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Control of Mycobacterium tuberculosis (Mtb) infection requires generation of T cells that migrate to granulomas, complex immune structures surrounding sites of bacterial replication. Here we compared the gene expression profiles of T cells in pulmonary granulomas, bronchoalveolar lavage, and blood of Mtb-infected rhesus macaques to identify granuloma-enriched T cell genes. TNFRSF8/CD30 was among the top genes upregulated in both CD4 and CD8 T cells from granulomas. In mice, CD30 expression on CD4 T cells is required for survival of Mtb infection, and there is no major role for CD30 in protection by other cell types. Transcriptomic comparison of WT and CD30−/− CD4 T cells from the lungs of Mtb-infected mixed bone marrow chimeric mice showed that CD30 directly promotes CD4 T cell differentiation and the expression of multiple effector molecules. These results demonstrate that the CD30 co-stimulatory axis is highly upregulated on granuloma T cells and is critical for protective T cell responses against Mtb infection.

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Purpose:Ovarian cancer is the most lethal gynecologic cancer and intrinsically resistant to checkpoint immunotherapies. We sought to augment innate immunity, building on previous work with IFNs and monocytes.Patients and Methods:Preclinical experiments were designed to define the mechanisms of cancer cell death mediated by the combination of IFNs α and γ with monocytes. We translated these preclinical findings into a phase I trial of autologous IFN-activated monocytes administered intraperitoneally to platinum-resistant or -refractory ovarian cancer patients.Results:IFN-treated monocytes induced caspase 8–dependent apoptosis by the proapoptotic TRAIL and mediated by the death receptors 4 and 5 (DR4 and DR5, respectively) on cancer cells. Therapy was well tolerated with evidence of clinical activity, as 2 of 9 evaluable patients had a partial response by RECIST criteria, and 1 additional patient had a CA-125 response. Upregulation of monocyte-produced TRAIL and cytokines was confirmed in peripheral blood. Long-term responders had alterations in innate and adaptive immune compartments.Conclusions:Given the mechanism of cancer cell death, and the acceptable tolerability of the clinical regimen, this platform presents a possibility for future combination therapies to augment anticancer immunity.See related commentary by Chow and Dorigo, p. 299

Comparison between TCGA and TumorPortal (replication) set

2016 Cancer Statistics data used to normalize for cancer incidence rates in the US

Comparing previous NSCLC and melanoma studies of checkpoint inhibition response regarding an NsM estimated ROC analysis threshold

Conditional logistic regression results for {greater than or equal to}192 NsM and gene mutations using ICGC and TP Samples

Copy-number, expression and mutation comparision for MET, ERBB2, PTEN, NF2

Immune checkpoint inhibitor treatment represents a promising approach toward treating cancer and has been shown to be effective in a subset of melanoma, non–small cell lung cancer (NSCLC), and kidney cancers. Recent studies have suggested that the number of nonsynonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from checkpoint inhibitor treatment. It is hypothesized that a higher burden of NsM generates novel epitopes and gene products, detected by the immune system as foreign. We conducted an assessment of NsM across 7,757 tumor samples drawn from 26 cancers sequenced in the Cancer Genome Atlas (TCGA) Project to estimate the subset of cancers (both types and fractions thereof) that fit the profile suggested for melanoma and NSCLC. An additional independent set of 613 tumors drawn from 5 cancers were analyzed for replication. An analysis of the receiver operating characteristic curves of published data on checkpoint inhibitor response in melanoma and NSCLC data estimates a cutoff of 192 NsM with 74% sensitivity and 59.3% specificity to discriminate potential clinical benefit. Across the 7,757 samples of TCGA, 16.2% displayed an NsM count that exceeded the threshold of 192. It is notable that more than 30% of bladder, colon, gastric, and endometrial cancers have NsM counts above 192, which was also confirmed in melanoma and NSCLC. Our data could inform the prioritization of tumor types (and subtypes) for possible clinical trials to investigate further indications for effective use of immune checkpoint inhibitors, particularly in adult cancers. Cancer Res; 76(13); 3767–72. ©2016 AACR.

