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Nonperennial streams dominate global river networks and are increasing in occurrence across space and time. When surface flow ceases or the surface water dries, flow or moisture can be retained in the subsurface sediments of the hyporheic zone, supporting aquatic communities and ecosystem processes. However, hydrological and ecological definitions of the hyporheic zone have been developed in perennial rivers and emphasize the mixing of water and organisms, respectively, from both the surface stream and groundwater. The adaptation of such definitions to include both humid and dry unsaturated conditions could promote characterization of how hydrological and biogeochemical variability shape ecological communities within nonperennial hyporheic zones, advancing our understanding of both ecosystem structure and function in these habitats. To conceptualize hyporheic zones for nonperennial streams, we review how water sources and surface and subsurface structure influence hydrological and physicochemical conditions. We consider the extent of this zone and how biogeochemistry and ecology might vary with surface states. We then link these components to the composition of nonperennial stream communities. Next, we examine literature to identify priorities for hydrological and ecological research exploring nonperennial hyporheic zones. Lastly, by integrating hydrology, biogeochemistry, and ecology, we recommend a multidisciplinary conceptualization of the nonperennial hyporheic zone as the porous subsurface streambed sediments that shift between lotic, lentic, humid, and dry conditions in space and time to support aquatic–terrestrial biodiversity. As river drying increases in extent because of global change, we call for holistic, interdisciplinary research across the terrestrial and aquatic sciences to apply this conceptualization to characterize hyporheic zone structure and function across the full spectrum of hydrological states.

Hydrologic data collected from river gauges inform critical decisions for allocating water resources, conserving ecosystems and predicting the occurrence of droughts and floods. The current global river gauge network is biased towards large, perennial rivers, and strategic adaptations are needed to capture the full scope of rivers on Earth. Knowing where and when rivers flow is paramount to managing freshwater ecosystems. Yet stream gauging stations are distributed sparsely across rivers globally and may not capture the diversity of fluvial network properties and anthropogenic influences. Here we evaluate the placement bias of a global stream gauge dataset on its representation of socioecological, hydrologic, climatic and physiographic diversity of rivers. We find that gauges are located disproportionally in large, perennial rivers draining more human-occupied watersheds. Gauges are sparsely distributed in protected areas and rivers characterized by non-perennial flow regimes, both of which are critical to freshwater conservation and water security concerns. Disparities between the geography of the global gauging network and the broad diversity of streams and rivers weakens our ability to understand critical hydrologic processes and make informed water-management and policy decisions. Our findings underscore the need to address current gauge placement biases by investing in and prioritizing the installation of new gauging stations, embracing alternative water-monitoring strategies, advancing innovation in hydrologic modelling, and increasing accessibility of local and regional gauging data to support human responses to water challenges, both today and in the future. US National Science Foundation [DEB-1754389, 2207232] Published version US National Science Foundation(National Science Foundation (NSF)) Public domain – authored by a U.S. government employee

The structure of the critical zone is a product of feedbacks between hydrologic, climatic, biotic, and chemical processes. Ample research within snow-dominated systems has shown that aspect-dependent solar radiation inputs can produce striking differences in vegetation composition, topography, and soil depth between opposing hillslopes. However, more research is needed to understand the role of microclimates on critical zone development within rain-dominated systems, especially below the soil and into weathered bedrock. To address this need, we characterized the critical zone of a north-facing and south-facing slope within a first-order headwater catchment located in central coastal California. We combined terrain analysis of vegetation distribution and topography with field-based soil pit characterization, geophysical surveys and hydrologic measurements between slope-aspects. We observed thicker soil profiles, higher shallow soil moisture, and denser vegetation on north facing slopes, which matched previously documented observations in snow-dominated sites. However, average topographic gradient and saprolite thickness were uniform across our study hillslopes, which did not match common observations from the literature. These results suggest dominant processes for critical zone evolution are not necessarily transferable across regions. Thus, there is a continued need to expand critical zone research, especially in rain-dominated systems. Here, we present four non-exclusive, testable hypotheses of mechanisms that may explain these unexpected similarities in slope and saprolite thickness between hillslopes with opposing aspects. Specifically, we propose both past and present ecohydrologic processes must be taken into account to understand what shaped the present day critical zone.

