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Basin-scale planning is needed to minimize impacts in mega-diverse rivers The world's most biodiverse river basins—the Amazon, Congo, and Mekong—are experiencing an unprecedented boom in construction of hydropower dams. These projects address important energy needs, but advocates often overestimate economic benefits and underestimate far-reaching effects on biodiversity and critically important fisheries. Powerful new analytical tools and high-resolution environmental data can clarify trade-offs between engineering and environmental goals and can enable governments and funding institutions to compare alternative sites for dam building. Current site-specific assessment protocols largely ignore cumulative impacts on hydrology and ecosystem services as ever more dams are constructed within a watershed ( 1 ). To achieve true sustainability, assessments of new projects must go beyond local impacts by accounting for synergies with existing dams, as well as land cover changes and likely climatic shifts ( 2 , 3 ). We call for more sophisticated and holistic hydropower planning, including validation of technologies intended to mitigate environmental impacts. Should anything less be required when tampering with the world's great river ecosystems?

GWAS have generally focused on common variants from genotyping arrays or rare protein-coding variants from exome sequencing. Here, we use whole-genome sequencing data to evaluate the contribution to and architecture of rare non-coding variants for three commonly studied anthropometric traits: height, BMI and waist-hip ratio adjusted for BMI. Analysing 447,461 individuals in the UK Biobank for discovery and 225,515 individuals in All of Us for replication, we identify 90 rare and low-frequency single variant associations, including two independent rare variants upstream of IGF2BP2 that substantially reduce waist-hip ratio adjusted for BMI, but have distinct effects on other adiposity traits. We further identify 135 coding variant aggregates. For example, UBR3 protein-truncating variants are associated with a 2.7 kg/m2 increase in BMI. We additionally identify 51 non-coding variant aggregate associations, including one in the 5’UTR of FGF18 associated with up to 6 cm effects on height. We show that 97% of rare variant associations occur near GWAS-identified loci, demonstrating convergence of rare and common variant associations. Finally, we show that ultra rare variants explain a small fraction of heritability compared to common variants for these traits, that heritability is largely shared across ancestries, and that it concentrates around common variant loci. Most GWAS have focused on common variants or rare protein coding variants. Here, the authors interrogate the contribution of rare non-coding variants for anthropometric traits, identifying new genes associated with increased BMI and height.

The blood–cerebrospinal fluid barrier (BCSFB) is a highly dynamic transport interface that serves brain homeostasis. To date, however, understanding of its role in brain development and pathology has been hindered by the absence of a non-invasive technique for functional assessment. Here we describe a method for non-invasive measurement of BSCFB function by using tracer-free MRI to quantify rates of water delivery from arterial blood to ventricular cerebrospinal fluid. Using this method, we record a 36% decrease in BCSFB function in aged mice, compared to a 13% decrease in parenchymal blood flow, itself a leading candidate biomarker of early neurodegenerative processes. We then apply the method to explore the relationship between BCSFB function and ventricular morphology. Finally, we provide proof of application to the human brain. Our findings position the BCSFB as a promising new diagnostic and therapeutic target, the function of which can now be safely quantified using non-invasive MRI. The blood–cerebrospinal fluid barrier (BCSFB) is an important interface for brain homeostasis. Here the authors describe a non-invasive MRI technique for the quantitative assessment of BCSFB function.

Action spectra are important biological weighting functions for risk/benefit analyses of ultraviolet (UV) radiation (UVR) exposure. One important human benefit of exposure to terrestrial solar UVB radiation (∼295 to 315 nm) is the cutaneous synthesis of vitamin D₃ that is initiated by the photoconversion of 7-dehydrocholesterol to previtamin D₃. An action spectrum for this process that is followed by other nonphotochemical steps to achieve biologically active vitamin D₃ has been established from ex vivo data and is widely used, although its validity has been questioned. We tested this action spectrum in vivo by full- or partial-body suberythemal irradiation of 75 healthy young volunteers with five different polychromatic UVR spectra on five serial occasions. Serum 25-hydroxyvitamin D₃ [25(OH) D₃] levels, as the most accurate measure of vitamin D₃ status, were assessed before, during, and after the exposures. These were then used to generate linear dose–response curves that were different for each UVR spectrum. It was established that the previtamin D₃ action spectrum was not valid when related to the serum 25(OH)D₃ levels, as weighting the UVR doses with this action spectrum did not result in a common regression line unless it was adjusted by a blue shift, with 5 nm giving the best fit. Such a blue shift is in accord with the published in vitro action spectra for vitamin D₃ synthesis. Thus, calculations regarding the risk (typically erythema) versus the benefit of exposure to solar UVR based on the ex vivo previtamin D₃ action spectrum require revision.