Table shows the information of NCI-Match drugs and genes used on the analysis.

Conditional logistic regression results for {greater than or equal to}192 NsM and gene mutaations using TCGA Samples

Conditional logistic regression results for {greater than or equal to}192 NsM and gene mutations comparing Stage I and II to III and IV

Violin plot for the number of non-synonymous mutations for smoking (dark gray) and (light gray) non-smoking patients for bladder urothelial carcinoma (BLCA), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and pancreatic adenocarcinoma (PAAD).

Violin plot for the number of non-synonymous mutations for stage I and II patients (light gray) and stage III and IV patients (dark gray).

Supplementary Figure Legends

Cancer treatments composed of immune checkpoint inhibitors and oncogene-targeted drugs might improve cancer management, but there has been little investigation of their combined potential as yet. To estimate the fraction of cancer cases that might benefit from such combination therapy, we conducted an exploratory study of cancer genomic datasets to determine the proportion with somatic mutation profiles amenable to either immunotherapy or targeted therapy. We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents or a burden of exome-wide nonsynonymous mutations (NsM) that exceed a proposed threshold for response to checkpoint inhibitors. Overall, 8.9% of cases displayed profiles that could benefit from combination therapy, which corresponded to approximately 11.2% of U.S. annual incident cancer cases. Frequently targetable mutations were in PIK3CA, BRAF, NF1, NRAS, and PTEN. We also noted a high burden of NsM in cases with targetable mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and MET. Our results indicate that a significant proportion of solid tumor patients are eligible for immuno-targeted combination therapy, and they suggest prioritizing specific cancers for trials of certain targeted and checkpoint inhibitor drugs. Cancer Res; 77(13); 3666–71. ©2017 AACR.

Table shows the information for TCGA, ICGC and TumorPortal samples.

A simple mathematical model to estimate the energy stored in a green roof is developed. Analytical solutions are derived corresponding to extensive (shallow) and intensive (deep) substrates. Results are presented for the surface temperature and energy stored in both green roofs and concrete during a typical day. Within the restrictions of the model assumptions the analytical solution demonstrates that both energy and surface temperature vary linearly with fractional leaf coverage, albedo and irradiance, while the effect of evaporation rate and convective heat transfer is non-linear. It is shown that a typical green roof is significantly cooler and stores less energy than a concrete one even when the concrete has a high albedo coating. Evaporation of even a few millimetres per day from the soil layer can reduce the stored energy by a factor of more than three when compared to an equivalent thickness concrete roof.

Pro-inflammatory T cells co-express multiple chemokine receptors, but the distinct functions of individual receptors on these cells are largely unknown. Human Th17 cells uniformly express the chemokine receptor CCR6, and we discovered that the subgroup of CD4+CCR6+cells that co-express CCR2 possess a pathogenic Th17 signature, can produce inflammatory cytokines independent of TCR activation, and are unusually efficient at transendothelial migration (TEM). The ligand for CCR6, CCL20, was capable of binding to activated endothelial cells (ECs) and inducing firm arrest of CCR6+CCR2+cells under conditions of flow - but CCR6 could not mediate TEM. By contrast, CCL2 and other ligands for CCR2, despite being secreted from both luminal and basal sides of ECs, failed to bind to the EC surfaces - and CCR2 could not mediate arrest. Nonetheless, CCR2 was required for TEM. To understand if CCR2’s inability to mediate arrest was due solely to an absence of EC-bound ligands, we generated a CCL2-CXCL9 chimeric chemokine that could bind to the EC surface. Although display of CCL2 on the ECs did indeed lead to CCR2-mediated arrest of CCR6+CCR2+cells, activating CCR2 with surface-bound CCL2 blocked TEM. We conclude that mediating arrest and TEM are mutually exclusive activities of chemokine receptors and/or their ligands that depend, respectively, on chemokines that bind to the EC luminal surfaces versus non-binding chemokines that form transendothelial gradients under conditions of flow. Our findings provide fundamental insights into mechanisms of lymphocyte extravasation and may lead to novel strategies to block or enhance their migration into tissue.