Using annual water balance analyses may mask intra-annual variability in runoff generation, which could limit our understanding of the similarities and differences between water- and energy-limited catchments. This may be especially limiting in comparisons between catchments close to the threshold between water- and energy-limitation. For this study, we examined runoff generation as a function of catchment storage in four watersheds, with focus on two that exist close to these thresholds to identify how year-to-year variability in storage resulted in intra-annual variations of runoff generation efficiency. Specifically, we focused on one energy-limited catchment in the humid subtropics and one water-limited in a Mediterranean climate. We used measured and calculated daily water balance components to calculate variations in the relative magnitude of daily storage. We isolated precipitation events to draw connections between storage and runoff generation at intra-annual scales and compared our findings to the same metrics in two intensely energy-limited landscapes. We observed distinct stages in daily storage across water years in watersheds at the threshold, where systems experienced wet-up, plateau, and dry-down stages. During the wet-up, precipitation was partitioned to storage, and runoff ratios ( RR) were low. In the plateau, storage was filled, precipitation was partitioned to runoff, causing high RRs. During the dry-down, storage decreased as precipitation was partitioned to evapotranspiration and runoff, causing low RRs. The critical role of evapotranspiration during the growing season resulted in relatively higher RRs during the wet-up than during the dry-down for a given storage value. Thus the same storage amount was partitioned to evapotranspiration or runoff differently throughout the year, depending on the storage stage. Despite their different positions on opposite sides of the threshold, the similarity between the two focus catchments suggests a potential characteristic behavior of systems at the threshold common to both humid and semi-arid landscapes.

The immune system can eliminate tumors, but checkpoints enable immune escape. Here, we identify immune evasion mechanisms using genome-scale in vivo CRISPR screens across cancer models treated with immune checkpoint blockade (ICB). We identify immune evasion genes and important immune inhibitory checkpoints conserved across cancers, including the non-classical major histocompatibility complex class I (MHC class I) molecule Qa-1

Ecosystems in the Anthropocene face pressures from multiple, interacting forms of environmental change. These pressures, resulting from land use change, altered hydrologic regimes, and climate change, will likely change the synchrony of ecosystem processes as distinct components of ecosystems are impacted in different ways. However, discipline-specific definitions and ad hoc methods for identifying synchrony and asynchrony have limited broader synthesis of this concept among studies and across disciplines. Drawing on concepts from ecology, hydrology, geomorphology, and biogeochemistry, we offer a unifying definition of synchrony for ecosystem science and propose a classification framework for synchrony and asynchrony of ecosystem processes. This framework classifies the relationships among ecosystem processes according to five key aspects: (1) the focal variables or relationships representative of the ecosystem processes of interest, (2) the spatial and temporal domain of interest, (3) the structural attributes of drivers and focal processes, (4) consistency in the relationships over time, and (5) the degree of causality among focal processes. Using this classification framework, we identify and differentiate types of synchrony and asynchrony, thereby providing the basis for comparing among studies and across disciplines. We apply this classification framework to existing studies in the ecological, hydrologic, geomorphic, and biogeochemical literature and discuss potential analytical tools that can be used to quantify synchronous and asynchronous processes. Furthermore, we seek to promote understanding of how different types of synchrony or asynchrony may shift in response to ongoing environmental change by providing a universal definition and explicit types and drivers with this framework.

T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8(+) tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8(+) TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8(+) TILs include a subpopulation of ‘progenitor exhausted’ cells that retain polyfunctionality, persist long term and differentiate into ‘terminally exhausted’ TILs. Consequently, progenitor exhausted CD8(+) TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8(+) T cells might be an important component of improving the response to checkpoint blockade.

Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.