Subfossil pollen and plant macrofossil data derived from 14 C-dated sediment profiles can provide quantitative information on glacial and interglacial climates. The data allow climate variables related to growing-season warmth, winter cold, and plant-available moisture to be reconstructed. Continental-scale reconstructions have been made for the mid-Holocene (MH, around 6 ka) and Last Glacial Maximum (LGM, around 21 ka), allowing comparison with palaeoclimate simulations currently being carried out as part of the fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change. The synthesis of the available MH and LGM climate reconstructions and their uncertainties, obtained using modern-analogue, regression and model-inversion techniques, is presented for four temperature variables and two moisture variables. Reconstructions of the same variables based on surface-pollen assemblages are shown to be accurate and unbiased. Reconstructed LGM and MH climate anomaly patterns are coherent, consistent between variables, and robust with respect to the choice of technique. They support a conceptual model of the controls of Late Quaternary climate change whereby the first-order effects of orbital variations and greenhouse forcing on the seasonal cycle of temperature are predictably modified by responses of the atmospheric circulation and surface energy balance.

Triazole antifungals function as ergosterol biosynthesis inhibitors and are frontline therapy for invasive fungal infections, such as invasive aspergillosis. The primary mechanism of action of triazoles is through the specific inhibition of a cytochrome P450 14-α-sterol demethylase enzyme, Cyp51A/B, resulting in depletion of cellular ergosterol. Here, we uncover a clinically relevant secondary mechanism of action for triazoles within the ergosterol biosynthesis pathway. We provide evidence that triazole-mediated inhibition of Cyp51A/B activity generates sterol intermediate perturbations that are likely decoded by the sterol sensing functions of HMG-CoA reductase and Insulin-Induced Gene orthologs as increased pathway activity. This, in turn, results in negative feedback regulation of HMG-CoA reductase, the rate-limiting step of sterol biosynthesis. We also provide evidence that HMG-CoA reductase sterol sensing domain mutations previously identified as generating resistance in clinical isolates of Aspergillus fumigatus partially disrupt this triazole-induced feedback. Therefore, our data point to a secondary mechanism of action for the triazoles: induction of HMG-CoA reductase negative feedback for downregulation of ergosterol biosynthesis pathway activity. Abrogation of this feedback through acquired mutations in the HMG-CoA reductase sterol sensing domain diminishes triazole antifungal activity against fungal pathogens and underpins HMG-CoA reductase-mediated resistance. Triazole antifungals are widely used and exert their action by inhibiting ergosterol biosynthesis. Here, Rybak et al show that these drugs both inhibit ergosterol biosynthesis and induce accumulation of pathway intermediates that directly induce inhibition of sterol synthesis.

Triazoles, the most widely used class of antifungal drugs, inhibit the biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Inhibition of a separate ergosterol biosynthetic step, catalyzed by the sterol C-24 methyltransferase Erg6, reduces the virulence of pathogenic yeasts, but its effects on filamentous fungal pathogens like Aspergillus fumigatus remain unexplored. Here, we show that the lipid droplet-associated enzyme Erg6 is essential for the viability of A. fumigatus and other Aspergillus species, including A. lentulus , A. terreus , and A. nidulans. Downregulation of erg6 causes loss of sterol-rich membrane domains required for apical extension of hyphae, as well as altered sterol profiles consistent with the Erg6 enzyme functioning upstream of the triazole drug target, Cyp51A/Cyp51B. Unexpectedly, erg6 -repressed strains display wild-type susceptibility against the ergosterol-active triazole and polyene antifungals. Finally, we show that erg6 repression results in significant reduction in mortality in a murine model of invasive aspergillosis. Taken together with recent studies, our work supports Erg6 as a potentially pan-fungal drug target. Antifungal triazoles inhibit biosynthesis of ergosterol, a crucial component of the fungal plasma membrane. Here, Xie et al. show that Erg6, the enzyme that catalyzes a previous step in ergosterol biosynthesis, is essential for the viability of Aspergillus fumigatus , and its repression reduces the virulence of this fungal pathogen in an animal model of infection.