The structure and evolution of the atmospheric boundary layer (ABL) under clear-sky fair weather conditions over mountainous terrain is dominated by the diurnal cycle of the surface energy balance and thus strongly depends on surface snow cover. We use data from three passive ground-based infrared spectrometers deployed in the East River Valley in Colorado’s Rocky Mountains to investigate the response of the thermal ABL structure to changes in surface energy balance during the seasonal transition from snow-free to snow-covered ground. Temperature profiles were retrieved from the infrared radiances using the optimal estimation physical retrieval TROPoe. A nocturnal surface inversion formed in the valley during clear-sky days, which was subsequently mixed out during daytime with the development of a convective boundary layer during snow-free periods. When the ground was snow covered, a very shallow convective boundary layer formed, above which the inversion persisted through the daytime hours. We compare these observations to NOAA’s operational High-Resolution-Rapid-Refresh (HRRR) model and find large warm biases on clear-sky days resulting from the model’s inability to form strong nocturnal inversions and to maintain the stable stratification in the valley during daytime when there was snow on the ground. A possible explanation for these model shortcomings is the influence of the model’s relatively coarse horizontal grid spacing (3 km) and its impact on the model’s ability to represent well-developed thermally driven flows, specifically nighttime drainage flows.

Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related (type 17) cells and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cellsin vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The CCR6+cells’ phenotypes and epigenomes are stable across cell divisions under homeostatic conditions. Nonetheless, activation in polarizing and non-polarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the continuum to yield the unusual plasticity ascribed to type 17 cells.

Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.

Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.

Purpose: Ovarian cancer is the most lethal gynecologic cancer and intrinsically resistant to checkpoint immunotherapies. We sought to augment innate immunity, building on previous work with IFNs and monocytes. Patients and Methods: Preclinical experiments were designed to define the mechanisms of cancer cell death mediated by the combination of IFNs α and γ with monocytes. We translated these preclinical findings into a phase I trial of autologous IFN-activated monocytes administered intraperitoneally to platinum-resistant or -refractory ovarian cancer patients. Results: IFN-treated monocytes induced caspase 8–dependent apoptosis by the proapoptotic TRAIL and mediated by the death receptors 4 and 5 (DR4 and DR5, respectively) on cancer cells. Therapy was well tolerated with evidence of clinical activity, as 2 of 9 evaluable patients had a partial response by RECIST criteria, and 1 additional patient had a CA-125 response. Upregulation of monocyte-produced TRAIL and cytokines was confirmed in peripheral blood. Long-term responders had alterations in innate and adaptive immune compartments. Conclusions: Given the mechanism of cancer cell death, and the acceptable tolerability of the clinical regimen, this platform presents a possibility for future combination therapies to augment anticancer immunity. See related commentary by Chow and Dorigo, p. 299

With the goal of determining strategies to maximise drug delivery to a specific site in the body, we developed a mathematical model for the transport of drug nanocarriers (nanoparticles) in the bloodstream under the influence of an external magnetic field. Under the assumption of long (compared to the radius) blood vessels the Navier-Stokes equations are reduced, to a simpler model consistently with lubrication theory. Under these assumptions, analytical results are compared for Newtonian, power-law, Carreau and Ellis fluids, and these clearly demonstrate the importance of shear thinning effects when modelling blood flow. Incorporating nanoparticles and a magnetic field to the model we develop a numerical scheme and study the particle motion for different field strengths. We demonstrate the importance of the non-Newtonian behaviour: for the flow regimes investigated in this work, consistent with those in blood micro vessels, we find that the field strength needed to absorb a certain amount of particles in a non-Newtonian fluid has to be larger than the one needed in a Newtonian fluid. Specifically, for one case examined, a two times larger magnetic force had to be applied in the Ellis fluid than in the Newtonian fluid for the same number of particles to be absorbed through the vessel wall. Consequently, models based on a Newtonian fluid can drastically overestimate the effect of a magnetic field. Finally, we evaluate the particle concentration at the vessel wall and compute the evolution of the particle flux through the wall for different permeability values, as that is important when assessing the efficacy of drug delivery applications. The insights from our work bring us a step closer to successfully transferring magnetic nanoparticle drug delivery to the clinic.

Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set of compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as a moderately active hit. Structure-activity relationship (SAR) studies demonstrated a clear scope to improve whole cell potency to MIC values of

Marine low clouds strongly cool the planet. How this cooling effect will respond to climate change is a leading source of uncertainty in climate sensitivity, the planetary warming resulting from CO2 doubling. Here, we observationally constrain this low cloud feedback at a near-global scale. Satellite observations are used to estimate the sensitivity of low clouds to interannual meteorological perturbations. Combined with model predictions of meteorological changes under greenhouse warming, this permits quantification of spatially resolved cloud feedbacks. We predict positive feedbacks from midlatitude low clouds and eastern ocean stratocumulus, nearly unchanged trade cumulus and a near-global marine low cloud feedback of 0.19 ± 0.12 W m−2 K−1 (90% confidence). These constraints imply a moderate climate sensitivity (~3 K). Despite improved midlatitude cloud feedback simulation by several current-generation climate models, their erroneously positive trade cumulus feedbacks produce unrealistically high climate sensitivities. Conversely, models simulating erroneously weak low cloud feedbacks produce unrealistically low climate sensitivities. Marine low clouds cool the planet, but their response to warming is uncertain and dominates the spread in model-based climate sensitivities. Observational constraints suggest smaller cloud feedbacks than previously reported and imply a more moderate climate sensitivity.

The Whitehorse Group and Quartermaster Formation are extensive red-bed terrestrial sequences representing the final episode of sedimentation in the Palo Duro Basin in north-central Texas, U.S.A. Regionally, these strata record the culmination of a long-term regression sequence beginning in the middle to late Permian. The Whitehorse Group includes beds of abundant laminated to massive red quartz siltstone to fine sandstone and rare dolomite, laminated to massive gypsum, and claystones, as well as diagenetic gypsum. The Quartermaster Formation exhibits a change from nearly equal amounts of thin planar and lenticular fine sandstone and laminated to massive mudstone in its lower half to overlying strata with coarser-grained, cross-bedded sandstones indicative of meandering channels up to 7 m deep and rare overbank mudstones. Paleosols are absent in the Upper Whitehorse Group and only poorly developed in the Quartermaster Formation. Volcanic ash-fall deposits (tuffs) present in uppermost Whitehorse Group and lower Quartermaster Formation strata permit correlation among five stratigraphic sections distributed over ∼150 km and provide geochronologic age information for these rocks. Both the Whitehorse Group and Quartermaster Formation have traditionally been assigned to the late Permian Ochoan (Changhsingian) stage, and workers assumed that the Permian-Triassic boundary is characterized by a regionally significant unconformity. Chemostratigraphic or biostratigraphic evidence for this age assignment, however, have been lacking to date. Single zircon U-Pb CA-TIMS analyses from at least two distinct volcanic ash fall layers in the lower Quartermaster Formation, which were identified and collected from five different localities across the Palo Duro Basin, yield interpreted depositional ages ranging from 252.19 ± 0.30 to 251.74 ± 0.28 Ma. Single zircon U-Pb CA-TIMS analyses of detrital zircons from sandstones located only a few meters beneath the top of the Quartermaster Formation yield a range of dates from Mesoproterozoic (1418 Ma) to Middle Triassic (244.5 Ma; Anisian), the latter of which is interpreted as a maximum depositional age, which is no older than Anisian, thus indicating the Permian-Triassic boundary to lie somewhere within the lower Quartermaster Formation/upper Whitehorse Group succession. Stable carbon isotope data from 180 samples of early-burial dolomicrite cements preserve a chemostratigraphic signal that is similar among sections, with a large ∼−8‰ negative isotope excursion ∼20 m beneath the Whitehorse Group-Quartermaster Formation boundary. This large negative carbon isotope excursion is interpreted to be the same excursion associated with the end-Permian extinction and this is in concert with the new high precision radioisotopic age data presented and the fact that the excursion lies within a normal polarity stratigraphic magnetozone. Dolomite cement δ13C values remain less negative (between about −5 and −8 permil) into the lower part of the Quartermaster Formation before becoming more positive toward the top of the section. This long interval of negative δ13C values in the Quartermaster Formation is interpreted to represent the earliest Triassic (Induan) inception of biotic and ecosystem “recovery.” Oxygen isotope values of dolomicrite cements show a progressive trend toward more positive values through the boundary interval, suggesting substantially warmer conditions around the end-Permian extinction event and a trend toward cooler conditions after the earliest Triassic. Our observations on these strata show that the paleoenvironment and paleoclimate across the Permian-Triassic boundary in western, sub-equatorial Pangea was characterized by depositional systems that were not conducive to plant preservation.

