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Cancer genomics studies have identified thousands of putative cancer driver genes 1 . Development of high-throughput and accurate models to define the functions of these genes is a major challenge. Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif 2 from the α-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities. CRISPR screens in a 3D spheroid cancer model system more accurately recapitulate cancer phenotypes than existing 2D models and were used to identify carboxypeptidase D, acting via the IGF1R, as a 3D-specific driver of cancer growth.

The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25D3), regulates a number of physiological and pathological processes, including cell proliferation and differentiation. Thousands of analogues of 1,25D3 have been developed with the aim of selective effects for medical use. Here we describe the synthesis of two new unconventional vitamin D analogues bearing A-ring modifications with ortho-carborane (dicarba-o-closo-1,2-dodecaborane) units. The ligands function as agonists for VDR with similar antiproliferative activities as 1,25D3. Whereas mice treated with the analogues 4 and 5 exhibited similar hypercalcemic activities as 1,25D3, only compound 4 and 1,25D3 induced the strong activation of CYP24A1 mRNA expression but not compound 5.

Background. Nocardia species cause infections in both immunocompromised and otherwise immunocompetent patients, although the mechanisms defining susceptibility in the latter group are elusive. Anticytokine autoantibodies are an emerging cause of pathogen-specific susceptibility in previously healthy human immunodeficiency virus-uninfected adults, including anti–granulocyte macrophage colony-stimulating factor (GM-CSF) autoantibodies with cryptococcal meningitis. Methods. Plasma from patients with disseminated/extrapulmonary nocardiosis and healthy controls was screened for anticytokine autoantibodies using a particle-based approach. Autoantibody function was assessed by intranuclear staining for GM-CSF–induced STAT5 phosphorylation in normal cells incubated with either patient or normal plasma. GM-CSF–mediated cellular activation by Nocardia was assessed by staining for intracellular cytokine production and intranuclear STAT5 phosphorylation. Results. We identified neutralizing anti–GM-CSF autoantibodies in 5 of 7 patients studied with central nervous system nocardiosis and in no healthy controls (n = 14). GM-CSF production was induced by Nocardia in vitro, suggesting a causative role for anti–GM-CSF autoantibodies in Nocardia susceptibility and dissemination. Conclusions. In previously healthy adults with otherwise unexplained disseminated/extrapulmonary Nocardia infections, anti–GM-CSF autoantibodies should be considered. Their presence may suggest that these patients may be at risk for later development of pulmonary alveolar proteinosis or other opportunistic infections, and that patients may benefit from therapeutic GM-CSF administration.

[...]the Every Woman Every Child movement attracted more than US$60 billion dollars to women's and children's health between 2010 and 2015, with commitments from over 300 partners.6 The movement has spurred partnership mechanisms to support country-led implementation of the global strategy (2016-2030) - including the Global Financing Facility in support of Every Woman Every Child, the Innovation Marketplace, Unified Accountability Framework and the UN system's health agencies' H6 partnership.1 The global strategy (2016-2030) recognizes that human rights and other fundamental development principles - such as equity, community ownership and development effectiveness - are drivers of transformative change.1 In Peru, principles of equity underpinned a programme of poverty mapping to identify and prioritize reaching poor, rural and indigenous populations with social protection programmes and culturally appropriate, affordable care.7 In Kenya, the institutionalization of human rights principles is benefiting women's health following complaints alleging systematic violation of women's reproductive health rights in health facilities.

Over the past decades, stable isotopes have been infrequently used to characterise host-parasite trophic relationships. This is because we have not yet identified consistent patterns in stable isotope values between parasites and their host tissues across species, which are crucial for understanding host-parasite dynamics. To address this, we initiated a worldwide collaboration to establish a unique database of stable isotope values of novel host-parasite pairs, effectively doubling the existing data in published literature. This database includes nitrogen, carbon, and sulphur stable isotope values. We present 3213 stable isotope data entries, representing 586 previously unpublished host-parasite pairs. Additionally, while existing literature was particularly limited in sulphur isotope values, we tripled information on this crucial element. By publishing unreported host-parasite pairs from previously unsampled areas of the world and using appropriate host tissues, our dataset stands unparalleled. We anticipate that end-users will utilise our database to uncover generalisable patterns, deepening our understanding of the complexities of parasite-host relationships and driving future research efforts in stable isotope parasitology.

This study examines the dynamics and robustness of large-scale evapotranspiration products in water-limited environments. Four types of ET products are tested against rainfall in two large semi-arid to arid Australian basins from 2003 to 2010: two energy balance ET methods which are forced by optical satellite retrievals from MODIS; a newly developed land surface model (AWRA); and one approach based on observations from the Gravity Recovery and Climate Experiment (GRACE) and rainfall data. The two basins are quasi (Murray-Darling Basin: 1.06 million km2) and completely (Lake Eyre Basin: 1.14 million km2) endorheic. During the study period, two extreme climatic events—the Millennium drought and the strongest La Niña event—were recorded in the basins and are used in our assessment. The two remotely-sensed ET products constrained by the energy balance tended to overestimate ET flux over water-stressed regions. They had low sensitivity to climatic extremes and poor capability to close the water balance. However, these two remotely-sensed and energy balance products demonstrated their superiority in capturing spatial features including over small-scale and complicated landscapes. AWRA and GRACE formulated in the water balance framework were more sensitive to rainfall variability and yielded more realistic ET estimates during climate extremes. GRACE demonstrated its ability to account for seasonal and inter-annual change in water storage for ET evaluation.

The University of Georgia Board of Regents' action to end formal recognition of the UGA Foundation is incomprehensible. The regents would like to establish a separate foundation and transfer the UGA Foundation's assets to it. This would violate the trust of thousands of donors to the UGA Foundation and invite a court battle. Three cheers to the University of Georgia Board of Regents for standing up for UGA and putting the needs of the school ahead of the desires of the money brokers. For too long, many of the UGA Foundation directors and contributors wrongly believed that their money should entitle them to control and influence. Photo University System Chancellor Thomas Meredith (right), with regents Vice Chairman Joel Wooten Jr. and Chairman Joe Frank Harris, said the regents were tired of the UGA Foundation's efforts to exercise control. / BRANT SANDERLIN / Staff Photo The matricula consular is issued by Mexico to its nationals living abroad.

Over the past decades, stable isotopes have been infrequently used to characterise host-parasite trophic relationships. This is because we have not yet identified consistent patterns in stable isotope values between parasites and their host tissues across species, which are crucial for understanding host-parasite dynamics. To address this, we initiated a worldwide collaboration to establish a unique database of stable isotope values of novel host-parasite pairs, effectively doubling the existing data in published literature. This database includes nitrogen, carbon, and sulphur stable isotope values. We present 3213 stable isotope data entries, representing 586 previously unpublished host-parasite pairs. Additionally, while existing literature was particularly limited in sulphur isotope values, we tripled information on this crucial element. By publishing unreported host-parasite pairs from previously unsampled areas of the world and using appropriate host tissues, our dataset stands unparalleled. We anticipate that end-users will utilise our database to uncover generalisable patterns, deepening our understanding of the complexities of parasite-host relationships and driving future research efforts in stable isotope parasitology.