Agricultural watersheds are significant contributors to downstream nutrient excess issues. The timing and magnitude of nutrient mobilization in these watersheds are driven by a combination of anthropogenic, hydrologic, and biogeochemical factors that operate across a range of spatial and temporal scales. However, how, when, and where these complex factors drive nutrient mobilization has previously been difficult to capture with low-frequency or spatially limited data sets. To address this knowledge gap, we analyzed daily nitrate concentration (c) and discharge (Q) data for a 4-year period (2016–2019) from five nested, agricultural watersheds in the midwestern United States that contribute nutrient loads to the Gulf of Mexico. These records allow us to investigate nutrient mobilization patterns at a temporal and spatial resolution not previously possible. The watersheds span two distinct landforms shaped by differences in glacial history, resulting in natural soil properties that necessitated different drainage infrastructure across the study area. To investigate nutrient export patterns under different hydrologic conditions, we partitioned the hydrograph into stormflow and baseflow periods and examined those periods separately through the analysis of their concentration–discharge (c–Q) relationships on annual, seasonal, and event timescales. Stormflow showed consistent chemostatic patterns across all seasons, while baseflow showed seasonally dynamic c–Q patterns. Baseflow exhibited chemodynamic conditions in the summer and fall and more chemostatic conditions in the winter and spring, suggesting that water source contributions during baseflow were nonstationary. Baseflow chemodynamic behavior was driven by low-flow, low-NO3- conditions during which in-stream and near-stream biological processing likely moderated in-stream NO3- concentrations. Additionally, inputs from deeper groundwater with longer residence times and lower-NO3- concentration likely contributed to low-NO3- conditions in stream, particularly in the larger watersheds. Stormflow c–Q behavior was consistent across watersheds, but baseflow c–Q behavior was linked to the intensity of agriculture and the density of built drainage infrastructure, with more drainage infrastructure associated with higher loads and more chemostatic export patterns across the watersheds. This suggests that the way humans replumb the subsurface in response to geologic conditions has implications for hydrologic connectivity, homogenization of source areas, and, subsequently, nutrient export during both baseflow and stormflow. Our analysis also showed that anomalous flow periods greatly influenced overall c–Q patterns, suggesting that the analysis of high-resolution records at multiple scales is critical when interpreting seasonal or annual patterns.

The paradigm of surface water flow regimes is central to the aquatic sciences, where the timing, duration, frequency, magnitude, and rate of change of flow drive physical, chemical, and biological functions in aquatic systems. However, non-perennial streams comprise the majority of the global river network and there is a need to understand not just whether or not a stream periodically dries, but how it dries. Here, we propose to flip the script on flow regimes by presenting a comprehensive 'drying regime' framework to characterize stream drying. We then identify similar drying characteristics in streams across watersheds with a broad range of climates, physiographic regions, and land uses. Using daily streamflow from 894 U.S. Geological Survey streamflow gages we isolated over 25,000 unique drying events over a period from 1979 - 2018. From these drying events we identified and calculated streamflow metrics that describe timing, duration, magnitude, frequency, and rate of change of stream drying. Using multivariate statistics, k-means clustering, and random forest analyses we grouped drying events into distinct drying regimes and determined the drivers of the clustered regimes. K-means clustering resulted in 4 distinct drying regimes characterized by (1) more frequent drying, (2) longer no-flow duration, (3) drying occurring following low antecedent flows, and (4) flashy high frequency drying, respectively. The majority of gages had more than one drying regime present at different times within each year, suggesting that dominant flow paths or drivers varied through time Clustered drying regimes show low event-scale spatial coherence, and while drying regimes (1) and (2) show similar frequency throughout the year, (3) and (4) are substantially more frequent during summer months. Based on random forest analysis, land cover characteristics appear to drive drying event assignment to drying regimes more than climate variables. Furthermore, increased importance of individual watershed properties shows that the structural makeup of the watershed is notably more important to how an intermittent system dries than climate or physiographic characteristics. Non-perennial systems have unique functions due to the occurrence of both flowing and dry states, yet most of the past efforts rely on frameworks built around perennial streamflow behavior. Our work presents a novel drying regime framework to allow future studies to more effectively connect river drying to the physical, chemical, and biological functioning in these systems. This framework may also aid in current sustainable river management, including engineered flow regimes that are designed to balance water allocations with ecosystem requirements.