Understanding how marine low clouds and their radiative effects respond to changing meteorological conditions is crucial to constrain low-cloud feedbacks to greenhouse warming and internal climate variability. In this study, we use observations to quantify the low-cloud radiative response to meteorological perturbations over the global oceans to shed light on physical processes governing low-cloud and planetary radiation budget variability in different climate regimes. We assess the independent effect of perturbations in sea surface temperature, estimated inversion strength, horizontal surface temperature advection, 700-hPa relative humidity, 700-hPa vertical velocity, and near-surface wind speed. Stronger inversions and stronger cold advection greatly enhance low-level cloudiness and planetary albedo in eastern ocean stratocumulus and midlatitude regimes. Warming of the sea surface drives pronounced reductions of eastern ocean stratocumulus cloud amount and optical depth, and hence reflectivity, but has a weaker and more variable impact on low clouds in the tropics and middle latitudes. By reducing entrainment drying, higher free-tropospheric relative humidity enhances low-level cloudiness. At low latitudes, where cold advection destabilizes the boundary layer, stronger winds enhance low-level cloudiness; by contrast, wind speed variations have weak influence at midlatitudes where warm advection frequently stabilizes the marine boundary layer, thus inhibiting vertical mixing. These observational constraints provide a framework for understanding and evaluating marine low-cloud feedbacks and their simulation by models.

Malaria infection induces complex and diverse immune responses. To elucidate the mechanisms underlying host–parasite interaction, we performed a genetic screen during early (24 h) Plasmodium yoelii infection in mice and identified a large number of interacting host and parasite genes/loci after transspecies expression quantitative trait locus (Ts-eQTL) analysis. We next investigated a host E3 ubiquitin ligase gene (March1) that was clustered with interferon (IFN)-stimulated genes (ISGs) based on the similarity of the genome-wide pattern of logarithm of the odds (LOD) scores (GPLS). March1 inhibits MAVS/STING/TRIF-induced type I IFN (IFN-I) signaling in vitro and in vivo. However, in malaria-infected hosts, deficiency of March1 reduces IFN-I production by activating inhibitors such as SOCS1, USP18, and TRIM24 and by altering immune cell populations. March1 deficiency increases CD86(+)DC (dendritic cell) populations and levels of IFN-γ and interleukin 10 (IL-10) at day 4 post infection, leading to improved host survival. T cell depletion reduces IFN-γ level and reverse the protective effects of March1 deficiency, which can also be achieved by antibody neutralization of IFN-γ. This study reveals functions of MARCH1 (membrane-associated ring-CH–type finger 1) in innate immune responses and provides potential avenues for activating antimalaria immunity and enhancing vaccine efficacy.

