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ABSTRACTThis study seeks to investigate academics’ perceptions and experiences with traditional final examinations in engineering courses. An online survey of 40 academics was conducted to understand the academics’ beliefs and rationale for the use of final examinations in their teaching practices. The survey was followed by in-person interviews with 11 academics to clarify the outcomes of the online survey. The results indicated that most academics considered the final examination as an effective and equitable way of assessing student knowledge and skills. However, the findings also showed that final examinations generally might not provide students with proper feedback, and traditional final examinations might not be effective in testing students’ practical and soft skills required by industry.

Bone development and bone remodelling during adult life are highly anabolic processes requiring an adequate supply of oxygen and nutrients. Bone-forming osteoblasts and bone-resorbing osteoclasts interact closely to preserve bone mass and architecture and are often located close to blood vessels. Chondrocytes within the developing growth plate ensure that bone lengthening occurs before puberty, but these cells function in an avascular environment. With ageing, numerous bone marrow adipocytes appear, often with negative effects on bone properties. Many studies have now indicated that skeletal cells have specific metabolic profiles that correspond to the nutritional microenvironment and their stage-specific functions. These metabolic networks provide not only skeletal cells with sufficient energy, but also biosynthetic intermediates that are necessary for proliferation and extracellular matrix synthesis. Moreover, these metabolic pathways control redox homeostasis to avoid oxidative stress and safeguard cell survival. Finally, several intracellular metabolites regulate the activity of epigenetic enzymes and thus control the fate and function of skeletal cells. The metabolic profile of skeletal cells therefore not only reflects their cellular state, but can also drive cellular activity. Insight into skeletal cell metabolism will thus not only advance our understanding of skeletal development and homeostasis, but also of skeletal disorders, such as osteoarthritis, diabetic bone disease and bone malignancies.

Although time series in ecosystem metabolism are well characterized in small and medium rivers, patterns in the world's largest rivers are almost unknown. Large rivers present technical difficulties, including depth measurements, gas exchange (K, d−1) estimates, and the presence of large dams, which can supersaturate gases. We estimated reach‐scale metabolism for the Hanford Reach of the Columbia River (Washington state, USA), a free‐flowing stretch with an average discharge of 3173 m3s−1. We calculated Kfrom semi‐empirical models and directly estimated it from tracer measurements. We fixed Kat the median value from these calculations (0.5 d−1), and used maximum likelihood to estimate reach‐scale, open‐channel metabolism. Both gross primary production (GPP) and ecosystem respiration (ER) were high (GPP range: 0.3–30.8 g O2m2d−1, ER range: 0.8–30.6 g O2m2d−1), with peak GPP and ER occurring in the late summer or early fall. GPP increased exponentially with temperature, consistent with metabolic theory, while light was seasonally saturating. Annual average GPP, estimated at 1500 g carbon m−2yr−1, was in the top 2% of estimates for other rivers. GPP and ER were tightly coupled and 90% of GPP was immediately respired, resulting in net ecosystem production near 0. Patterns in the Hanford Reach contrast with those in small‐medium rivers, suggesting that metabolism magnitudes and patterns in large rivers may not be simply scaled from knowledge of smaller rivers.

Terrestrial disturbances are increasing in frequency and severity, perturbing the hydrologic cycle by altering vegetation-mediated water use and microclimate. Here, we synthesize the literature on post-disturbance ecohydrological coupling, including the mechanistic relationship between vegetation and streamflow, under changing disturbance regimes, atmospheric CO2, and climate. Disturbance can cause decoupling between transpiration and streamflow by altering the connectivity, size, availability, and spatial distribution of their source pools. Successional trajectories influence the dynamics of source water partitioning. Changing climate and disturbance regimes can alter succession and prolong decoupling. Increasing rates, severity, and spread of disturbances along with warming could promote greater decoupling globally. From this review emerges a framework of testable hypotheses that identify the critical processes regulating ecohydrological coupling and provide a roadmap for future research. Accurate prediction of post-disturbance coupling requires understanding the degree of hydraulic connectivity between source water pools and their response to succession under changing disturbance and climate regimes.

