Impacts of hydrological alteration on ecosystem services changes of a large river-connected lake (Poyang Lake), China.

Large lakes provide various types of ecosystem services (ESs), of which stocks and variations induced by hydrological alterations are largely unquantified. The present study investigates the long-term changes of five key ESs (i.e., flood regulation, water supply, fish production, nutrient retention and biodiversity conservation) in a large river connected lake (Poyang Lake), with special attention to impacts of hydrological alteration induced by the Three Gorges Dam (TGD). Hydrological data series, hydrodynamic model, the nutrient balance, fishery statistics, and wetland winter waterbird survey data from 1980 to 2016 were employed. Results showed that Poyang Lake provide significant ESs, with long-term average flood regulation, water supply and nutrient retention services of 167.7 × 108 m3, 31.53 × 108 m3, and 15.12% of total phosphorus load, respectively. The fish production service ranged from 1.74 × 104t to 7.19 × 104t, with an average value of 3.12 × 104t. All five key ESs exhibited a downward trend since the 2000s, especially for water supply, fish production and nutrient retention services (p < 0.05), which might be largely attributed to the hydrological condition changes induced by TGD operation. Nevertheless, more detailed monitoring data and biophysical models are required to further acknowledge the changes in biodiversity conservation and fish production services and their linkages with the TGD. The present study sheds light on long-term ES changes in large lakes and their possible linkages with human influences through hydropower projects.

Land use change and climate dynamics in the Rift Valley Lake Basin, Ethiopia.

Land use and climate dynamics have a pronounced impact on water resources, biodiversity, land degradation, and productivity at all scales. Thus, in this study, we present the spatio-temporal dynamics of land use change and climate aiming to provide a scientific evidence about gains and losses in major land use categories and associated drivers and significancy and homogeneity of climate change. To this end, Landsat images and historical climate data have been used to determine the dynamics. In addition, population census data and land use policy have been considered to assess the potential drivers of land use change. The spatio-temporal land use dynamics have been evaluated using transition matrix and dynamics index. Likewise, shifts in the climate data were analyzed using change point analysis and three homogenous climate zones have been identified using principal component analysis. The results show that, from 1989 to 2019, the areal percentage of agricultural land increased by 27.5%, settlement by 0.8%, and barren land 0.4% while the natural vegetation, wetland, water body, and grass land decreased by 24.5%, 1.6%, 0.5%, and 2.1%, respectively. The land use dynamics have been stronger in the first decade of the study period. An abrupt shift of climate has occurred in the 1980s. In the last four decades, rainfall shows a not significant decreasing trend. However, a significant increasing trend has been observed for temperature. Rapid population growth, agricultural expansion policy, and climate variability have been identified as the underlying drivers of land use dynamics.

Spatial and temporal assessment of human-water interactions at the Inle Lake, Myanmar: a socio-hydrological DPSIR analysis.

Freshwater resources as a key aspect of socio-economic development, provide a large number of services in human and environmental systems. Nevertheless, human appropriation of these water resources and the modification of landscapes lead to potential threats on water availability and quality from local to global scales. The Inle Lake in Myanmar is an economically, traditionally, and ecologically important freshwater ecosystem that faced severe degradation from the 2000s. In its catchment area, a Driver-Pressure-State-Impact-Response (DPSIR) framework is applied for an assessment period of 30 years from 1990 to 2020. The analysis results are complemented with a socio-hydrological survey, water quality assessment, a land use classification based on ground truth and satellite data, and hydrologic models. The resulting land use changes, - 13% forest, + 13% agriculture, and + 5% urban areas, lead to increased water yield, decreased evapotranspiration, and increased sediment yield. Together with other drivers and pressures such as climate change and anthropogenic pollution, these human activities are major threats for freshwater resources and the ecosystem. However, the existing awareness of the local population for the environmental degradation is obstructed by national and international crises and responses to negative developments can accelerate degradation if they are unplanned and short-term solutions. Our study shows that environmental degradation processes have a complex nature and can only be tackled in a coordinated way with a long-term perspective. DPSIR is a suitable approach to assess human-water dynamics and disentangle the complex interconnectedness of social and environmental systems in freshwater ecosystems, even in data-scarce regions.

LARAMOTIONS: a conceptual study on laser networks for near-term collision avoidance for space debris in the low Earth orbit.

A conceptual study has been carried out on laser station networks to enhance Space Situational Awareness and contribute to collision avoidance in the low Earth orbit by high-precision laser tracking of debris objects and momentum transfer via photon pressure from ground-based high-power lasers. Depending on the network size, geographical distribution of stations, orbit parameters, and remaining time to conjunction, multipass irradiation enhances the efficiency of photon momentum coupling by 1-2 orders of magnitude and has the potential to eventually yield a promisingly significant reduction of the collision rate in low Earth orbit.