Marine low clouds cool the Earth's climate, with their coverage (LCC) being controlled by their environment. Here, an observed significant decrease of LCC in the northeastern Pacific over the past two decades is linked quantitatively to changes in cloud‐controlling factors. In a comparison of different statistical and machine learning methods, a decrease in the inversion strength and near‐surface winds, and an increase in sea surface temperatures (SSTs) are unanimously shown to be the main causes of the LCC decrease. While the decreased inversion strength leads to more entrainment of dry free‐tropospheric air, the increasing SSTs are shown to lead to an increased vertical moisture gradient that enhances evaporation when entrainment takes place. While the LCC trend is likely driven by natural variability, the trend‐attribution framework developed here can be used with any method in future analyses. We find the choice of predictors is more important than the method., Plain Language Summary: Marine low clouds efficiently cool the Earth's climate, and their prevalence is controlled by environmental factors. Here, a decrease of the cover of marine low clouds in the northeastern Pacific over the past 20 years is analyzed to attribute the trend to changes in environmental factors known to be important for low clouds. A decrease in the strength of the temperature inversion and an increase in sea surface temperatures (SSTs) are shown to be the main causes of the low‐cloud trend. The decreased inversion strength leads to more mixing in of dry air from above the clouds, leading to cloud evaporation. The increasing SSTs increase the atmospheric moisture levels near the surface more than above the cloud, enhancing evaporation when the mixing takes place. While the trend in low clouds is likely driven by natural variability rather than climate change, the analytical framework developed here can be deployed to attribute causes for trends with any statistical or machine learning method in the future. The analysis shows that the choice of environmental factors used for the analysis has a larger impact on the results than the method., Key Points: Significant decrease of low cloud cover in northeastern Pacific in last two decades. Increased vertical moisture gradient, decreased inversion strength, and winds drive low cloud trend. Good agreement between statistical and machine‐learning methods, predictor choice more important., Horizon 2020 research and innovation program, https://doi.org/10.24381/cds.f17050d7, https://doi.org/10.24381/cds.6860a573, https://dx.doi.org/10.5067/MODIS/MOD08_M3.061, http://dx.doi.org/10.5067/MODIS/MYD08_M3.061, https://doi.org/10.5067/TERRA-AQUA/CERES/EBAF-TOA_L3B004.1, https://doi.org/10.5281/zenodo.5747221

The persistent and growing spread in effective climate sensitivity (ECS) across global climate models necessitates rigorous evaluation of their cloud feedbacks. Here we evaluate several cloud feedb...

Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set of compounds against

In this report we investigate the thermal evolution in a one-dimensional bagasse stockpile. The mathematical model is taken from the work of Gray et al. and involves four unknowns, the temperature, oxygen, liquid water and water vapour. We first non-dimensionalise the model to identify dominant terms and so simplify the system. We then calculate solutions for the approximate and full system. It is shown that under certain conditions spontaneous combustion will occur. Most importantly we show that spontaneous combustion can be avoided by sequential building. For example, in a situation where say a 6 m stockpile can spontaneously combust we could construct a 3 m pile then some days later add another 3 m to produce a stable 6 m pile.

Summary HIV-specific T cells have diminished effector function and fail to control/eliminate the virus. IL-27, a member of the IL-6/IL-12 cytokine superfamily has been shown to inhibit HIV replication. However, whether or not IL-27 can enhance HIV-specific T cell function is largely unknown. In the present manuscript, we investigated the role of IL-27 signaling in human T cells by evaluating the global transcriptional changes related to the function of HIV-specific T cells. We found that T cells from people living with HIV (PLWH), expressed higher levels of STAT1 leading to enhanced STAT1 activation upon IL-27 stimulation. Observed IL-27 induced transcriptional changes were associated with IFN/STAT1-dependent pathways in CD4 and CD8 T cells. Importantly, IL-27 dependent modulation of T-bet expression promoted IFNγ secretion by TIGIT+HIVGag-specific T cells. This new immunomodulatory effect of IL-27 on HIV-specific T cell function suggests its potential therapeutic use in cure strategies., Graphical abstract, Highlights • IL-27 induced transcriptional changes associated with IFN/STAT1-dependent pathways • HIV infection alters IL-27 signaling in T cells by enhancing STAT1 phosphorylation • IL-27 upregulates T-bet expression and enhances TIGIT+ HIVGag-specific T cell function, Immune response; Components of the immune system; Transcriptomics