Over half of global rivers and streams lack perennial flow, and understanding the distribution and drivers of their flow regimes is critical for understanding their hydrologic, biogeochemical, and ecological functions. We analyzed nonperennial flow regimes using 540 U.S. Geological Survey watersheds across the contiguous United States from 1979 to 2018. Multivariate analyses revealed regional differences in no-flow fraction, date of first no flow, and duration of the dry-down period, with further divergence between natural and human-altered watersheds. Aridity was a primary driver of no-flow metrics at the continental scale, while unique combinations of climatic, physiographic and anthropogenic drivers emerged at regional scales. Dry-down duration showed stronger associations with nonclimate drivers compared to no-flow fraction and timing. Although the sparse distribution of nonperennial gages limits our understanding of such streams, the watersheds examined here suggest the important role of aridity and land cover change in modulating future stream drying. Plain Language Summary A majority of global streams are nonperennial, flowing only part of the year, and are critical for sustaining flow downstream, providing habitat for many organisms, and regulating chemical and biological processes. Using long-term U.S. Geological Survey measurements for 540 watersheds across the contiguous United States, we mapped patterns and examined the causes of no-flow fraction, the fraction of each climate year with no flow, no-flow timing, the date of the climate year on which the first recorded no flow takes place, and length of the dry-down period, the average number of days from a local peak in daily flow to the first occurrence of no flow. We found differences in patterns of no-flow characteristics between regions, with higher no-flow fraction, earlier timing, and shorter dry-down duration in the western United States. No-flow fractions were greater and less variable in natural watersheds, while no-flow timing was earlier and dry-down duration was shorter in human-modified watersheds. Aridity had the greatest effect on intermittence across the United States, but unique combinations of climate, biophysical, and human impacts were important in different regions. The number of gages measuring streamflow in nonperennial streams is small compared to perennial streams, and increased monitoring is needed to better understand drying behavior. Key Points . Three metrics reveal regional and human-driven patterns of nonperennial flow: no-flow fraction, day of first no flow, and dry-down duration Streams with human modifications generally dry more quickly than unmodified streams, especially in California and the Southern Great Plains Climate strongly influences no-flow fraction and timing, but physiographic variables are more important for the duration of dry down National Science FoundationNational Science Foundation (NSF) [DEB-1754389]; Kansas Water Resources Institute Published version This manuscript is a product of the Dry Rivers Research Coordination Network, supported by funding from the National Science Foundation (DEB-1754389). Although this work was approved for publication by the EPA, it may not reflect official Agency policy. S.C.Z. was supported by the Kansas Water Resources Institute. We thank David Wolock and two anonymous reviewers for their suggestions and edits. Public domain – authored by a U.S. government employee

Agricultural watersheds are significant contributors to downstream nutrient excess issues. The timing and magnitude of nutrient mobilization in these watersheds are driven by a combination of anthropogenic, hydrologic, and biogeochemical factors that operate across a range of spatial and temporal scales. However, how, when, and where these complex factors drive nutrient mobilization has previously been difficult to capture with low-frequency or spatially limited datasets. To address this knowledge gap, we analyzed daily nitrate concentration (c) and discharge (Q) data for a four-year period (2016–2019) from five nested, agricultural watersheds in the midwestern United States that contribute nutrient loads to the Gulf of Mexico. The watersheds span two distinct landforms shaped by differences in glacial history resulting in natural soil properties that necessitated different drainage infrastructure across the study area. To investigate nutrient export patterns under different hydrologic conditions, we partitioned the hydrograph into stormflow and baseflow periods and examined those periods separately through the analysis of their concentration-discharge (c-Q) relationships on annual, seasonal, and event time scales. Stormflow showed consistent chemostatic patterns across all seasons, while baseflow showed seasonally dynamic c-Q patterns. Baseflow exhibited chemodyanmic conditions in the summer and fall and more chemostatic conditions in the winter and spring, suggesting that water source contributions during baseflow were nonstationary. Baseflow chemodynamic behavior was driven by low-flow, low-NO3− conditions during which in-stream and near-stream biological processing likely moderated in-stream NO3− concentrations. Additionally, inputs from deeper groundwater with longer residence times and lower NO3− concentration likely contributed to low-NO3− conditions in-stream, particularly in the larger watersheds. Stormflow c-Q behavior was consistent across watersheds, but baseflow c-Q behavior was linked to intensity of agriculture and density of built drainage infrastructure, with more drainage infrastructure associated with higher loads and more chemostatic export patterns across the watersheds. This suggests that how humans replumb the subsurface in response to geologic conditions has implications for hydrologic connectivity, homogenization of source areas, and subsequently nutrient export during both baseflow and stormflow. Our analysis also showed that anomalous flow periods greatly influenced overall c-Q patterns, suggesting that the analysis of high-resolution records at multiple scales is critical when interpreting seasonal or annual patterns.

