is also sensitive to the chosen reference Lyα EW distribution values and reionization models.
We present a detailed stellar population analysis of 11 bright (H < 26.6) galaxies at z=9−11 (three spectroscopically confirmed) to constrain the chemical enrichment and growth of stellar mass of ...early galaxies. We use the flexible Bayesian spectral energy distribution (SED) fitting code Prospector with a range of star-formation histories (SFHs), a flexible dust attenuation law and a self-consistent modeling of emission lines. This approach allows us to assess how different priors affect our results, and how well we can break degeneracies between dust attenuation, stellar ages, metallicity and emission lines using data which probe only the rest-frame ultraviolet to optical wavelengths. We measure a median observed ultraviolet spectral slope β= −1.87+0.35−0.43 for relatively massive star-forming galaxies (9<log(M?/M)<10), consistent with no change from z=4 to z=9−10 at these stellar masses, implying rapid enrichment. Our SED-fitting results are consistent with a star-forming main sequence with sub-linear slope (0.7±0.2) and specific star-formation rates of 3−10 Gyr−1. However, the stellar ages and SFHs are less well constrained. Using different SFH priors, we cannot distinguish between median mass-weighted ages of ∼50−150 Myr, which corresponds to 50% formation redshifts of z50∼10−12 atz∼9 and is of the order of the dynamical timescales of these systems. Importantly, the models with different SFH priors are able to fit the data equally well. We conclude that the current observational data cannot tightly constrain the mass-buildup timescales of these z=9−11 galaxies, with our results consistent with SFHs implying both a shallow and steep increase of the cosmic SFR density with time at z >10
Psychometric assessments are tests or questionnaires that have been designed to measure constructs of interest in an individual or a target population. A goal of many of these self-report instruments ...is to provide researchers with the ability to gather subjective information in a manner that might allow for quantitative analysis and interpretation of these results. This requires the instrument of choice to have adequate psychometric properties of reliability and validity. Much research has been conducted on creating self-report quality of life questionnaires for individuals with multiple sclerosis (MS). This article focuses on one in particular, the Modified Fatigue Impact Scale (MFIS). The article starts with a brief description of the rationale, construction, and scoring of the inventory. Next, the best available reliability and validity data on the MFIS are presented. The article concludes with a brief discussion on the interpretation of scores, followed by suggestions for future research. This summative analysis is intended to examine whether the instrument is adequately measuring the impact of fatigue and whether the scores allow for meaningful interpretations.
The cellular processes that govern tumor resistance to immunotherapy remain poorly understood. To gain insight into these processes, here we perform a genome-scale CRISPR activation screen for genes ...that enable human melanoma cells to evade cytotoxic T cell killing. Overexpression of four top candidate genes (CD274 (PD-L1), MCL1, JUNB, and B3GNT2) conferred resistance in diverse cancer cell types and mouse xenografts. By investigating the resistance mechanisms, we find that MCL1 and JUNB modulate the mitochondrial apoptosis pathway. JUNB encodes a transcription factor that downregulates FasL and TRAIL receptors, upregulates the MCL1 relative BCL2A1, and activates the NF-κB pathway. B3GNT2 encodes a poly-N-acetyllactosamine synthase that targets >10 ligands and receptors to disrupt interactions between tumor and T cells and reduce T cell activation. Inhibition of candidate genes sensitized tumor models to T cell cytotoxicity. Our results demonstrate that systematic gain-of-function screening can elucidate resistance pathways and identify potential targets for cancer immunotherapy.
•BES recover organic and ammoniacal nitrogen in dairy manure as ammonia.•BES technologies increase the sustainability of manure management.•Manure type and anode chamber aeration do not impact system ...performance.•Ion competition between ammonium and other ions is not a concern.
The sustainability of direct land application of dairy manure is challenged by significant nutrient losses. Bioelectrochemical systems for ammonia recovery offer a manure management strategy that can recover both ammoniacal and organic nitrogen as a stable ammonia fertilizer. In this research, a microbial fuel cell (MFC) was used to treat two types of dairy manure under a variety of imposed anode compartment conditions. The system achieved a maximum coulombic efficiency of 20 ± 18 % and exhibited both COD and total nitrogen removals of approximately 60 %. Furthermore, the MFC showed a maximum organic nitrogen removal of 73.8 ± 12.1 %, and no differences in organic nitrogen (orgN) removal were detected among different conditions tested. Decreasing concentrations of anolyte ammonia nitrogen coupled with the observed orgN removal from the anolyte indicate that the MFC is effective at recovering orgN in dairy manure as ammoniacal nitrogen in the catholyte. Additionally, ion competition between NH4+ and other relevant cations (Na+, K+, and Mg2+) for transport across the CEM was investigated, with only K+ showing minor competitive effects. Based on the results of this research, we propose three key processes and two sub-processes that contribute to the successful operation of the MFC for nitrogen recovery from dairy manure. Bioelectrochemical systems for nitrogen recovery from dairy manure offer a novel, robust technology for producing a valuable ammonia nitrogen fertilizer, a thus far untapped resource in dairy manure streams.
