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Systemic Candida albicans infection causes high morbidity and mortality and is associated with neutropenia; however, the roles of other innate immune cells in pathogenesis are poorly defined. Here, using a mouse model of systemic candidiasis, we found that resident macrophages accumulated in the kidney, the main target organ of infection, and formed direct contacts with the fungus in vivo mainly within the first few hours after infection. Macrophage accumulation and contact with Candida were both markedly reduced in mice lacking chemokine receptor CX3CR1, which was found almost exclusively on resident macrophages in uninfected kidneys. Infected Cx3cr1-/- mice uniformly succumbed to Candida-induced renal failure, but exhibited clearance of the fungus in all other organs tested. Renal macrophage deficiency in infected Cx3cr1-/- mice was due to reduced macrophage survival, not impaired proliferation, trafficking, or differentiation. In humans, the dysfunctional CX3CR1 allele CX3CR1-M280 was associated with increased risk of systemic candidiasis. Together, these data indicate that CX3CR1-mediated renal resident macrophage survival is a critical innate mechanism of early fungal control that influences host survival in systemic candidiasis.

Genetically regulated gene expression has helped elucidate the biological mechanisms underlying complex traits. Improved high-throughput technology allows similar interrogation of the genetically regulated proteome for understanding complex trait mechanisms. Here, we used the Trans-omics for Precision Medicine (TOPMed) Multi-omics pilot study, which comprises data from Multi-Ethnic Study of Atherosclerosis (MESA), to optimize genetic predictors of the plasma proteome for genetically regulated proteome-wide association studies (PWAS) in diverse populations. We built predictive models for protein abundances using data collected in TOPMed MESA, for which we have measured 1,305 proteins by a SOMAscan assay. We compared predictive models built via elastic net regression to models integrating posterior inclusion probabilities estimated by fine-mapping SNPs prior to elastic net. In order to investigate the transferability of predictive models across ancestries, we built protein prediction models in all four of the TOPMed MESA populations, African American (n = 183), Chinese (n = 71), European (n = 416), and Hispanic/Latino (n = 301), as well as in all populations combined. As expected, fine-mapping produced more significant protein prediction models, especially in African ancestries populations, potentially increasing opportunity for discovery. When we tested our TOPMed MESA models in the independent European INTERVAL study, fine-mapping improved cross-ancestries prediction for some proteins. Using GWAS summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study, which comprises ∼50,000 Hispanic/Latinos, African Americans, Asians, Native Hawaiians, and Native Americans, we applied S-PrediXcan to perform PWAS for 28 complex traits. The most protein-trait associations were discovered, colocalized, and replicated in large independent GWAS using proteome prediction model training populations with similar ancestries to PAGE. At current training population sample sizes, performance between baseline and fine-mapped protein prediction models in PWAS was similar, highlighting the utility of elastic net. Our predictive models in diverse populations are publicly available for use in proteome mapping methods at https://doi.org/10.5281/zenodo.4837327 .

The COVID-19 pandemic disrupted the world in 2020 by spreading at unprecedented rates and causing tens of thousands of fatalities within a few months. The number of deaths dramatically increased in regions where the number of patients in need of hospital care exceeded the availability of care. Many COVID-19 patients experience Acute Respiratory Distress Syndrome (ARDS), a condition that can be treated with mechanical ventilation. In response to the need for mechanical ventilators, designed and tested an emergency ventilator (EV) that can control a patient’s peak inspiratory pressure (PIP) and breathing rate, while keeping a positive end expiratory pressure (PEEP). This article describes the rapid design, prototyping, and testing of the EV. The development process was enabled by rapid design iterations using additive manufacturing (AM). In the initial design phase, iterations between design, AM, and testing enabled a working prototype within one week. The designs of the 16 different components of the ventilator were locked by additively manufacturing and testing a total of 283 parts having parametrically varied dimensions. In the second stage, AM was used to produce 75 functional prototypes to support engineering evaluation and animal testing. The devices were tested over more than two million cycles. We also developed an electronic monitoring system and with automatic alarm to provide for safe operation, along with training materials and user guides. The final designs are available online under a free license. The designs have been transferred to more than 70 organizations in 15 countries. This project demonstrates the potential for ultra-fast product design, engineering, and testing of medical devices needed for COVID-19 emergency response.

Since European settlement, over 50 % of coastal wetlands have been lost in the Laurentian Great Lakes basin, causing growing concern and increased monitoring by government agencies. For over a decade, monitoring efforts have focused on the development of regional and organism-specific measures. To facilitate collaboration and information sharing between public, private, and government agencies throughout the Great Lakes basin, we developed standardized methods and indicators used for assessing wetland condition. Using an ecosystem approach and a stratified random site selection process, birds, anurans, fish, macroinvertebrates, vegetation, and physico-chemical conditions were sampled in coastal wetlands of all five Great Lakes including sites from the United States and Canada. Our primary objective was to implement a standardized basin-wide coastal wetland monitoring program that would be a powerful tool to inform decision-makers on coastal wetland conservation and restoration priorities throughout the Great Lakes basin.