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The development of methods to derive induced pluripotent stem cells (iPSCs) has propelled stem cell research, and has the potential to revolutionize many areas of medicine, including cancer immunotherapy. These cells can be propagated limitlessly and can differentiate into nearly any specialized cell type. The ability to perform precise multigene engineering at the iPSC stage, generate master cell lines after clonal selection, and faithfully promote differentiation along natural killer (NK) cells and T-cell lineages is now leading to new opportunities for the administration of off-the-shelf cytotoxic lymphocytes with direct antigen targeting to treat patients with relapsed/refractory cancer. In this review, we highlight the recent progress in iPSC editing and guided differentiation in the development of NK- and T-cell products for immunotherapy. We also discuss some of the potential barriers that remain in unleashing the full potential of iPSC-derived cytotoxic effector cells in the adoptive transfer setting, and how some of these limitations may be overcome through gene editing.

To assess the intra‐ and interobserver reproducibility of fetal biometry measurements obtained by trainee (junior) and experienced sonographers (senior) in the contest of two training programs in obstetric ultrasound. This was a prospective study on 192 women recruited ensuring an even distribution throughout gestation (18–41 weeks), at University College London Hospital (UCLH), England (87 cases), and at Maternité Regionale Universitaire de Nancy (MRUN), France (105 cases). The training took place in two training centers with experience in ultrasound training and subspecialist training in fetal medicine. Measurements for head circumference (HC), abdominal circumference (AC), and femur length (FL) were obtained twice by junior and senior sonographers, blind to their own and each other's measurements. Differences between and within sonographers were expressed in millimeters and as a percentage of fetal dimensions. Reproducibility was assessed using Bland–Altman plots. Reproducibility was overall high with 95% confidence intervals (CI) within <6% for intraobserver and <8% for interobserver reproducibility. Intraobserver reproducibility was lower within junior than within senior sonographers' measurements for HC (95% CI: <4% versus <3%) and FL (95% CI: <6% and < 5%). Intraobserver reproducibility was similar between the two centers/training programs (AC 95% CI: <6%). Cumulative interobserver reproducibility in both centers was similar to the reproducibility within a single site (95% CI: <5%, <8%, and <7% for HC, AC, and FL, respectively). Reproducibility of fetal biometry measurement was high in centers with structured training programs regardless of sonographers' experience. Reproducibility was higher in sonographers who completed the training.

Dissolved organic matter (DOM) is a large and complex mixture of molecules that fuels microbial metabolism and regulates biogeochemical cycles. Individual DOM molecules have unique functional traits, but how their assemblages vary deterministically under global change remains poorly understood. Here, we examine DOM and associated bacteria in 300 aquatic microcosms deployed on mountainsides that span contrasting temperatures and nutrient gradients. Based on molecular trait dimensions of reactivity and activity, we partition the DOM composition into labile-active, recalcitrant-active, recalcitrant-inactive, and labile-inactive fractions and quantify the relative influences of deterministic and stochastic processes governing the assembly of each. At both subtropical and subarctic study sites, the assembly of labile or recalcitrant molecules in active fractions is primarily governed by deterministic processes, while stochastic processes are more important for the assembly of molecules within inactive fractions. Surprisingly, the importance of deterministic selection increases with global change gradients for recalcitrant molecules in both active and inactive fractions, and this trend is paralleled by changes in the deterministic assembly of microbial communities and environmental filtering, respectively. Together, our results highlight the shift in focus from potential reactivity to realized activity and indicate that active and inactive fractions of DOM assemblages are structured by contrasting processes, and their recalcitrant components are consistently sensitive to global change. Our study partitions the DOM molecular composition across functional traits and links DOM with microbes via a shared ecological framework of assembly processes. This integrated approach opens new avenues to understand the assembly and turnover of organic carbon in a changing world.

Chimeric antigen receptors (CARs) are receptors for antigen that direct potent immune responses. Tumor escape associated with low target antigen expression is emerging as one potential limitation of their efficacy. Here we edit the TRAClocus in human peripheral blood T cells to engage cell-surface targets through their T cell receptor–CD3 complex reconfigured to utilize the same immunoglobulin heavy and light chains as a matched CAR. We demonstrate that these HLA-independent T cell receptors (HIT receptors) consistently afford high antigen sensitivity and mediate tumor recognition beyond what CD28-based CARs, the most sensitive design to date, can provide. We demonstrate that the functional persistence of HIT T cells can be augmented by constitutive coexpression of CD80 and 4-1BBL. Finally, we validate the increased antigen sensitivity afforded by HIT receptors in xenograft mouse models of B cell leukemia and acute myeloid leukemia, targeting CD19 and CD70, respectively. Overall, HIT receptors are well suited for targeting cell surface antigens of low abundance.