Heterogeneous Nucleation onto Monoatomic Ions: Support for the Kelvin-Thomson Theory.

In this study, the process of heterogeneous nucleation is investigated by coupling a high-resolution differential mobility analyser (DMA) to an expansion-type condensation particle counter, the size-analyzing nuclei counter (SANC). More specifically, we measured the activation probabilities of monoatomic ions of both polarities by using n-butanol as condensing liquid. All seed ions were activated to grow into macroscopic sizes at saturation ratios well below the onset of homogeneous nucleation, showing for the first time that the SANC is capable of detecting sub-nanometer sized, atomic seed ions. The measured onset saturation ratios for each ion were compared to the Kelvin-Thomson (KT) theory. Despite the fact that certain dependencies of activation behaviour on seed ion properties cannot be predicted by the KT theory, it was found that with a simple adjustment of the n-butanol molecular volume (9-15 % lower compared to bulk properties) good agreement with experimental results is achievable. The corresponding density increase may result from the dipole-charge interaction. This study thus offers support for the application of the KT model for heterogeneous, ion-induced nucleation studies at the sub-nanometer level.

A unifying identity for the work of cluster formation in heterogeneous and homogeneous nucleation theory.

A unifying identity is derived relating the reversible work of cluster formation (W) and its molecular number content (n) and surface work (Φ) components, each ratioed to the corresponding values for a spherical capillary drop of critical size in classical nucleation theory. The result is a relationship that connects these ratios: fW = -2fN + 3fS, where fW = W/W*CNT, fN = n/n*CNT, and fS = Φ/Φ*CNT. Shown to generalize two early thermodynamic relationships of Gibbs, the new result is demonstrated here for Fletcher's model of heterogeneous nucleation, resulting in a unified treatment of condensation on flat and curved substrates and smooth passage to the homogeneous limit. Additional applications are made to clusters of non-critical as well as critical size and to a molecular-based extension of classical nucleation theory based on the Kelvin relation. The new identity serves as a consistency check on complicated theoretical expressions and numerical calculations and can be used to guide the construction of theory and interpretation of measurements.

Full-field optical coherence tomography in a balanced detection mode.

We discuss balanced time-domain full-field optical coherence tomography (FF-OCT) realized in a Mach-Zehnder configuration. The balanced detection scheme and spatial phase shifting allow single-shot acquisition and reconstruction in FF-OCT. Combined with a 2D quadrature signal-based demodulation technique applying the Riesz transform, previously illustrated for a dual-shot temporal phase shifting in FF-OCT, we demonstrate the concept for single-shot spatial phase shifting. The monitoring of dynamic processes by time-domain FF-OCT is enabled by this approach. The advantage of single-shot acquisition consists of having no failure due to phase changes over time. However, it demands an accurate registration of both spatially shifted interferograms.

Effects of dark chocolate and cocoa consumption on endothelial function and arterial stiffness in overweight adults.

The consumption of cocoa and dark chocolate is associated with a lower risk of CVD, and improvements in endothelial function may mediate this relationship. Less is known about the effects of cocoa/chocolate on the augmentation index (AI), a measure of vascular stiffness and vascular tone in the peripheral arterioles. We enrolled thirty middle-aged, overweight adults in a randomised, placebo-controlled, 4-week, cross-over study. During the active treatment (cocoa) period, the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage (total cocoa = 22 g/d, total flavanols (TF) = 814 mg/d). Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar (TF = 3 mg/d). Treatments were matched for total fat, saturated fat, carbohydrates and protein. The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6% (+2 mm) and basal blood flow volume by 22%. Substantial decreases in the AI, a measure of arterial stiffness, were observed in only women. Flow-mediated dilation and the reactive hyperaemia index remained unchanged. The consumption of cocoa had no effect on fasting blood measures, while the control treatment increased fasting insulin concentration and insulin resistance (P= 0·01). Fasting blood pressure (BP) remained unchanged, although the acute consumption of cocoa increased resting BP by 4 mmHg. In summary, the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women.

Near-unity mass accommodation coefficient of organic molecules of varying structure.