Premise of research. Over the past 3 decades, angiosperm woods have been reported from the Campanian to the Maastrichtian of southern Laramidia, including Coahuila and Chihuahua, Mexico; Big Bend National Park, Texas; and the San Juan Basin, New Mexico. Recent investigations of the upper Campanian (76.5 to >72.5 Ma) Jose Creek Member of the McRae Formation, south-central New Mexico, indicate an abundance of well-preserved silicified woods, representing one of the most diverse Cretaceous wood floras in the world. In this report, we describe four new angiosperm wood types. Methodology. The fossil woods described here were collected from the upper Campanian of south-central New Mexico, along the northeastern flank of the Caballo Mountains and in the adjacent Cutter Sag, and were studied using thin sections. The potential affinities of these McRae woods were determined by comparison with fossil and extant woods. Pivotal results. The woods reported here comprise one magnoliid and three eudicots with varying levels of comparability to extant taxa. Laurinoxylon rennerae sp. nov. belongs to Lauraceae and has a combination of features found in multiple extant genera variously referred to as Cinnamomeae Nees, Laureae Maout & Decaisne, or Lauroideae Burnett/core Lauraceae. Turneroxylon newmexicoense gen. et sp. nov. is a eudicot with many similarities to Dilleniaceae but differs in having narrower rays. Mcraeoxylon waddellii gen. et sp. nov. has a suite of features seen in several families of Malpighiales, Myrtales, and Oxalidales. McRae angiosperm wood type 1 has a suite of features found in genera of Dilleniales, Ericales, and Malpighiales. Conclusions. All wood types, with the exception of M. waddellii, have minimum axis diameters of >10 cm (12–50 cm), indicating that they represent trees. This reinforces previous evidence for the presence of small to large angiosperm trees in the Jose Creek Member and underscores the importance of woody angiosperms in vegetation of the southern Western Interior during the Campanian-Maastrichtian.

Background This study examined (1) associations between sociodemographic and clinical variables with low muscle mass and radiodensity and their loss relative to treatment commencement in patients with lung cancer; and (2) the magnitude of change in muscle mass and association with treatment outcomes and survival. Methods Prospective study in patients planned for curative (chemo)radiotherapy for lung cancer. Low skeletal muscle mass and radiodensity and muscle loss were determined from pre- and post-treatment computed tomography images. Sociodemographic, clinical, functional, nutritional, physical activity and alternate body composition were assessed pre-treatment. Logistic and linear regression and Fisher’s exact tests were used to assess associations between variables and study outcomes. Cox proportional hazards models were fitted to examine associations with survival. Results Overall, 53 patients (62.3% male) with a mean age of 69 ± 9.3 years and 54.8% with stage III disease were included. Pre-treatment low calf circumference was associated with pre-treatment low muscle mass ( p  = 0.006). Higher comorbidity scores pre-treatment were associated with normal muscle radiodensity pre- and post-treatment ( p  = 0.015, p  = 0.027, respectively). Pre-treatment low energy and protein intake were associated with low muscle radiodensity post-treatment. Muscle mass and radiodensity were not associated with survival or treatment outcomes. Conclusions In patients with lung cancer, there is some evidence anthropometric measures of muscle mass are suggestive of low muscle mass pre-radiotherapy, while low energy intake pre-treatment may indicate low muscle radiodensity after treatment. However, these findings are limited by the small sample size and further prospective studies with larger samples are required.

Use of viral vectors to deliver therapeutic genes to the central nervous system holds promise for the treatment of neurodegenerative diseases and neurotrauma. Adeno-associated viral (AAV) vectors encoding brain-derived neurotrophic factor (BDNF) or ciliary derived neurotrophic factor (CNTF) promote the viability and regeneration of injured adult rat retinal ganglion cells. However, these growth-inducing transgenes are driven by a constitutively active promoter, thus we examined whether long-term AAV-mediated secretion of BDNF or CNTF affected endogenous retinal gene expression. One year after the intravitreal injection of AAV-green fluorescent protein (GFP), bi- tronic AAV-BDNF-GFP or AAV-CNTF-GFP, mRNA was extracted and analyzed using custom 96 well polymerase chain reaction arrays. Of 93 test genes, 56% showed significantly altered expression in AAV-BDNF-GFP and/or AAV-CNTF-GFP retinas compared with AAV-GFP controls. Of these genes, 73% showed differential expression in AAV-BDNF versus AAV-CNTF injected eyes. To focus on retinal ganglion cell changes, quantitative polymerase chain reaction was undertaken on mRNA (16 genes) obtained from fixed retinal sections in which the ganglion cell layer was enriched. The sign and extent of fold changes in ganglion cell layer gene expression differed markedly from whole retinal samples. Sustained and global alteration in endogenous mRNA expression after gene therapy should be factored into any interpretation of experimental/clinical outcomes, particularly when introducing factors into the central nervous system that require secretion to evoke functionality.