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Cell-based therapies are emerging as effective agents against cancer and other diseases. As autonomous "living drugs," these therapies lack precise control. Chimeric antigen receptor (CAR) T cells ...effectively target hematologic malignancies but can proliferate rapidly and cause toxicity. We developed ON and OFF switches for CAR T cells using the clinically approved drug lenalidomide, which mediates the proteasomal degradation of several target proteins by inducing interactions between the CRL4
E3 ubiquitin ligase and a C2H2 zinc finger degron motif. We performed a systematic screen to identify "super-degron" tags with enhanced sensitivity to lenalidomide-induced degradation and used these degradable tags to generate OFF-switch degradable CARs. To create an ON switch, we engineered a lenalidomide-inducible dimerization system and developed split CARs that required both lenalidomide and target antigen for activation. Subtherapeutic lenalidomide concentrations controlled the effector functions of ON- and OFF-switch CAR T cells. In vivo, ON-switch split CARs demonstrated lenalidomide-dependent antitumor activity, and OFF-switch degradable CARs were depleted by drug treatment to limit inflammatory cytokine production while retaining antitumor efficacy. Together, the data showed that these lenalidomide-gated switches are rapid, reversible, and clinically suitable systems to control transgene function in diverse gene- and cell-based therapies.
Chimeric antigen receptor (CAR) therapy has had a transformative effect on the treatment of haematologic malignancies
, but it has shown limited efficacy against solid tumours. Solid tumours may have ...cell-intrinsic resistance mechanisms to CAR T cell cytotoxicity. Here, to systematically identify potential resistance pathways in an unbiased manner, we conducted a genome-wide CRISPR knockout screen in glioblastoma, a disease in which CAR T cells have had limited efficacy
. We found that the loss of genes in the interferon-γ receptor (IFNγR) signalling pathway (IFNGR1, JAK1 or JAK2) rendered glioblastoma and other solid tumours more resistant to killing by CAR T cells both in vitro and in vivo. However, loss of this pathway did not render leukaemia or lymphoma cell lines insensitive to CAR T cells. Using transcriptional profiling, we determined that glioblastoma cells lacking IFNγR1 had lower upregulation of cell-adhesion pathways after exposure to CAR T cells. We found that loss of IFNγR1 in glioblastoma cells reduced overall CAR T cell binding duration and avidity. The critical role of IFNγR signalling in susceptibility of solid tumours to CAR T cells is surprising, given that CAR T cells do not require traditional antigen-presentation pathways. Instead, in glioblastoma tumours, IFNγR signalling was required for sufficient adhesion of CAR T cells to mediate productive cytotoxicity. Our work demonstrates that liquid and solid tumours differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumour cells may yield improved responses in solid tumours.
Almost 60% of all ammonia (NH3) emissions are from livestock manure. Understanding the sources and magnitude of NH3 emissions from manure systems is critical to implement mitigation strategies. This ...study models 13 archetypical conventional (5 farms), organic (5 farms), and grazing (3 farms) dairy farms to estimate NH3 emissions from manure at the barn, storage, and after land application. Mitigation practices related to management of the herd, crop production, and manure are subsequently modeled to quantify the change in NH3 emissions from manure by comparing archetypical practices with these alternative practices. A mass balance of nutrients is also conducted. Emissions per tonne of excreted manure for the manure system (barn, storage, and land application) range from 3.0 to 4.4 g of NH3 for conventional farms, 3.5 to 4.4 g of NH3 for organic farms, and 3.4 to 3.9 g of NH3 for grazing farms. For all farm types, storage and land application are the main sources of NH3 emissions from manure. In general, solid manures have higher emission intensities due to higher pH during storage (pH = 7.4 for liquid, 7.8 for slurry, and 8.5 for solid manure) and lower infiltration rates after land application when compared with slurry and liquid manures. The most effective management practices to reduce NH3 emissions from manure systems are combining solid-liquid separation with manure injection (up to 49% reduction in NH3 emissions), followed by injection alone, and reducing crude protein in the dairy ration, especially in organic and grazing farms that have grazing and forages as the main component of the dairy ration. This study also shows that the intensity of NH3 emissions from manure depends significantly on the functional unit and presents results per manure excreted, total solids in excreted manure, animal units, and fat- and protein-corrected milk.
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