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Seasonal streamflow forecasts provide key information for decision-making in fields such as water supply management, hydropower generation, and irrigation scheduling. The predictability of streamflow on seasonal timescales relies heavily on initial hydrological conditions, such as the presence of snow and the availability of soil moisture. In high-latitude and high-altitude headwater basins in North America, snowmelt serves as the primary source of runoff generation. This study presents and evaluates a data-driven workflow for probabilistic seasonal streamflow forecasting in snow-fed river basins across North America (Canada and the USA). The workflow employs snow water equivalent (SWE) measurements as predictors and streamflow observations as predictands. Gap-filling of SWE datasets is accomplished using quantile mapping from neighboring SWE and precipitation stations, and principal component analysis is used to identify independent predictor components. These components are then utilized in a regression model to generate ensemble hindcasts of streamflow volumes for 75 nival basins with limited regulation from 1979 to 2021, encompassing diverse geographies and climates. Using a hindcast evaluation approach that is user-oriented provides key insights for snow-monitoring experts, forecasters, decision-makers, and workflow developers. The analysis presented here unveils a wide spectrum of predictability and offers a glimpse into potential future changes in predictability. Late-season snowpack emerges as a key factor in predicting spring and summer volumes, while high precipitation during the target period presents challenges to forecast skill and streamflow predictability. Notably, we can predict lower-than-normal and higher-than-normal streamflows during spring to early summer with lead times of up to 5 months in some basins. Our workflow is available on GitHub as a collection of Jupyter Notebooks, facilitating broader applications in cold regions and contributing to the ongoing advancement of methodologies.

Abstract Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.

Abstract Campylobacter commonly causes foodborne infections and antibiotic resistance is an imminent concern. It is not clear, however, if the human gut ‘resistome’ is affected by Campylobacter during infection. Application of shotgun metagenomics on stools from 26 cases with Campylobacter infections and 44 healthy family members (controls) identified 406 unique antibiotic resistance genes (ARGs) representing 153 genes/operons, 40 mechanisms, and 18 classes. Cases had greater ARG richness (p

At high latitudes and altitudes one of the main controls on hydrological and biogeochemical processes is the breakup and freeze-up of lake and river ice. This study uses 3510 time series from across 678 Northern Hemisphere lakes and rivers to explore historical patterns in lake and river ice phenology across five overlapping time periods (1931–1960, 1946–1975, 1961–1990, 1976–2005, and 1931–2005). These time series show that the number of annual open-water days increased by 0.63 d per decade from 1931–2005 across the Northern Hemisphere, with trends for breakup and, to a lesser extent, freeze-up closely correlating with regionally averaged temperature. Breakup and freeze-up trends display a spatiotemporally complex evolution and reveal considerable caveats with interpreting the implications of ice phenology changes at lake and river sites that may only have breakup or freeze-up data, rather than both. These results provide an important contribution by showing regional variation in ice phenology trends through time that can be hidden by longer-term trends. The overlapping 30-year time periods also show evidence for an acceleration in warming trends through time. Understanding the changes on both long- and short-term timescales will be important for determining the causes of this change, the underlying biogeochemical processes associated with it, and the wider climatological significance as global temperatures rise.

Abstract Background Siaya County in Western Kenya has one of the highest maternal mortality rates in Kenya. We sought to elucidate factors that influence mothers’ decisions regarding where to seek obstetrical care, to inform interventions that seek to promote effective use of obstetric services and reduce maternal mortalities. To guide our research, we used the “Three Delays Model”, focusing on the first delay—seeking care. While interventions to reduce maternal mortalities have focused on addressing delays in accessing and receiving care, context-specific data on drivers of the first delay are scarce. Methods We used a mixed-method study to assess how maternal decision-making of birth location is influenced by personal, contextual, and cultural factors. We conducted structured interviews with women aged 14 years or older living in Siaya, Bondo, and Yala, rural districts in Western Kenya. We then conducted focus group interviews with a subset of women to elucidate this question: How do drivers of the first delay (i.e., seeking care) affect the decision to seek home versus hospital delivery, potentially negatively influencing maternal mortality. Results Three hundred and seven women responded to the surveys, and 67 women (22%) from this group participated in focus group interviews. Although we focused on type 1 delays, we discovered that several factors that impact type 2 and type 3 delays directly contribute to type 1 delays. Our findings highlighted that factors influencing women’s decisions to seek care are not simply medical or cultural but rather contextual, involving many elements of life, particularly in rural communities. Conclusions It is imperative to address multiple-level factors that influence women’s decisions to seek care and have in-hospital deliveries. To curtail maternal mortality in rural Western Kenya and comparable settings, targeted interventions must take into consideration these important influencers.

