Legacy nitrogen (N) sources originating from anthropogenic N inputs (NANI) may be a major cause of increasing riverine N exports in many regions, despite a significant decline in NANI. However, little quantitative knowledge exists concerning the lag effect of NANI on riverine N export. As a result, the N leaching lag effect is not well represented in most current watershed models. This study developed a lagged variable model (LVM) to address temporally dynamic export of watershed NANI to rivers. Employing a Koyck transformation approach used in economic analyses, the LVM expresses the indefinite number of lag terms from previous years’ NANI with a lag term that incorporates the previous year’s riverine N flux, enabling us to inversely calibrate model parameters from measurable variables using Bayesian statistics. Applying the LVM to the upper Jiaojiang watershed in eastern China for 1980–2010 indicated that ~97 % of riverine export of annual NANI occurred in the current year and succeeding 10 years (~11 years lag time) and ~72 % of annual riverine N flux was derived from previous years’ NANI. Existing NANI over the 1993–2010 period would have required a 22 % reduction to attain the target TN level (1.0 mg N L−1), guiding watershed N source controls considering the lag effect. The LVM was developed with parsimony of model structure and parameters (only four parameters in this study); thus, it is easy to develop and apply in other watersheds. The LVM provides a simple and effective tool for quantifying the lag effect of anthropogenic N input on riverine export in support of efficient development and evaluation of watershed N control strategies.

A quantitative understanding of riverine phosphorus (P) export in response to changes in anthropogenic P inputs (NAPI), land use and climate is critical for developing effective watershed P control measures. This study indicated that annual riverine TP export for the six catchments of the Yongan River watershed in eastern China increased 4.1–30.3-fold over the 1980–2010 period. Increased riverine TP export resulted from a 61–85 % increase in NAPI and a 2.6–14.6-fold increase in riverine export fraction of NAPI due to 36–43, 30–125, and 65–76 % increases in developed land area (D%), drained agricultural land area (DA%), and storm events, respectively. For the 31-year cumulative record, 1.6–14 % of NAPI was exported by rivers, 40–64 % was stored in the upper 20 cm of agricultural soils, and 30–55 % was retained in other landscape positions. An empirical model that incorporates annual NAPI, precipitation, D%, and DA% accounted for 94 % of the variation in annual riverine TP fluxes across the six catchments and 31 years. The model estimated that NAPI and legacy P contributed 42–92 % and 8–58 % of annual riverine TP flux, respectively. The model forecasts an 8–18 % increase in riverine TP flux by 2030 due to a 4 % increase in precipitation with no changes in NAPI and land use compared to the 2000–2010 baseline condition. Enhanced export of NAPI and legacy P by changes in land use and climate will delay the decrease in riverine P flux in response to NAPI reductions and should be considered in developing and assessing watershed P management strategies.

Controlling brine flow is important for the safe disposal of radioactive waste in salt rocks. Thermal and mechanical processes can have a significant impact on brine flow, although this has never been thoroughly investigated. In this study, we conduct fully coupled THM modeling for analyzing brine flow in rock salt, considering non-isothermal two-phase flow through deformable porous media. To rigorously represent rock salt behavior, we incorporate suitable phenomenological models for creep and shear and tensile-induced dilatancy/damage, and their effect on the flow properties. To validate such a complex model, we use it to analyze an experiment on a meter-scale salt block subjected to multistage heating and cooling under controlled laboratory conditions. The experimental data and our model predictions of temperature and brine inflow show good agreement. Our modeling shows that it is important to consider the coupling between the heating- and cooling-induced damage and the flow properties for rigorously estimating brine inflow. Based on our modeling, a cooling-induced brine inflow spike is caused by a permeability increase due to tensile dilatancy. Thus, our modeling will be useful for a proper design of a cooling phase in the salt repositories to avoid or minimize damage and the resulting brine inflow.