Atmospheric aerosol particles have a significant effect on global climate, air quality, and consequently human health. Condensation of organic vapors is a key process in the growth of nanometer-sized particles to climate relevant sizes. This growth is very sensitive to the mass accommodation coefficient α, a quantity describing the vapor uptake ability of the particles, but knowledge on α of atmospheric organics is lacking. In this work, we have determined α for four organic molecules with diverse structural properties: adipic acid, succinic acid, naphthalene, and nonane. The coefficients are studied using molecular dynamics simulations, complemented with expansion chamber measurements. Our results are consistent with α = 1 (indicating nearly perfect accommodation), regardless of the molecular structural properties, the phase state of the bulk condensed phase, or surface curvature. The results highlight the need for experimental techniques capable of resolving the internal structure of nanoparticles to better constrain the accommodation of atmospheric organics.

Examining characteristics and sampling methods of phosphor dynamics in lowland catchments.

Despite over two decades since the EU Water Framework Directive have passed, achieving the desired water quality in German surface waters remains challenging, regardless of efforts to reduce phosphorus inputs and associated environmental impacts. This study aims at analyzing the characteristics governing the concentrations of four key water quality parameters (total phosphorus, orthophosphate, particulate phosphate, and suspended solids) in two lowland catchments: the 50 km2 catchment of the Kielstau, Germany, and its 7 km2 tributary, the Moorau, which are dominated by agricultural land use. To this end, different sampling methods, particularly high-resolution precipitation event-based sampling and daily mixed samples, are conducted and evaluated, and their effectiveness is compared. The identification of sources and characteristics that affect phosphorus and suspended sediment dynamics, both in general and specifically during heavy precipitation events, is one focus of the study. Over a 15-year period, increasing concentrations of these parameters were observed in daily mixed samples, exhibiting distinct seasonal patterns-higher in summer and lower in winter-consistent with lowland catchment behavior. Particularly during heavy precipitation events, the smaller catchment exhibits a more complex and less predictable response to chemical concentrations compared with the dilution effect observed in the larger catchment. The results underline the complexity of phosphorus dynamics in small catchments and emphasize the importance of event-based sampling for capturing short-term concentration peaks for all four parameters, particularly beneficial regarding measuring suspended solids. While daily mixed samples capture average phosphorus concentrations, event-based sampling is crucial for detecting short-term spikes, providing a more comprehensive understanding of phosphorus dynamics.

Molecular basis for the interactions of eIF2ß with eIF5, eIF2B, and 5MP1 and their regulation by CK2.

The heterotrimeric GTPase eukaryotic translation initiation factor 2 (eIF2) delivers the initiator Met-tRNAi to the ribosomal translation preinitiation complex. eIF2ß has three lysine-rich repeats (K-boxes) in its N-terminal tail, which are important for binding to the GTPase-activating protein (GAP) eIF5, the guanine nucleotide exchange factor (GEF) eIF2B, and the regulator eIF5-mimic protein (5MP). Here, we combine X-ray crystallography with NMR to understand the molecular basis and dynamics of these interactions. The crystal structure of yeast eIF5-CTD in complex with K-box 3 of eIF2ß reveals an extended binding site on eIF2ß, far beyond the K-box. We show that human eIF5, eIF2Bε, and 5MP1 can all bind to each of the three K-boxes, while reducing each other's affinities. Moreover, all these affinities are increased by CK2 phosphomimetic mutations. Our results reveal how eIF5, eIF2B, and 5MP displace each other from eIF2, and elucidate the role of CK2 in remodeling the translation apparatus.

A spatio-temporal analysis of environmental fate and transport processes of pesticides and their transformation products in agricultural landscapes dominated by subsurface drainage with SWAT.

Pesticides are detected in surface water and groundwater, endangering the environment. In lowland regions with subsurface drainage systems, drained depressions become hotspots for transport of pesticides and their transformation products (TPs). This study focuses on detailed modelling of the degradation and transport of pesticides with different physico-chemical properties. The objective is to analyse complex hydrological transport processes, to understand the temporal and spatial dynamics of the degradation and transport of pesticides. The ecohydrological model SWAT+ simulates hydrological processes as well as agricultural management and pesticide degradation, and can therefore be used to develop pesticide loss reduction strategies. This study focuses on modelling of three pesticides (pendimethalin, diflufenican, and flufenacet), and two TPs, flufenacet-oxalic acid (FOA) and flufenacet sulfonic acid (FESA). The study area is a 100-hectare farmland in the northern German lowlands of Schleswig-Holstein that is characterized by an spacious drainage network of 6.3 km and managed according to common conventional agricultural practice. SWAT+ modelled streamflow with very good agreement between observed and simulated data during calibration and validation. Regarding pesticides, the model performance for highly mobile substances is better than for non-mobile pesticides. While the transport of the moderately to very mobile substances via tile drains played an important role in both wet and dry conditions, no transport via tile drains was modelled for the highly sorptive and non-mobile pendimethalin. In conclusion, the model can reliably represent the degradation of moderately to very mobile pesticides in small-scale tile drainage-dominated catchments, as well as surface runoff-induced peak loads. However, it has weaknesses in accounting for the subsurface transport of non-mobile substances, which can lead to an underestimation of the subsequent delivery after precipitation events and thus underestimates the total load.