In recent years, insect meal has received considerable attention as an alternative ingredient for aquaculture feeds. When insects are reared on underutilised biomass streams, the resulting meal can potentially offer a reduced environmental impact compared to fishmeal and soybean meal. However, due to legislative restrictions, insects are commonly reared on materials that are also suitable to feed farm animals directly, including farmed fish. This practice compromises both the environmental and economic sustainability of insects as feed. For insect rearing to realise its potential and upcycle organic waste back into the food chain, substrates should thus consist of underutilised biomass. The aim of this study was to identify and assess the feasibility of underutilised biomass streams in Scotland for producing insect-based salmon feed ingredients, specifically defatted meal and oil from black soldier fly (BSF) larvae. Key information was collected on the most important biomass streams in Scotland, including their origin, available volumes, current utilisation, composition, geographic distribution, and legal status for insect rearing. To estimate the performance and body composition of BSF larvae reared on these biomass streams, a literature review was performed. The obtained data were then used to model the feasibility of different biomass streams as substrates for larvae meal and oil production. Based on the results, two whisky by-products are identified as the most promising biomass streams for BSF larvae rearing in Scotland, namely draff and pot ale. Draff is increasingly burned for bioenergy and most pot ale remains unused. It is estimated that 8.500 tonnes of larvae meal and 3.800 tonnes of larvae oil could potentially be produced from the largest geographical concentration of these distillery by-products in Scotland. This would make a considerable contribution to the raw material supply for Scottish salmon feed, whilst generating added value and upcycling otherwise wasted nutrients. However, more studies are required to examine and optimise the actual suitability and feasibility of whisky by-products as a substrate for rearing BSF larvae.

A geohazard assessment workflow is presented that maximizes the use of 3D seismic reflection data to improve the safety and success of offshore scientific drilling. This workflow has been implemented for International Ocean Discovery Program (IODP) Proposal 909 that aims to core seven sites with targets between 300 and 1000 m below seabed across the north-western Greenland continental shelf. This glaciated margin is a frontier petroleum province containing potential drilling hazards that must be avoided during drilling. Modern seismic interpretation techniques are used to identify, map and spatially analyse seismic features that may represent subsurface drilling hazards, such as seabed structures, faults, fluids and challenging lithologies. These hazards are compared against the spatial distribution of stratigraphic targets to guide site selection and minimize risk. The 3D seismic geohazard assessment specifically advanced the proposal by providing a more detailed and spatially extensive understanding of hazard distribution that was used to confidently select eight new site locations, abandon four others and fine-tune sites originally selected using 2D seismic data. Had several of the more challenging areas targeted by this proposal only been covered by 2D seismic data, it is likely that they would have been abandoned, restricting access to stratigraphic targets. The results informed the targeted location of an ultra-high-resolution 2D seismic survey by minimizing acquisition in unnecessary areas, saving valuable resources. With future IODP missions targeting similarly challenging frontier environments where 3D seismic data are available, this workflow provides a template for geohazard assessments that will enhance the success of future scientific drilling.

Ice streams provide a fundamental control on ice sheet discharge and depositional patterns along glaciated margins. This paper investigates ancient ice streams by presenting the first 3D seismic geomorphological analysis of a major glacigenic succession offshore Greenland. In Melville Bugt, northwest Greenland, six sets of landforms (five buried and one on the seafloor) have been interpreted as mega-scale glacial lineations (MSGLs) that provide evidence for extensive ice streams on outer palaeo-shelves. A gradual change in mean MSGL orientation and associated depocentres through time suggests that the palaeo-ice flow and sediment transport pathways migrated in response to the evolving submarine topography through each glacial–interglacial cycle. The stratigraphy and available chronology show that the MSGLs are confined to separate stratigraphic units and were most likely formed after the onset of the Middle Pleistocene Transition at ∼1.3 Ma. The MSGL record in Melville Bugt suggests that since ∼1.3 Ma, ice streams have regularly advanced across the continental shelf during glacial stages. High-resolution buried 3D landform records such as these have not been previously observed anywhere on the Greenland continental shelf margin and provide a crucial benchmark for testing how accurately numerical models are able to recreate past configurations of the Greenland Ice Sheet.