Conceptual models underpin river ecosystem research. However, current models focus on continuously flowing rivers and few explicitly address characteristics such as flow cessation and drying. The applicability of existing conceptual models to nonperennial rivers that cease to flow (intermittent rivers and ephemeral streams, IRES) has not been evaluated. We reviewed 18 models, finding that they collectively describe main drivers of biogeochemical and ecological patterns and processes longitudinally (upstream‐downstream), laterally (channel‐riparian‐floodplain), vertically (surface water‐groundwater), and temporally across local and landscape scales. However, perennial rivers are longitudinally continuous while IRES are longitudinally discontinuous. Whereas perennial rivers have bidirectional lateral connections between aquatic and terrestrial ecosystems, in IRES, this connection is unidirectional for much of the time, from terrestrial‐to‐aquatic only. Vertical connectivity between surface and subsurface water occurs bidirectionally and is temporally consistent in perennial rivers. However, in IRES, this exchange is temporally variable, and can become unidirectional during drying or rewetting phases. Finally, drying adds another dimension of flow variation to be considered across temporal and spatial scales in IRES, much as flooding is considered as a temporally and spatially dynamic process in perennial rivers. Here, we focus on ways in which existing models could be modified to accommodate drying as a fundamental process that can alter these patterns and processes across spatial and temporal dimensions in streams. This perspective is needed to support river science and management in our era of rapid global change, including increasing duration, frequency, and occurrence of drying.

Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.

International audience; Rivers that cease to flow are globally prevalent. Although many epithets have been used for these rivers, a consensus on terminology has not yet been reached. Doing so would facilitate a marked increase in interdisciplinary interest as well as critical need for clear regulations. Here we reviewed literature from Web of Science database searches of 12 epithets to learn (Objective 1-O1) if epithet topics are consistent across Web of Science categories using latent Dirichlet allocation topic modeling. We also analyzed publication rates and topics over time to (O2) assess changes in epithet use. We compiled literature definitions to (O3) identify how epithets have been delineated and, lastly, suggest universal terms and definitions. We found a lack of consensus in epithet use between and among various fields. We also found that epithet usage has changed over time, as research focus has shifted from description to modeling. We conclude that multiple epithets are redundant. We offer specific definitions for three epithets (non-perennial, intermittent, and ephemeral) to guide consensus on epithet use. Limiting the number of epithets used in non-perennial river research can facilitate more effective communication among research fields and provide clear guidelines for writing regulatory documents.