The avascular nature of cartilage makes it a unique tissue1–4, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.

The hyporheic zone is a hotspot for biogeochemical cycling where interactions with mineral metals preserve the release and biodegradation of organic matter (OM). A small fraction of OM can still be exchanged between localized sediments and the overlying water column, and recent evidence suggests there exists a longitudinal structuring in sediment dissolved OM (DOM) chemistry across the continental United States (CONUS). In this study, we tested a hypothesis that water extractable sediment DOM chemistry could be explained by sediment metal contents and integrative watershed scale features at the CONUS scale. Crowdsourced samples were characterized for high resolution mass spectrometry and coupled with sediment metals determined via x‐ray fluorescence as well as with land cover and soil elemental information obtained from national databases. Our results highlight weak relationships between DOM chemistry and elemental composition at the CONUS scale indicating limited transferability of organo‐metal linkages into multi‐scale hydrobiogeochemical models. The hyporheic zone is a vital area for chemical cycling that influences the breakdown of organic matter due to interactions with minerals and metals. Some organic matter moves between sediment and water. Recent findings show that sediment organic matter chemistry displays unique east‐west patterns across the continental United States. We tested whether crowdsourced sample sediment organic matter composition could be explained by its mineral metal composition and surrounding environmental features (land cover and soil metal composition). Results revealed weak connections between dissolved organic matter chemistry and elements, indicating limits in applying these connections to continental scale models. Sediment dissolved organic matter chemistry is longitudinally structured across the continental United StatesSediment and soil mineral elemental compositions were weakly correlated with sediment dissolved organic matter compositionLocalized metal‐organic matter linkages likely have limited capacity to inform continental‐scale hydrobiogeochemical models Sediment dissolved organic matter chemistry is longitudinally structured across the continental United States Sediment and soil mineral elemental compositions were weakly correlated with sediment dissolved organic matter composition Localized metal‐organic matter linkages likely have limited capacity to inform continental‐scale hydrobiogeochemical models

•Novel topology concept for wireless charging that merges permanent magnets, electric motor and inductive wireless charging.•Application requires low manufacturing which reduces application costs.•Prototype experiment demonstrated that the proposed topology concept is ideal for wireless charging AGV systems due to the reduced leakage flux and improved power stability

Even before the COVID-19 pandemic, attending to the mental wellbeing of all doctors was high on the political agenda. The quality of patient care is also known to be related to doctors’ wellbeing. Now, in the midst of a global pandemic, doctors are having to cope with ever more trauma and moral injury. Group-based peer support and regular reflective practice are interventions known to reduce clinician burnout and optimise wellbeing.

Microbial community succession is a fundamental process that affects underlying functions of almost all ecosystems; yet the roles and fates of the most abundant colonizers are often poorly understood. Does early abundance spur long term persistence? How do deterministic and stochastic processes influence the ecological contribution of colonizers? We performed a succession experiment within a hypersaline ecosystem to investigate how different processes contributed to the turnover of founder species. Bacterial and eukaryotic colonizers were identified during primary succession and tracked through a defined, 79-day biofilm maturation period using 16S and 18S rRNA gene sequencing in combination with high resolution imaging that utilized stable isotope tracers to evaluate successional patterns of primary producers and nitrogen fixers. The majority of the founder species did not maintain high abundance throughout succession. Species replacement (versus loss) was the dominant process shaping community succession. We also asked if different ecological processes acted on bacteria versus Eukaryotes during succession and found deterministic and stochastic forces corresponded more with microeukaryote and bacterial colonization, respectively. Our results show that taxa and functions belonging to different kingdoms, which share habitat in the tight spatial confines of a biofilm, were influenced by different ecological processes and time scales of succession.