Subsurface CO2 storage is considered a key element of reducing anthropogenic emissions in virtually all scenarios compatible with limiting global warming to 1.5°C. The Utsira-Skade Aquifer (Utsira, Eir and Skade Formations), northern North Sea, has been identified as a suitable reservoir. Although the overall storage capacity of the full aquifer has been estimated based on regional data, it is lacking an integrated assessment of containment and internal heterogeneity, to identify optimal areas for injection and for calculation of site-specific storage capacities. A high-resolution, broadband 3D seismic reflection dataset, full waveform inverted velocity data and 102 exploration wells are utilised to provide a catalogue of CO2 storage prospects in the northern Utsira-Skade Aquifer. This is achieved through: 1) definition of the aquifer’s spatial limits; 2) calculation of porosity distribution; 3) assessment of the extent, geomorphology, thickness variability, and containment confidence (CC) of mudstones; and 4) mapping of closures through fill-to-spill simulations. CO2 storage capacity was calculated for the prospects using two approaches; using the full reservoir thickness (FRT) beneath the closures and using only the thickness from the closure top to the spill point (TSP), i.e., within structural traps. Porosity ranges from 29 to 39% across the aquifer and is higher in the Utsira and Eir Fms. relative to the underlying Skade Fm. The mudstone separating the Skade and Eir/Utsira Fm. has a thickness > 50 m, and is a potential barrier for CO2. Other intra-aquifer mudstones were mainly interpreted to act as baffles to flow. Structural traps at the top Utsira and Skade Fms. yield fifteen prospects, with criteria of > 700 m depth and FRT storage capacity of > 5 Mt CO2. They have a combined storage capacity of 330 Mt CO2 (FRT) or 196 Mt CO2 (TSP). Five prospects have a positive CC score (total capacity: 54 Mt CO2 FRT or 39 Mt CO2 TSP). Additional storage capacity could be achieved through more detailed analysis of the seal to upgrade the CC scores, or through use of a network of the mapped closures with a fill-to-spill approach, utilising more of the aquifer.

Sustainability analyses of aquaculture typically ignore the fate and value of processing by-products. The aim of this study was to characterise the nutritional content of the common processing by-products (heads, frames, trimmings, skin, and viscera) of five important finfish species farmed in Europe; Atlantic salmon (Salmo salar), European seabass (Dicentrarchus labrax), gilthead seabream (Sparus aurata), common carp (Cyprinus carpio), and turbot (Psetta maxima) to inform on best utilisation strategies. Our results indicate a substantially higher total flesh yield (64–77%) can be achieved if fully processed, compared to fillet only (30–56%). We found that heads, frames, trimmings and skin from Atlantic salmon, European seabass, gilthead seabream and turbot frames showed medium to high edible yields, medium to high lipid, and medium to high eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content, indicating significant potential for direct use in human food. By-products which are unattractive for use in food directly but have low ash content and medium to high crude protein, lipid and EPA and DHA content, such as viscera, could be directed to animal feed. Skin showed interesting nutritional values, but has more potential in non-food applications, such as the fashion, cosmetic and pharmaceutical industries. The results indicate potential to increase the direct food, animal feed and non-food value of European aquaculture, without an increase in production volumes or the use of additional resources. The importance of changing consumer perceptions and addressing infrastructure and legislative barriers to maximise utilisation is emphasised.

BackgroundIndicators to evaluate progress towards timely access to safe surgical, anaesthesia, and obstetric (SAO) care were proposed in 2015 by the Lancet Commission on Global Surgery. These aimed to capture access to surgery, surgical workforce, surgical volume, perioperative mortality rate, and catastrophic and impoverishing financial consequences of surgery. Despite being rapidly taken up by practitioners, data points from which to derive the indicators were not defined, limiting comparability across time or settings. We convened global experts to evaluate and explicitly define-for the first time-the indicators to improve comparability and support achievement of 2030 goals to improve access to safe affordable surgical and anaesthesia care globally.Methods and findingsThe Utstein process for developing and reporting guidelines through a consensus building process was followed. In-person discussions at a 2-day meeting were followed by an iterative process conducted by email and virtual group meetings until consensus was reached. The meeting was held between June 16 to 18, 2019; discussions continued until August 2020. Participants consisted of experts in surgery, anaesthesia, and obstetric care, data science, and health indicators from high-, middle-, and low-income countries. Considering each of the 6 indicators in turn, we refined overarching descriptions and agreed upon data points needed for construction of each indicator at current time (basic data points), and as each evolves over 2 to 5 (intermediate) and >5 year (full) time frames. We removed one of the original 6 indicators (one of 2 financial risk protection indicators was eliminated) and refined descriptions and defined data points required to construct the 5 remaining indicators: geospatial access, workforce, surgical volume, perioperative mortality, and catastrophic expenditure. A strength of the process was the number of people from global institutes and multilateral agencies involved in the collection and reporting of global health metrics; a limitation was the limited number of participants from low- or middle-income countries-who only made up 21% of the total attendees.ConclusionsTo track global progress towards timely access to quality SAO care, these indicators-at the basic level-should be implemented universally as soon as possible. Intermediate and full indicator sets should be achieved by all countries over time. Meanwhile, these evolutions can assist in the short term in developing national surgical plans and collecting more detailed data for research studies.