Spatial expression of claudin 18.2 in matched primaries and metastases of tubo-ovarian carcinoma of all subtypes.

Physiologically, claudin 18 splice variant 2 (CLDN18.2) expression is restricted to the gastric epithelium, but its expression has been detected in solid cancers. Zolbetuximab, a chimeric IgG1 antibody targeting CLDN18.2, has demonstrated promising effects in patients suffering from CLDN18.2-positive, HER2-negative locally advanced gastric cancer and is currently being studied further. To date, little is known about CLDN18.2 expression in other histological subtypes of tubo-ovarian carcinoma (TOC) and their matching metastases.Using a cohort of all histological TOC subtypes, we investigated the immunohistochemical (IHC) CLDN18.2 expression in both TOCs (n = 536), their matching metastatic tissue (n = 385) and in 93 metastases without primary. Tissue microarrays comprised both the tumor center and periphery. IHC positivity was defined as biomarker expression of ≥ 75% in tumor cells with moderate-to-strong membranous staining.Overall CLDN18.2 positivity was 4.1% (21/515) in the TOC centers and 3.6% (18/498) in their peripheries. In primaries of mucinous tubo-ovarian carcinoma (MTOC), CLDN18.2 positivity rates were 45% (18/40) and 36.6% (15/41), respectively. Positivity rates for the corresponding metastases were 33% (4/12, center) and 27% (3/11, periphery). The expression was relatively homogenous throughout all tumor sites. With no expression in 99.5% of nonmucinous tumors, CLDN18.2 positivity was almost exclusively seen in the mucinous subtype.In tubo-ovarian carcinoma, CLDN18.2 expression was, with rare exceptions, restricted to the mucinous subtype. Among them, 33% of metastasized MTOCs presented with CLDN18.2 positivity. Hence, CLDN18.2 might display a promising target for personalized therapy in patients with advanced MTOC.

Designing Rigorous and Efficient Clinical Utility Studies for Early Detection Biomarkers.

Before implementing a biomarker in routine clinical care, it must demonstrate clinical utility by leading to clinical actions that positively affect patient-relevant outcomes. Randomly controlled early detection utility trials, especially those targeting mortality endpoint, are challenging due to their high costs and prolonged duration. Special design considerations are required to determine the clinical utility of early detection assays. This commentary reports on discussions among the National Cancer Institute's Early Detection Research Network investigators, outlining the recommended process for carrying out single-organ biomarker-driven clinical utility studies. We present the early detection utility studies in the context of phased biomarker development. We describe aspects of the studies related to the features of biomarker tests, the clinical context of endpoints, the performance criteria for later phase evaluation, and study size. We discuss novel adaptive design approaches for improving the efficiency and practicality of clinical utility trials. We recommend using multiple strategies, including adopting real-world evidence, emulated trials, and mathematical modeling to circumvent the challenges in conducting early detection utility trials.

Proposal for a Novel Histological Scoring System as a Potential Grading Approach for Muscle-invasive Urothelial Bladder Cancer Correlating with Disease Aggressiveness and Patient Outcomes.

BACKGROUND: Grading of muscle-invasive bladder cancer (MIBC) according to the current World Health Organization (WHO) criteria is controversial due to its limited prognostic value. All MIBC cases except a tiny minority are of high grade. OBJECTIVE: To develop a prognostic histological scoring system for MIBC integrating histomorphological phenotype, stromal tumor-infiltrating lymphocytes (sTILs), tumor budding, and growth and spreading patterns. DESIGN, SETTING, AND PARTICIPANTS: Tissue specimens and clinical data of 484 patients receiving cystectomy and lymphadenectomy with curative intent with or without adjuvant chemotherapy. Histomorphological phenotypes, sTILs, tumor budding, and growth and spreading patterns were evaluated and categorized into four grade groups (GGs). GGs were correlated with molecular subtypes, immune infiltration, immune checkpoint expression, extracellular matrix (ECM) remodeling, and epithelial-mesenchymal transition (EMT) activity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: GGs were associated with overall (OS), disease-specific (DSS), and progression-free (PFS) survival in univariable and multivariable analyses. Association with biological features was analyzed with descriptive statistics. RESULTS AND LIMITATIONS: Integration of two histomorphological tumor groups, three sTILs groups, three tumor budding groups, and four growth/spread patterns yielded four novel GGs that had high significance in the univariable survival analysis (OS, DSS, and PFS). GGs were confirmed as independent prognostic predictors with the greatest effect in the multivariable Cox regression analysis. Correlation with molecular data showed a gradual transition from basal to luminal subtypes from GG1 to GG4; a gradual decrease in survival, immune infiltration, and immune checkpoint activity; and a gradual increase in ECM remodeling and EMT activity. CONCLUSIONS: We propose a novel, prognostically relevant, and biologically based scoring system for MIBC in cystectomies applicable to routine pathological sections. PATIENT SUMMARY: We developed a novel approach to assess the aggressiveness of advanced bladder cancer, which allows improved risk stratification compared with the method currently proposed by the World Health Organization.

Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties.

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.

Development of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided optimization of a 1,2,3-benzotriazole lead.

A series of amino-pyrimidines was developed based upon an initial kinase cross-screening hit from a CDK2 program. Kinase profiling and structure-based drug design guided the optimization from the initial 1,2,3-benzotriazole hit to a potent and selective JNK inhibitor, compound 24f (JNK1 and 2 IC(50)=16 and 66 nM, respectively), with bioavailability in rats and suitable for further in vivo pharmacological evaluation.

National Cancer Institute's early detection research network: a model organization for biomarker research.

For many cancers a primary cause of poor survival is that they are detected at a late stage when therapies are less effective. Although screening methods exist to detect some types of cancer at an early stage, there are currently no effective methods to screen for most types of cancer. Biomarkers have the potential to improve detection of early-stage cancers, risk stratification, and prediction of which pre-cancerous lesions are likely to progress and to make screening tests less invasive. Although thousands of research articles on biomarkers for early detection are published every year, few of these biomarkers have been validated and shown to be clinically useful. This reflects both the inherent difficulty in detecting early-stage cancers and a disconnect between the process of discovering biomarkers and their use in the clinic. To overcome this limitation the US National Cancer Institute created the Early Detection Research Network. It is a highly collaborative program that brings together biomarker discoverers, assay developers, and clinicians. It provides an infrastructure that is essential for developing and validating biomarkers and imaging methods for early cancer detection and has successfully completed several multicenter validation studies.

Integrated modeling of global change impacts on land and water resources.

There is a common scientific understanding that global change impact analysis, mitigation, and adaptation require interdisciplinary work. Integrated modeling could help to address the challenges associated with the impacts of global change. Particularly, integrated modeling that takes feedback effects into account will allow for the derivation of climate resilient land use and land management. Here, we call for more of such integrated modeling work focusing on the interdisciplinary subject of water resources and land management. As a proof-of-concept, we tightly couple a hydrologic (SWAT) and a land use model (CLUE-s) and illustrate the benefits of this coupled land and water modeling framework (LaWaCoMo) with a scenario on cropland abandonment induced by water stress. As compared to standalone model runs of SWAT and CLUE-s for the past, LaWaCoMo performs slightly better regarding measured river discharge (PBIAS: +0.8% and +1.5% compared at two gauges) and land use change (figure of merit: +6.4% and +2.3% compared to land use maps at two points in time). We show that LaWaCoMo is suitable for global change impact analysis as it is sensitive to climate and land use inputs as well as to management decisions. Our results shed light on the importance of feedback effects between land use and hydrology to assess impacts of global change on land and water resources accurately and consistently. To facilitate that the developed methodology can serve as a blueprint for integrated modeling of global change impacts, we used two freely available models that belong to the most widely used models in their respective disciplines.

PreCancer Atlas: Present and Future.

Precancer atlases have the potential to revolutionize how we think about the topographic and morphologic structures of precancerous lesions in relation to cellular, molecular, genetic, and pathophysiologic states. This mini review uses the Human Tumor Atlas Network (HTAN), established by the National Cancer Institute (NCI), to illustrate the construction of cellular and molecular three-dimensional atlases of human cancers as they evolve from precancerous lesions to advanced disease. We describe the collaborative nature of the network and the research to determine how and when premalignant lesions progress to invasive cancer, regress or obtain a state of equilibrium. We have attempted to highlight progress made by HTAN in building precancer atlases and discuss possible future directions. It is hoped that the lessons from our experience with HTAN will help other investigators engaged in the construction of precancer atlases to crystallize their thoughts on logistics, rationale, and implementation.