Increased hyperphosphorylated tau and the formation of intracellular neurofibrillary tangles are associated with the loss of neurons and cognitive decline in Alzheimer's disease, and related neurodegenerative conditions. We applied two diffusion models, diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to in vivo diffusion magnetic resonance images (dMRI) of a mouse model of human tauopathy (rTg4510) at 8.5months of age. In grey matter regions with the highest degree of tau burden, microstructural indices provided by both NODDI and DTI discriminated the rTg4510 (TG) animals from wild type (WT) controls; however only the neurite density index (NDI) (the volume fraction that comprises axons or dendrites) from the NODDI model correlated with the histological measurements of the levels of hyperphosphorylated tau protein. Reductions in diffusion directionality were observed when implementing both models in the white matter region of the corpus callosum, with lower fractional anisotropy (DTI) and higher orientation dispersion (NODDI) observed in the TG animals. In comparison to DTI, histological measures of tau pathology were more closely correlated with NODDI parameters in this region. This in vivo dMRI study demonstrates that NODDI identifies potential tissue sources contributing to DTI indices and NODDI may provide greater specificity to pathology in Alzheimer's disease. •We analyzed the microstructural changes in rTg4510 and wild type mice at 8.5months.•We correlated microstructural findings with histological measures of tau burden•We compare two diffusion MR models: DTI and NODDI.•Both models revealed changes in tissue microstructure due to tau pathology.•The NODDI metrics demonstrated a good correlation with histological measures of tau burden.

Fungal pathogens must exhibit strong nutritional plasticity, effectively sensing and utilizing diverse nutrients to support virulence. How the signals generated by nutritional sensing are efficiently translated to the morphogenetic machinery for optimal growth and support of virulence remains incompletely understood. Here, we show that the conserved morphogenesis-related kinase, CotA, imparts isoform-specific control over Aspergillus fumigatus invasive growth in host-mimicking environments and during infection. CotA-mediated invasive growth is responsive to exogenous carbon source quality, with only preferred carbon sources supporting hyphal morphogenesis in a mutant lacking one of two identified protein isoforms. Strikingly, we find that the CotA protein does not regulate, nor is cotA gene expression regulated by, the carbon catabolite repression system. Instead, we show that CotA partially mediates invasive growth in specific carbon sources and virulence through the conserved downstream effector and translational repressor, SsdA. Therefore, A. fumigatus CotA accomplishes its conserved morphogenetic functions to drive pathogenic growth by translating host-relevant carbon source quality signals into morphogenetic outputs for efficient tissue invasive growth. Here, Martin-Vicente et al. show that the Aspergillus fumigatus protein kinase, CotA, controls invasive growth in an isoform dependent manner in response to carbon source diversity, partially mediated by the downstream effector, SsdA.

Background In response to growing pressures on primary care, leaders have introduced a wide range of workforce and practice innovations, including team redesigns that delegate some physician tasks to nonphysicians. One important question is how such innovations affect care team members, particularly in view of growing dissatisfaction and burnout among healthcare professionals. We examine the work experiences of primary care physicians and staff after implementing Lean-based workflow redesigns. This included co-locating physician and medical assistant dyads, delegating significant responsibilities to nonphysician staff, and mandating greater coordination and communication among all care team members. Methods The redesigns were implemented and scaled in three phases across 46 primary care departments in a large ambulatory care delivery system. We fielded 1164 baseline and 1333 follow-up surveys to physicians and other nonphysician staff (average 73% response rate) to assess workforce engagement (e.g., job satisfaction, motivation), perceptions of the work environment, and job-related burnout. We conducted multivariate regressions to detect changes in experiences after the redesign, adjusting for respondent characteristics and clustering of within-clinic responses. Results We found that both physicians and nonphysician staff reported higher levels of engagement and teamwork after implementing redesigns. However, they also experienced higher levels of burnout and perceptions of the workplace as stressful. Trends were the same for both occupational groups, but the increased reports of stress were greater among physicians. Additionally, members of all clinics, except for the pilot site that developed the new workflows, reported higher burnout, while perceptions of workplace stress increased in all clinics after the redesign. Conclusions Our findings partially align with expectations of work redesign as a route to improving physician and staff experiences in delivering care. Although teamwork and engagement increased, the redesigns in our study were not enough to moderate long-standing challenges facing primary care. Yet higher levels of empowerment and engagement, as observed in the pilot clinic, may be particularly effective in facilitating improvements while combating fatigue. To help practices cope with increasing burdens, interventions must directly benefit healthcare professionals without overtaxing an already overstretched workforce.