The Heat Balance Integral Method (HBIM) is generally applied to one-dimensional Cartesian heat flow and Stefan problems. The main reason for this being that solutions in spherical and cylindrical coordinates are less accurate than in Cartesian. Consequently, in this paper we examine the application of the HBIM to Stefan problems in spherical and cylindrical coordinates, with the aim of improving accuracy. The standard version as well as one designed to minimise errors will be applied on the original and transformed system. Results are compared against numerical and perturbation solutions. It is shown that for the spherical case it is possible to obtain highly accurate approximate solutions (more accurate than the first order perturbation for realistic values of the Stefan number). For the cylindrical problem the results are significantly less accurate.

Patients with classic hydroa vacciniforme–like lymphoproliferative disorder (HVLPD) typically have high levels of Epstein-Barr virus (EBV) DNA in T cells and/or natural killer (NK) cells in blood and skin lesions induced by sun exposure that are infiltrated with EBV-infected lymphocytes. HVLPD is very rare in the United States and Europe but more common in Asia and South America. The disease can progress to a systemic form that may result in fatal lymphoma. We report our 11-year experience with 16 HVLPD patients from the United States and England and found that whites were less likely to develop systemic EBV disease (1/10) than nonwhites (5/6). All (10/10) of the white patients were generally in good health at last follow-up, while two-thirds (4/6) of the nonwhite patients required hematopoietic stem cell transplantation. Nonwhite patients had later age of onset of HVLPD than white patients (median age, 8 vs 5 years) and higher levels of EBV DNA (median, 1 515 000 vs 250 000 copies/ml) and more often had low numbers of NK cells (83% vs 50% of patients) and T-cell clones in the blood (83% vs 30% of patients). RNA-sequencing analysis of an HVLPD skin lesion in a white patient compared with his normal skin showed increased expression of interferon-γ and chemokines that attract T cells and NK cells. Thus, white patients with HVLPD were less likely to have systemic disease with EBV and had a much better prognosis than nonwhite patients. This trial was registered at www.clinicaltrials.gov as #NCT00369421 and #NCT00032513.

The question posed at the study group, by a South African premiership team based in Johannesburg, was basically, ‘Can we choose a match ball that will disadvantage opponents?’ In this report we answer the question through focussing on the motion of a football through the air (which is where the difference in the ball’s behaviour due to altitude is greatest). The forces affecting a ball’s motion are described and we show how this translates into a mathematical problem consisting of a system of coupled nonlinear differential equations. Numerical and approximate analytical solutions are presented and compared. We then show how the mathematical results may be used to guide the choice of ball.

Nanoparticles, small units of matter with dimensions in the range 1-100 nm, exhibit many advantageous size-dependent magnetic, electrical, chemical and optical prop- erties, which are not observed at the microscale or bulk. These properties are extremely sensitive to particle size, and thus the ability to produce monodisperse particles is critical. Due to its ease of use and flexibility, precipitation of nanoparticles from solution is one of the most widely used synthesis methods. The main disadvantage of this method is that the relationship between particle growth and system conditions is not fully understood. In practice, the optimal reaction conditions are usually ascertained empirically or intuitively. In this report we consider several different applied mathematical techniques to explain nanoparticle growth via the precipitation method. In particular, we describe the impact of size focussing and defocussing (or Ostwald ripening) on the evolution of the nanoparticle size distribution., EU COST Action MI-Net (Maths for Industry Network)

Genome-wide association studies have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP, and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). As ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWAS identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor gene (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. As AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus, and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression, and altering melanocyte growth phenotypes upon exposure.