Microbial community succession is a fundamental process that affects underlying functions of almost all ecosystems; yet the roles and fates of the most abundant colonizers are often poorly understood. Does early abundance spur long term persistence? How do deterministic and stochastic processes influence the ecological contribution of colonizers? We performed a succession experiment within a hypersaline ecosystem to investigate how different processes contributed to the turnover of founder species. Bacterial and eukaryotic colonizers were identified during primary succession and tracked through a defined, 79-day biofilm maturation period using 16S and 18S rRNA gene sequencing in combination with high resolution imaging that utilized stable isotope tracers to evaluate successional patterns of primary producers and nitrogen fixers. The majority of the founder species did not maintain high abundance throughout succession. Species replacement (versus loss) was the dominant process shaping community succession. We also asked if different ecological processes acted on bacteria versus Eukaryotes during succession and found deterministic and stochastic forces corresponded more with microeukaryote and bacterial colonization, respectively. Our results show that taxa and functions belonging to different kingdoms, which share habitat in the tight spatial confines of a biofilm, were influenced by different ecological processes and time scales of succession.

Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence1. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies1–3, and the results of early clinical trials suggest activity in multiple myeloma4. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low1,2,4–9. Unlike the mechanisms that result in complete and permanent antigen loss6,8,9, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.

The extracellular matrix is a major component of the local environment—that is, the niche—that determines cell behaviour1. During metastatic growth, cancer cells shape the extracellular matrix of the metastatic niche by hydroxylating collagen to promote their own metastatic growth2,3. However, only particular nutrients might support the ability of cancer cells to hydroxylate collagen, because nutrients dictate which enzymatic reactions are active in cancer cells4,5. Here we show that breast cancer cells rely on the nutrient pyruvate to drive collagen-based remodelling of the extracellular matrix in the lung metastatic niche. Specifically, we discovered that pyruvate uptake induces the production of α-ketoglutarate. This metabolite in turn activates collagen hydroxylation by increasing the activity of the enzyme collagen prolyl-4-hydroxylase (P4HA). Inhibition of pyruvate metabolism was sufficient to impair collagen hydroxylation and consequently the growth of breast-cancer-derived lung metastases in different mouse models. In summary, we provide a mechanistic understanding of the link between collagen remodelling and the nutrient environment in the metastatic niche.

Microbial dynamics drive the biotic machinery of early soil evolution. However, integrated knowledge of microbial community establishment, functional associations, and community assembly processes in incipient soil is lacking. This study presents a novel approach of combining microbial phylogenetic profiling, functional predictions, and community assembly processes to analyze drivers of microbial community establishment in an emerging soil system. Rigorous submeter sampling of a basalt‐soil lysimeter after 2 years of irrigation revealed that microbial community colonization patterns and associated soil parameters were depth dependent. Phylogenetic analysis of 16S rRNA gene sequences indicated the presence of diverse bacterial and archaeal phyla, with high relative abundance of Actinomyceles on the surface and a consistently high abundance of Proteobacteria(Alpha, Beta, Gamma, and Delta) at all depths. Despite depth‐dependent variation in community diversity, predicted functional gene analysis suggested that microbial metabolisms did not differ with depth, thereby suggesting redundancy in functional potential throughout the system. Null modeling revealed that microbial community assembly patterns were predominantly governed by variable selection. The relative influence of variable selection decreased with depth, indicating unique and relatively harsh environmental conditions near the surface and more benign conditions with depth. Additionally, community composition near the center of the domain was influenced by high levels of dispersal, suggesting that spatial processes interact with deterministic selection imposed by the environment. These results suggest that for oligotrophic systems, there are major differences in the length scales of variation between vertical and horizontal dimensions with the vertical dimension dominating variation in physical, chemical, and biological features. A submeter sampling regime in an incipient homogenous basalt soil system revealed depth‐dependent heterogeneous microbial presenceNull modeling revealed strong influences of variable selection, resulting from localized abiotic environment selection pressuresLength of scales of variation of hydrobiogeochemical signatures varied significantly along the vertical dimension but not horizontal

Seasonally adjusted series of Gross Domestic Product (GDP) and its breakdown in underlying categories or domains are generally not consistent with each other. Statistical differences between the total GDP and the sum of the underlying domains arise for two reasons. If series are expressed in constant prices, differences arise due to the process of chain linking. These differences increase if, in addition, a univariate seasonal adjustment, with for instance X-13ARIMA-SEATS, is applied to each series separately. In this article, we propose to model the series for total GDP and its breakdown in underlying domains in a multivariate structural time series model, with the restriction that the sum over the different time series components for the domains are equal to the corresponding values for the total GDP. In the proposed procedure, this approach is applied as a pretreatment to remove outliers, level shifts, seasonal breaks and calendar effects, while obeying the aforementioned consistency restrictions. Subsequently, X-13ARIMA-SEATS is used for seasonal adjustment. This reduces inconsistencies remarkably. Remaining inconsistencies due to seasonal adjustment are removed with a benchmarking procedure.