Streamflow observations can be used to understand, predict, and contextualize hydrologic, ecological, and biogeochemical processes and conditions in streams. Stream gages are point measurements along rivers where streamflow is measured, and are often used to infer upstream watershed-scale processes. When stream gages read zero, this may indicate that the stream has dried at this location; however, zero-flow readings can also be caused by a wide range of other factors. Our ability to identify whether or not a zero-flow gage reading indicates a dry fluvial system has far reaching environmental implications. Incorrect identification and interpretation by the data user can lead to inaccurate hydrologic, ecological, and/or biogeochemical predictions from models and analyses. Here, we describe several causes of zero-flow gage readings: frozen surface water, flow reversals, instrument error, and natural or human-driven upstream source losses or bypass flow. For these examples, we discuss the implications of zero-flow interpretations. We also highlight additional methods for determining flow presence, including direct observations, statistical methods, and hydrologic models, which can be applied to interpret causes of zero-flow gage readings and implications for reach- and watershed-scale dynamics. Such efforts are necessary to improve our ability to understand and predict surface flow activation, cessation, and connectivity across river networks. Developing this integrated understanding of the wide range of possible meanings of zero-flows will only attain greater importance in a more variable and changing hydrologic climate. This article is categorized under: Science of Water > Methods Science of Water > Hydrological Processes Water and Life > Conservation, Management, and Awareness National Science FoundationNational Science Foundation (NSF) [DEB-1754389]; NSFNational Science Foundation (NSF) [DEB-1830178, EAR-1653998, EAR-1652293]; NSF Konza Long Term Ecological Research grant [1440484]; Department of Energy Office of Science Multisector Dynamics ProgramUnited States Department of Energy (DOE); Australian Research CouncilAustralian Research Council [DE150100302]; Department of EnergyUnited States Department of Energy (DOE) [DE-SC0019377] This manuscript is a product of the Dry Rivers Research Coordination Network, which was supported by funding from the National Science Foundation (DEB-1754389). DelVecchia was supported in part by funding from NSF DEB-1830178. Dodds was supported in part by NSF Konza Long Term Ecological Research grant number 1440484. Godsey was supported in part by NSF award EAR-1653998. Kaiser was supported in part by the Department of Energy Office of Science Multisector Dynamics Program. Shanafield was supported in part by funding from the Australian Research Council under grant DE150100302. Ward was supported in part by Department of Energy award DE-SC0019377 and NSF award EAR-1652293. The opinions expressed are those of the researchers, and not necessarily the funding agencies. Although this work was reviewed by the USGS and USEPA, and approved for publication, it might not necessarily reflect official USEPA policy. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government. The authors thank Heather Golden, Brent Johnson, Rosemary Fanelli, Albert Ruhi, as well as two anonymous reviewers for helpful comments on earlier versions of the manuscript. USGS data used to support this study are available from the U.S. Geological Survey National Water Information System database (U.S. Geological Survey, 2019). For the exact dataset used in this study, see: Hammond (2020). Public domain – authored by a U.S. government employee

Nonperennial rivers are a major—and growing—part of the global river network. New research and science-based policies are needed to ensure the sustainability of these long-overlooked waterways.

Forest management guidelines are designed to protect water quality from unintended effects of land use changes such as timber harvest, mining, or forest road construction. Although streams that periodically cease to flow (nonperennial) drain the majority of forested areas, these streams are not consistently included in forest management guidelines. This paper reviews management guidelines for nonperennial (intermittent and ephemeral) streams draining temperate forests in the continental U.S., evaluates potential impacts of land use activities on ecosystem services provided by these streams, and identifies information needed to incorporate nonperennial streams into water quality protection practices. For federally administered lands, national management guidance is deliberately nonprescriptive, deferring to regional and forest-level recommendations for both perennial and nonperennial streams. Most state guidelines recommend riparian management zone (RMZ) protection for perennial streams (48/50 states) and intermittent streams (45/50 states), but only Alaska and West Virginia require RMZs around ephemeral streams. Based on the National Hydrography Dataset, an average of 58% of forested land area in the U.S. drains to nonperennial headwater streams, making these stream types the most common connectors between forested lands and the aquatic system. Land uses that modify flow regimes in these streams can affect sediment and organic matter transport and distribution, stream temperature dynamics, and biogeochemical processing. Nonperennial streams also provide material subsidies to downstream waters and serve as temporary habitats for some aquatic species. However, limited research has examined how forest land uses affect ecosystem services and biota in these streams. Therefore we highlight a set of key questions about nonperennial streams in forests, not the least of which is simply understanding where headwater stream channels are located and associated patterns of flow duration. Although many questions remain, we also note where recent advances in data collection, modeling and process-level research provide opportunties to resolve uncertainties around nonperennial streams in forested landscapes of the continental U.S.