Campylobacter jejuni is the leading cause of bacterial gastroenteritis and antibiotic resistant C. jejuni are a serious threat to public health. Herein, we sought to evaluate trends in C. jejuni infections, quantify resistance frequencies, and identify epidemiological factors associated with infection. Campylobacter jejuni isolates (n = 214) were collected from patients via an active surveillance system at four metropolitan hospitals in Michigan between 2011 and 2014. The minimum inhibitory concentration for nine antibiotics was determined using microbroth dilution, while demographic and clinical data were used for the univariate and multivariate analyses. Over the 4-year period, a significant increase in the recovery of C. jejuni was observed (p ≤ 0.0001). Differences in infection rates were observed by hospital and several factors were linked to more severe disease. Patients residing in urban areas, for instance, were significantly more likely to be hospitalized than rural residents as were patients over 40 years of age and those self-identifying as non-White, highlighting potential disparities in disease outcomes. Among the 214 C. jejuni isolates, 135 (63.1%) were resistant to at least one antibiotic. Resistance was observed for all nine antibiotics tested yielding 11 distinct resistance phenotypes. Tetracycline resistance predominated (n = 120; 56.1%) followed by resistance to ciprofloxacin (n = 49; 22.9%), which increased from 15.6% in 2011 to 25.0% in 2014. Resistance to two antibiotic classes was observed in 38 (17.8%) isolates, while multidrug resistance, or resistance to three or more classes, was observed in four (1.9%). Notably, patients with ciprofloxacin resistant infections were more likely to report traveling in the past month (Odds Ratio (OR): 3.0; 95% confidence interval (CI): 1.37, 6.68) and international travel (OR: 9.8; 95% CI: 3.69, 26.09). Relative to patients with only tetracycline resistant infections, those with ciprofloxacin resistance were more likely to travel internationally, be hospitalized and have an infection during the fall or summer. Together, these findings show increasing rates of infection and resistance and highlight specific factors that impact both outcomes. Enhancing understanding of factors linked to C. jejuni resistance and more severe infections is critical for disease prevention, particularly since many clinical laboratories have switched to the use of culture-independent tests for the detection of Campylobacter.

The highly conserved DNA damage response (DDR) pathway monitors the genomic integrity of the cell and protects against genotoxic stresses. The apical kinases, Mec1 and Tel1 (ATR and ATM in human, respectively), initiate the DNA damage signaling cascade through the effector kinases, Rad53 and Chk1, to regulate a variety of cellular processes including cell cycle progression, DNA damage repair, chromatin remodeling, and transcription. The DDR also regulates other cellular pathways, but direct substrates and mechanisms are still lacking. Using a mass spectrometry-based phosphoproteomic screen in Saccharomyces cerevisiae, we identified novel targets of Rad53, many of which are proteins that are involved in RNA metabolism. Of the 33 novel substrates identified, we verified that 12 are directly phosphorylated by Rad53 in vitro: Xrn1, Gcd11, Rps7b, Ded1, Cho2, Pus1, Hst1, Srv2, Set3, Snu23, Alb1, and Scp160. We further characterized Xrn1, a highly conserved 5′ exoribonuclease that functions in RNA degradation and the most enriched in our phosphoproteomics screen. Phosphorylation of Xrn1 by Rad53 does not appear to affect Xrn1’s intrinsic nuclease activity in vitro, but may affect its activity or specificity in vivo.