Seasonally adjusted series of Gross Domestic Product (GDP) and its breakdown in underlying categories or domains are generally not consistent with each other. Statistical differences between the total GDP and the sum of the underlying domains arise for two reasons. If series are expressed in constant prices, differences arise due to the process of chain linking. These differences increase if, in addition, a univariate seasonal adjustment, with for instance X-13ARIMA-SEATS, is applied to each series separately. In this article, we propose to model the series for total GDP and its breakdown in underlying domains in a multivariate structural time series model, with the restriction that the sum over the different time series components for the domains are equal to the corresponding values for the total GDP. In the proposed procedure, this approach is applied as a pretreatment to remove outliers, level shifts, seasonal breaks and calendar effects, while obeying the aforementioned consistency restrictions. Subsequently, X-13ARIMA-SEATS is used for seasonal adjustment. This reduces inconsistencies remarkably. Remaining inconsistencies due to seasonal adjustment are removed with a benchmarking procedure.

Endochondral ossification, an important process in vertebrate bone formation, is highly dependent on correct functioning of growth plate chondrocytes1. Proliferation of these cells determines longitudinal bone growth and the matrix deposited provides a scaffold for future bone formation. However, these two energy-dependent anabolic processes occur in an avascular environment1,2. In addition, the centre of the expanding growth plate becomes hypoxic, and local activation of the hypoxia-inducible transcription factor HIF-1α is necessary for chondrocyte survival by unidentified cell-intrinsic mechanisms3–6. It is unknown whether there is a requirement for restriction of HIF-1α signalling in the other regions of the growth plate and whether chondrocyte metabolism controls cell function. Here we show that prolonged HIF-1α signalling in chondrocytes leads to skeletal dysplasia by interfering with cellular bioenergetics and biosynthesis. Decreased glucose oxidation results in an energy deficit, which limits proliferation, activates the unfolded protein response and reduces collagen synthesis. However, enhanced glutamine flux increases α-ketoglutarate levels, which in turn increases proline and lysine hydroxylation on collagen. This metabolically regulated collagen modification renders the cartilaginous matrix more resistant to protease-mediated degradation and thereby increases bone mass. Thus, inappropriate HIF-1α signalling results in skeletal dysplasia caused by collagen overmodification, an effect that may also contribute to other diseases involving the extracellular matrix such as cancer and fibrosis.

Osteocytes act within a hypoxic environment to control key steps in bone formation. FGF23, a critical phosphate-regulating hormone, is stimulated by low oxygen/iron in acute and chronic diseases, however the molecular mechanisms directing this process remain unclear. Our goal was to identify the osteocyte factors responsible for FGF23 production driven by changes in oxygen/iron utilization. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) which stabilize HIF transcription factors, increased Fgf23 in normal mice, as well as in osteocyte-like cells; in mice with conditional osteocyte Fgf23deletion, circulating iFGF23 was suppressed. An inducible MSC cell line (‘MPC2’) underwent FG-4592 treatment and ATACseq/RNAseq, and demonstrated that differentiated osteocytes significantly increased HIF genomic accessibility versus progenitor cells. Integrative genomics also revealed increased prolyl hydroxylase Egln1(Phd2) chromatin accessibility and expression, which was positively associated with osteocyte differentiation. In mice with chronic kidney disease (CKD), Phd1-3 enzymes were suppressed, consistent with FGF23 upregulation in this model. Conditional loss of Phd2 from osteocytes in vivo resulted in upregulated Fgf23, in line with our findings that the MPC2 cell line lacking Phd2 (CRISPR Phd2-KO cells) constitutively activated Fgf23 that was abolished by HIF1α blockade. In vitro, Phd2-KO cells lost iron-mediated suppression of Fgf23 and this activity was not compensated for by Phd1 or −3. In sum, osteocytes become adapted to oxygen/iron sensing during differentiation and are directly sensitive to bioavailable iron. Further, Phd2 is a critical mediator of osteocyte FGF23 production, thus our collective studies may provide new therapeutic targets for skeletal diseases involving disturbed oxygen/iron sensing.