Non-perennial streams are widespread, critical to ecosystems and society, and the subject of ongoing policy debate. Prior large-scale research on stream intermittency has been based on long-term averages, generally using annually aggregated data to characterize a highly variable process. As a result, it is not well understood if, how, or why the hydrology of non-perennial streams is changing. Here, we investigate trends and drivers of three intermittency signatures that describe the duration, timing, and dry-down period of stream intermittency across the continental United States (CONUS). Half of gages exhibited a significant trend through time in at least one of the three intermittency signatures, and changes in no-flow duration were most pervasive (41% of gages). Changes in intermittency were substantial for many streams, and 7% of gages exhibited changes in annual no-flow duration exceeding 100 days during the study period. Distinct regional patterns of change were evident, with widespread drying in southern CONUS and wetting in northern CONUS. These patterns are correlated with changes in aridity, though drivers of spatiotemporal variability were diverse across the three intermittency signatures. While the no-flow timing and duration were strongly related to climate, dry-down period was most strongly related to watershed land use and physiography. Our results indicate that non-perennial conditions are increasing in prevalence over much of CONUS and binary classifications of 'perennial' and 'non-perennial' are not an accurate reflection of this change. Water management and policy should reflect the changing nature and diverse drivers of changing intermittency both today and in the future. US National Science FoundationNational Science Foundation (NSF) [DEB-1754389] Published version This manuscript is a product of the Dry Rivers Research Coordination Network, which was supported by funding from the US National Science Foundation (DEB-1754389). Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the US Government. This manuscript was improved by constructive feedback from Kristin Jaeger and three anonymous reviews.

Summary CRISPR-Cas9 genome engineering has increased the pace of discovery for immunology and cancer biology, revealing potential therapeutic targets and providing insight into mechanisms underlying resistance to immunotherapy. However, endogenous immune recognition of Cas9 has limited the applicability of CRISPR technologies in vivo. Here, we characterized immune responses against Cas9 and other expressed CRISPR vector components that cause antigen-specific tumor rejection in several mouse cancer models. To avoid unwanted immune recognition, we designed a lentiviral vector system that allowed selective CRISPR antigen removal (SCAR) from tumor cells. The SCAR system reversed immune-mediated rejection of CRISPR-modified tumor cells in vivo and enabled high-throughput genetic screens in previously intractable models. A pooled in vivo screen using SCAR in a CRISPR-antigen-sensitive renal cell carcinoma revealed resistance pathways associated with autophagy and major histocompatibility complex class I (MHC class I) expression. Thus, SCAR presents a resource that enables CRISPR-based studies of tumor-immune interactions and prevents unwanted immune recognition of genetically engineered cells, with implications for clinical applications.

Epigenetic alterations are defining features of many tumor types and have recently been implicated in tumor immunity. However, the epigenetic mechanisms that mediate immune sensitivity or resistance in cancer cells are poorly characterized. To systematically identify epigenetic regulators of immune evasion in cancer, we performed in vivo loss of function CRISPR screens against 936 chromatin regulator genes in syngeneic murine tumor models treated with immune checkpoint blockade. These screens identified SETDB1, an H3K9-methyltransferase, and associated members of the HUSH and KAP1 complexes as intrinsic mediators of immune evasion in cancer cells. We also found that amplification of SETDB1 (1q21) in certain human tumors is associated with immune exclusion and resistance to immune checkpoint blockade. Mechanistically, we find that SETDB1 targets broad domains, hundreds of kilobases in size, that are predominantly located within the open genome compartment “A” (i.e., euchromatin). These SETDB1 domains show strong enrichment for transposable elements (TEs) of the LTR family, and gene loci that arose through segmental duplication events, a key driver of mammalian genome evolution. Setdb1 KO derepresses latent regulatory elements at TEs within these regions and leads to the transcriptional up-regulation of nearby immune genes, including canonical stimulatory ligands of the NKG2D receptor. SETDB1 loss also triggers the activation of hundreds of TEs with the potential to encode retroviral proteins (Gag, Pol, Env), and promotes immune responses dependent on CD8+ T cells and tumor expression of MHC Class I. Our study establishes SETDB1 as an epigenetic checkpoint that represses intrinsic immunogenicity in cancer cells, and thus represents a novel target to enhance the efficacy and scope of immunotherapy. Citation Format: Jingyi Wu, Arvin Iracheta-Vellve, James Patti, Jeffrey Hsu, Thomas Davis, Deborah Dele-Oni, Peter Du, Jeffrey Ishizuka, Sarah Kim, Susan Klaeger, Nelson Knudsen, Brian Miller, Tung Nguyen, Emily Robitschek, Emily Schneider, Margaret Zimmer, Jacob Jaffe, John Doench, W. Nicholas Haining, Kathleen Yates, Robert Manguso, Bradley Bernstein, Gabriel K. Griffin. Epigenetic silencing by SETDB1 represses tumor-cell intrinsic immunogenicity [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO009.