Failure of palatogenesis results in cleft palate, one of the most common congenital disabilities in humans. During the final phases of palatogenesis, the protective function of the peridermal cell layer must be eliminated for the medial edge epithelia to adhere properly, which is a prerequisite for the successful fusion of the secondary palate. However, a deeper understanding of the role and fate of the periderm in palatal adherence and fusion has been hampered due to a lack of appropriate periderm-specific genetic tools to examine this cell type in vivo. Here we used the cytokeratin-6A (Krt-6a) locus to develop both constitutive (Krt6ai-Cre) and inducible (Krt6ai-CreERT2) periderm-specific Cre driver mouse lines. These novel lines allowed us to achieve both the spatial and temporal control needed to dissect the periderm fate on a cellular resolution during palatogenesis. Our studies suggest that, already before the opposing palatal shelves contact each other, at least some palatal periderm cells start to gradually lose their squamous periderm-like phenotype and dedifferentiate into cuboidal cells, reminiscent of the basal epithelial cells seen in the palatal midline seam. Moreover, we show that transforming growth factor-β (TGF-β) signaling plays a critical periderm-specific role in palatogenesis. Thirty-three percent of embryos lacking a gene encoding the TGF-β type I receptor (Tgfbr1) in the periderm display a complete cleft of the secondary palate. Our subsequent experiments demonstrated that Tgfbr1-deficient periderm fails to undergo appropriate dedifferentiation. These studies define the periderm cell fate during palatogenesis and reveal a novel, critical role for TGF-β signaling in periderm dedifferentiation, which is a prerequisite for appropriate palatal epithelial adhesion and fusion.

Early PINP changes correlate with 18-month lumbar spine BMD changes and the correlation was greater with abaloparatide versus teriparatide. The uncoupling index was similar between the two agents.

Introduction

We evaluated the relationship between early PINP changes and subsequent changes in spine BMD following abaloparatide and teriparatide treatments. We also explored the use of an "uncoupling index" (UI), the balance between bone formation and bone resorption, which we hypothesised would be similar in response to these treatment groups.

Methods

Blood samples were taken for measurement of bone turnover markers (BTMs) s-PINP and s-CTX at baseline, 1, 3, 6, 12, and 18 months from 189 abaloparatide patients and 227 teriparatide patients randomly selected from all participants who completed the study. BMD was measured by DXA at baseline, 6, 12, and 18 months. Correlations were calculated between log ratio of BTMs from baseline to 3 months and percent change from baseline in BMD at 18 months. A UI was calculated using log transformation and subtraction of the standard deviate for s-CTX from the standard deviate for s-PINP for each patient.

Results

Early BTM changes were associated with subsequent BMD changes for both treatments. Pearson correlations for the log ratio of PINP over baseline at 3 months and BMD percent change from baseline at 18 months were larger (P < 0.0001) with abaloparatide (r = 0.561) than teriparatide (r = 0.198). The mean UI at 1 month was greater for abaloparatide versus teriparatide (1.743 and 1.493, respectively; P = 0.03) but was similar at 3 months or later time points.

Conclusions

Early s-PINP changes correlate with percentage change in lumbar spine BMD 18 months after treatment with both abaloparatide and teriparatide, though the correlation with abaloparatide was greater. The UI was similar between abaloparatide and teriparatide suggesting that the balance between formation and resorption markers was similar.

The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct

The shape of the cell is connected to its function; however, we do not fully understand underlying mechanisms by which global shape regulates a cell's functional capabilities. Using theory, experiments and simulation, we investigated how physiologically relevant cell shape changes affect subcellular organization, and consequently intracellular signaling, to control information flow needed for phenotypic function. Vascular smooth muscle cells going from a proliferative and motile circular shape to a contractile fusiform shape show changes in the location of the sarcoplasmic reticulum, inter-organelle distances, and differential distribution of receptors in the plasma membrane. These factors together lead to the modulation of signals transduced by the M₃ muscarinic receptor/G_q/PLCβ pathway at the plasma membrane, amplifying Ca²⁺ dynamics in the cytoplasm, and the nucleus resulting in phenotypic changes, as determined by increased activity of myosin light chain kinase in the cytoplasm and enhanced nuclear localization of the transcription factor NFAT. Taken together, our observations show a systems level phenomenon whereby global cell shape affects subcellular organization to modulate signaling that enables phenotypic changes.