The generation of off-the-shelf CAR-T cells from TiPSCs has been hindered by the difficulty to recapitulate adaptive T cell development and lower therapeutic efficacy compared to peripheral blood CAR-T cells. Ueda et al. address these issues in a triple-engineering strategy, combining optimized CAR expression with cytolytic and persistence enhancements.

The COVID-19 pandemic has imposed new, intense and, as yet, unquantifiable strain on the wellbeing of healthcare professionals. Similarities are seen internationally with regards to the uptake of psychological support offered to healthcare professionals during a pandemic. Junior doctors are in a unique position to offer and access peer support; this is an evidence-based strategy to promote psychological wellbeing of junior doctors through the COVID-19 pandemic and into the future. The development of peer support networks during the pandemic may lead to reduced physician burnout and improved patient care in the future. We discuss a peer support initiative to support medical trainees during the COVID-19 pandemic, discuss the barriers to the success of such schemes, and reflect on the value of grass-roots peer support initiatives.

Anthropogenic activities, especially dam operations, often induce larger and more frequent stage fluctuations than those occurring in natural rivers. However, long‐term impacts of such flow variations on thermal and biogeochemical dynamics of the associated hyporheic zone (HZ) are poorly understood. In this study, we built a heterogeneous, two‐dimensional, thermo‐hydro‐biogeochemical model for an aerobic respiration dominated river system. Our results revealed important interactions between subdaily to weekly flow variations and mean flow conditions controlled by snowpack at the watershed. High‐frequency stage fluctuations had their strongest thermal and biogeochemical impacts when mean river stage was low during fall and winter. In an abnormal drought year (2015) with low river stages during summer and early fall, high‐frequency stage fluctuations caused the HZ to be warmer than average. Furthermore, high‐frequency stage fluctuation enhanced all biogeochemical reactions by increasing nutrient supply and creating more oxygenated conditions. Overall carbon consumption in the HZ increased due to high‐frequency flow variations. Thermal dynamics altered by high‐frequency stage fluctuation impacted biogeochemical reactions in the HZ less than effects imposed by enhanced nutrient and oxygen supply. In addition to these results, we demonstrated that the HZ's hydrogeologic properties control flow paths that influence residence times and nutrient supply and consequently control spatial distribution of biogeochemical reaction hot spots in the HZ. Here we provide scientific basis for assessing potential ecological consequences of high‐frequency flow variations in a regulated river, as well as guidance for maximizing potential benefits—or minimizing drawbacks—of dam regulation to riverine ecosystems. High‐frequency flow variations enhance hydrologic exchange and create long‐term alterations to thermal regimes and biogeochemical reactionsHigh‐frequency flow variations have the largest impact on thermal regimes and biogeochemical reactions in hyporheic zone under droughtSpatial distribution of biogeochemical hot spots depends more on the subsurface hydraulic properties than high‐frequency flow variations

Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL)1 . Although a majority of patients will achieve a complete response following a single infusion of CD19-targeted CAR-modified T cells (CD19 CAR T cells)2–4, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines, including interleukin-6 (IL-6)2,5. CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden2–4. CRS may respond to IL-6 receptor blockade but can require further treatment with high dose corticosteroids to curb potentially lethal severity2–9. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. Here we report a murine model of CRS that develops within 2–3 d of CAR T cell infusion and that is potentially lethal and responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell–derived cytokines, but by IL-6, IL-1 and nitric oxide (NO) produced by recipient macrophages, which enables new therapeutic interventions. Blocking IL-1 and iNOS prevents CAR T cell–induced cytokine release syndrome.