Non-typhoidal Salmonella (NTS) are important enteric pathogens causing over 1 million foodborne illnesses in the U.S. annually. The widespread emergence of antibiotic resistance in NTS isolates has limited the availability of antibiotics that can be used for therapy. Since Michigan is not part of the FoodNet surveillance system, few studies have quantified antibiotic resistance frequencies and identified risk factors for NTS infections in the state. We obtained 198 clinical NTS isolates via active surveillance at four Michigan hospitals from 2011 to 2014 for classification of serovars and susceptibility to 24 antibiotics using broth microdilution. The 198 isolates belonged to 35 different serovars with Enteritidis (36.9%) predominating followed by Typhimurium (19.5%) and Newport (9.7%), though the proportion of each varied by year, residence, and season. The number of Enteritidis and Typhimurium cases was higher in the summer, while Enteritidis cases were significantly more common among urban vs. rural residents. A total of 30 (15.2%) NTS isolates were resistant to ≥1 antibiotic and 15 (7.5%) were resistant to ≥3 antimicrobial classes; a significantly greater proportion of Typhimurium isolates were resistant compared to Enteritidis isolates and an increasing trend in the frequency of tetracycline resistance and multidrug resistance was observed over the 4-year period. Resistant infections were associated with longer hospital stays as the mean stay was 5.9 days for patients with resistant isolates relative to 4.0 days for patients infected with susceptible isolates. Multinomial logistic regression indicated that infection with serovars other than Enteritidis [Odds ratio (OR): 3.8, 95% confidence interval (CI): 1.23–11.82] as well as infection during the fall (OR: 3.0; 95% CI: 1.22–7.60) were independently associated with resistance. Together, these findings demonstrate the importance of surveillance, monitoring resistance frequencies, and identifying risk factors that can aid in the development of new prevention strategies.

Summary: Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers. : The tumor suppressor PTEN is widely inactivated in cancers and tumor syndromes. Currently, there is no effective therapeutic strategy in the clinic for PTEN-deficient cancers. Chatterjee et al. found that PTEN-deficient cells and cancers are uniquely sensitive to PDHK1 inhibition and propose PDHK1 as a potential therapeutic target in PTEN-deficient cancers. Keywords: PTEN, protein phosphatase, PDHK1, NKAP, NF-κB, synthetic lethality, metabolism, signaling, cancer

Reconstructing past ocean conditions, particularly current velocity, is difficult due to a lack of available proxies. Here, the authors present a set of well-preserved buried iceberg scours from the mid-Norwegian slope, from which they are able to infer North Atlantic current speeds during the third-last glacial.

The HIV-1 Tat protein hijacks P-TEFb kinase to activate paused RNA polymerase II (RNAP II) at the viral promoter. Tat binds additional host factors, but it is unclear how they regulate RNAP II elongation. Here, we identify the cytoplasmic ubiquitin ligase UBE2O as critical for Tat transcriptional activity. Tat hijacks UBE2O to ubiquitinate the P-TEFb kinase inhibitor HEXIM1 of the 7SK snRNP, a fraction of which also resides in the cytoplasm bound to P-TEFb. HEXIM1 ubiquitination sequesters it in the cytoplasm and releases P-TEFb from the inhibitory 7SK complex. Free P-TEFb then becomes enriched in chromatin, a process that is also stimulated by treating cells with a CDK9 inhibitor. Finally, we demonstrate that UBE2O is critical for P-TEFb recruitment to the HIV-1 promoter. Together, the data support a unique model of elongation control where non-degradative ubiquitination of nuclear and cytoplasmic 7SK snRNP pools increases P-TEFb levels for transcriptional activation.

HIV-1 encodes the accessory protein Vif, which hijacks a host Cullin-RING ubiquitin ligase (CRL) complex as well as the non-canonical cofactor CBFβ, to antagonize APOBEC3 antiviral proteins. Non-canonical cofactor recruitment to CRL complexes by viral factors, to date, has only been attributed to HIV-1 Vif. To further study this phenomenon, we employed a comparative approach combining proteomic, biochemical, structural, and virological techniques to investigate Vif complexes across the lentivirus genus, including primate (HIV-1 and simian immunodeficiency virus macaque [SIVmac]) and non-primate (FIV, BIV, and MVV) viruses. We find that CBFβ is completely dispensable for the activity of non-primate lentiviral Vif proteins. Furthermore, we find that BIV Vif requires no cofactor and that MVV Vif requires a novel cofactor, cyclophilin A (CYPA), for stable CRL complex formation and anti-APOBEC3 activity. We propose modular conservation of Vif complexes allows for potential exaptation of functions through the acquisition of non-CRL-associated host cofactors while preserving anti-APOBEC3 activity.