Reach-scale stream restoration with natural channel design is often used to improve stream ecosystem structure and function. Some investigators have studied the effects of restoration on the hyporheic zone, but most used space-for-time substitution instead of comparing the same reach before and after restoration. We examined spatial patterns of hyporheic exchange rates and geochemistry during base flow in a 30-m pool–riffle–pool sequence before and 1 y after the stream was restored by installation of a cross-vane and engineered rock-riffle. Prerestoration vertical hyporheic exchange rates were relatively uniform across the riffle bedform. Average downwelling was 30 cm/d at or upstream of the riffle, and average upwelling was 30 cm/d downstream of the riffle. Downwelling hyporheic exchange rates increased up to an order of magnitude adjacent to the cross-vane and in the engineered rock-riffle. Prerestoration porewater [NO3−] was distributed along a wide and continuous gradient (0.1–3.8 mg/L), with ...

Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

While restoring hyporheic flowpaths has been cited as a benefit to stream restoration structures, little documentation exists confirming that constructed restoration structures induce comparable hyporheic exchange to natural stream features. This study compares a stream restoration structure (cross-vane) to a natural feature (riffle) concurrently in the same stream reach using time-lapsed electrical resistivity (ER) tomography. Using this hydrogeophysical approach, we were able to quantify hyporheic extent and transport beneath the cross-vane structure and the riffle. We interpret from the geophysical data that the cross-vane and the natural riffle induced spatially and temporally unique hyporheic extent and transport, and the cross-vane created both spatially larger and temporally longer hyporheic flowpaths than the natural riffle. Tracer from the 4.67-h injection was detected along flowpaths for 4.6 h at the cross-vane and 4.2 h at the riffle. The spatial extent of the hyporheic zone at the cross-vane was 12% larger than that at the riffle. We compare ER results of this study to vertical fluxes calculated from temperature profiles and conclude significant differences in the interpretation of hyporheic transport from these different field techniques. Results of this study demonstrate a high degree of heterogeneity in transport metrics at both the cross-vane and the riffle and differences between the hyporheic flowpath networks at the two different features. Our results suggest that restoration structures may be capable of creating sufficient exchange flux and timescales of transport to achieve the same ecological functions as natural features, but engineering of the physical and biogeochemical environment may be necessary to realize these benefits.

Although there has been recent focus on understanding spatial variability in hyporheic zone geochemistry across different morphological units under baseflow conditions, less attention has been paid to temporal responses of hyporheic zone geochemistry to non-steady-state conditions. We documented spatial and temporal variability of hyporheic zone geochemistry in response to a large-scale storm event, Tropical Storm Irene (August 2011), across a pool–riffle–pool sequence along Chittenango Creek in Chittenango, NY, USA. We sampled stream water as well as pore water at 15 cm depth in the streambed at 14 locations across a 30 m reach. Sampling occurred seven times at daily intervals: once during baseflow conditions, once during the rising limb of the storm hydrograph, and five times during the receding limb. Principal component analysis was used to interpret temporal and spatial changes and dominant drivers in stream and pore water geochemistry (n = 111). Results show the majority of spatial variance in hyporheic geochemistry (62%) is driven by differential mixing of stream and ground water in the hyporheic zone. The second largest driver (17%) of hyporheic geochemistry was temporal dilution and enrichment of infiltrating stream water during the storm. Hyporheic sites minimally influenced by discharging groundwater (‘connected’ sites) showed temporal changes in water chemistry in response to the storm event. Connected sites within and upstream of the riffle reflected stream geochemistry throughout the storm, whereas downstream sites showed temporally lagged responses in some conservative and biogeochemically reactive solutes. This suggests temporal changes in hyporheic geochemistry at these locations reflect a combination of changes in infiltrating stream chemistry and hyporheic flowpath length and residence time. The portion of the study area strongly influenced by groundwater discharge increased in size throughout the storm, producing elevated Ca2+ and concentrations in the streambed, suggesting zones of localized groundwater inputs expand in response to storms. Copyright © 2013 John Wiley & Sons, Ltd.