Background:The current nursing shortage affects all settings. In an effort to promote retention of nursing faculty, an “attitude of gratitude” was cultivated to improve job satisfaction and increase collaboration in one school of nursing.Method:This was a quantitative study using a convenience sample of faculty at one school of nursing. A presurvey of faculty on perceived gratitude levels and job satisfaction was administered prior to the start of the school year. Multiple gratitude interventions were implemented throughout the year and a postsurvey was administered to measure the effectiveness of interventions.Results:The findings of this study show an improvement of 17.9% in overall job satisfaction, which is consistent with other studies on the topic. Collaboration was not affected by gratitude interventions.Conclusion:Implementing gratitude is a cost-effective and easy way to improve job satisfaction to increase faculty retention rates. [Implementing gratitude is a cost-effective and easy way to improve job satisfaction to increase faculty retention rates. [J Nurs Educ.2018;57(6):375–378.]

Hydrologic exchange flux (HEF) is an important hydrologic component in river corridors that includes both bidirectional (hyporheic) and unidirectional (gaining/losing) surface water‐groundwater exchanges. Quantifying HEF rates in a large regulated river is difficult due to the large spatial domains, complexity of geomorphologic features and subsurface properties, and the great stage variations created by dam operations at multiple time scales. In this study, we developed a method that combined numerical modeling and field measurements for estimating HEF rates across the riverbed in a 7 km long reach of the highly regulated Columbia River. A high‐resolution computational fluid dynamics (CFD) modeling framework was developed and validated by field measurements and other modeling results to characterize the HEF dynamics across the riverbed. We found that about 85% of the time from 2008 to 2014 the river was losing water with an annual average net HEF rates across the riverbed (Qz) of −2.3 m3s−1(negative indicating downwelling). June was the only month that the river gained water, with monthly averaged Qzof 0.8 m3s−1. We also found that the daily dam operations increased the hourly gross gaining and losing rate over an average year of 8% and 2%, respectively. By investigating the HEF feedbacks at various time scales, we suggest that the dam operations could reduce the HEF at seasonal time scale by decreasing the seasonal flow variations, while also enhance the HEF at subdaily time scale by generating high‐frequency discharge variations. These changes could generate significant impacts on biogeochemical processes in the hyporheic zone. Dam operations regulate downstream water flow and modify the surface water and groundwater interactions. In this study, we simulated river and groundwater dynamics in a 7 km long reach of Columbia River using a high‐resolution numerical model. Due to the upstream dam regulations, the daily river stage variation of our study reach could be as high as 2 m. We found that about 85% of the time from 2008 to 2014 the river was losing water with an annual average net HEF rates across the riverbed of 2.3 m3s−1. June was the only month that the river gained water, with gaining rate of 0.8 m3s−1. We also found that the daily dam operations enhanced the losing and gaining activities, which may lead to great impact on riverbed biogeochemical processes. A coupled CFD model was used to simulate hydrologic dynamics in a large regulated river reach (about 7 km long, 800 m wide)Daily dam operations increased the river gaining and losing rates by 8% and 2%, respectivelyThis approach can be extended to basin scale by combining with geomorphological and hydrogeological characterizations

Little is known about the factors affecting the relative influences of stochastic and deterministic processes that govern the assembly of microbial communities in successional soils. Here, we conducted a meta-analysis of bacterial communities using six different successional soil datasets distributed across different regions. Different relationships between pH and successional age across these datasets allowed us to separate the influences of successional age (i.e., time) from soil pH. We found that extreme acidic or alkaline pH conditions lead to assembly of phylogenetically more clustered bacterial communities through deterministic processes, whereas pH conditions close to neutral lead to phylogenetically less clustered bacterial communities with more stochasticity. We suggest that the influence of pH, rather than successional age, is the main driving force in producing trends in phylogenetic assembly of bacteria, and that pH also influences the relative balance of stochastic and deterministic processes along successional soils. Given that pH had a much stronger association with community assembly than did successional age, we evaluated whether the inferred influence of pH was maintained when studying globally distributed samples collected without regard for successional age. This dataset confirmed the strong influence of pH, suggesting that the influence of soil pH on community assembly processes occurs globally. Extreme pH conditions likely exert more stringent limits on survival and fitness, imposing strong selective pressures through ecological and evolutionary time. Taken together, these findings suggest that the degree to which stochastic vs. deterministic processes shape soil bacterial community assembly is a consequence of soil pH rather than successional age.

Little is known about the factors affecting the relative influences of stochastic and deterministic processes that govern the assembly of microbial communities in successional soils. Here, we conducted a meta-analysis of bacterial communities using six different successional soil datasets distributed across different regions. Different relationships between pH and successional age across these datasets allowed us to separate the influences of successional age (i.e., time) from soil pH. We found that extreme acidic or alkaline pH conditions lead to assembly of phylogenetically more clustered bacterial communities through deterministic processes, whereas pH conditions close to neutral lead to phylogenetically less clustered bacterial communities with more stochasticity. We suggest that the influence of pH, rather than successional age, is the main driving force in producing trends in phylogenetic assembly of bacteria, and that pH also influences the relative balance of stochastic and deterministic processes along successional soils. Given that pH had a much stronger association with community assembly than did successional age, we evaluated whether the inferred influence of pH was maintained when studying globally distributed samples collected without regard for successional age. This dataset confirmed the strong influence of pH, suggesting that the influence of soil pH on community assembly processes occurs globally. Extreme pH conditions likely exert more stringent limits on survival and fitness, imposing strong selective pressures through ecological and evolutionary time. Taken together, these findings suggest that the degree to which stochastic vs. deterministic processes shape soil bacterial community assembly is a consequence of soil pH rather than successional age.

In light of increasing terrestrial carbon (C) transport across aquatic boundaries, the mechanisms governing organic carbon (OC) oxidation along terrestrial‐aquatic interfaces are crucial to future climate predictions. Here we investigate the biochemistry, metabolic pathways, and thermodynamics corresponding to OC oxidation in the Columbia River corridor using ultrahigh‐resolution C characterization. We leverage natural vegetative differences to encompass variation in terrestrial C inputs. Our results suggest that decreases in terrestrial C deposition associated with diminished riparian vegetation induce oxidation of physically bound OC. We also find that contrasting metabolic pathways oxidize OC in the presence and absence of vegetation and—in direct conflict with the “priming” concept—that inputs of water‐soluble and thermodynamically favorable terrestrial OC protect bound‐OC from oxidation. In both environments, the most thermodynamically favorable compounds appear to be preferentially oxidized regardless of which OC pool microbiomes metabolize. In turn, we suggest that the extent of riparian vegetation causes sediment microbiomes to locally adapt to oxidize a particular pool of OC but that common thermodynamic principles govern the oxidation of each pool (i.e., water‐soluble or physically bound). Finally, we propose a mechanistic conceptualization of OC oxidation along terrestrial‐aquatic interfaces that can be used to model heterogeneous patterns of OC loss under changing land cover distributions. Riparian vegetation protects bound‐OC stocksBiochemical processes associated with OC oxidation vary with vegetation stateCommon thermodynamic principles underlie OC oxidation regardless of vegetation state

The recent arrival of Batrachochytrium salamandrivorans in Europe was followed by rapid expansion of its geographical distribution and host range, confirming the unprecedented threat that this chytrid fungus poses to western Palaearctic amphibians. Mitigating this hazard requires a thorough understanding of the pathogen’s disease ecology that is driving the extinction process. Here, we monitored infection, disease and host population dynamics in a Belgian fire salamander (Salamandra salamandra) population for two years immediately after the first signs of infection. We show that arrival of this chytrid is associated with rapid population collapse without any sign of recovery, largely due to lack of increased resistance in the surviving salamanders and a demographic shift that prevents compensation for mortality. The pathogen adopts a dual transmission strategy, with environmentally resistant non-motile spores in addition to the motile spores identified in its sister species B. dendrobatidis. The fungus retains its virulence not only in water and soil, but also in anurans and less susceptible urodelan species that function as infection reservoirs. The combined characteristics of the disease ecology suggest that further expansion of this fungus will behave as a ‘perfect storm’ that is able to rapidly extirpate highly susceptible salamander populations across Europe.

Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing. Recent advances in genome editing enable efficient sequence-specific interventions in human cells, including targeted gene delivery to the CCR5 and AAVS1 loci. Here we show that directing a CD19-specific CAR to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukaemia. We further demonstrate that targeting the CAR to the TRAC locus averts tonic CAR signalling and establishes effective internalization and re-expression of the CAR following single or repeated exposure to antigen, delaying effector T-cell differentiation and exhaustion. These findings uncover facets of CAR immunobiology and underscore the potential of CRISPR/Cas9 genome editing to advance immunotherapies.