Description: Hyperhomocysteinemia (HHcy) has been observed to promote hypertension, but the mechanisms are unclear. Toll-like receptor 4 (TLR-4) is a cellular membrane protein that is ubiquitously expressed in all cell types of the vasculature. TLR-4 activation has been known to promote inflammation that has been associated with the pathogenesis of hypertension. In this study we hypothesize that HHcy induces hypertension by TLR-4 activation, which promotes inflammatory cytokine (IL-1β, IL-6, and TNF-α) upregulation and initiation of mitochondria-dependent apoptosis, leading to cell death and chronic vascular inflammation. To test this hypothesis, we used C57BL/6J (WT) mice, cystathionine β-synthase (CBS)-deficient (CBS +/– ) mice with genetic mild HHcy, C3H/HeJ (C3H) mice with TLR-4 mutation, and mice with combined genetic HHcy and TLR-4 mutation (CBS +/– /C3H). Ultrasonography of the superior mesenteric artery (SMA) detected an increase in wall-to-lumen ratio, resistive index (RI), and pulsatility index (PI). Tail cuff blood pressure (BP) measurement revealed elevated BP in CBS +/– mice. RI, PI, and wall-to-lumen ratio of the SMA in CBS +/– /C3H mice were similar to the control group, and BP was significantly alleviated. TLR-4, IL-1β, IL-6, and TNF-α expression were upregulated in the SMA of CBS +/– mice and reduced in the SMA of CBS +/– /C3H mice. Molecules involved in the mitochondria-mediated cell death pathway (BAX, caspase-9, and caspase-3) were upregulated in CBS +/– mice and attenuated in CBS +/– /C3H mice. We conclude that HHcy promotes TLR-4-driven chronic vascular inflammation and mitochondria-mediated cell death, inducing hypertension. TLR-4 mutation attenuates vascular inflammation and cell death, which suppress hypertension.

Description: ABSTRACT Recent USGS water use report suggests that increasing water-use efficiency could mitigate the supply-and-demand imbalance arising from changing climate and growing population. However, this rich data has not been analyzed to understand the underlying patterns, nor have been investigated to identify the factors contributing to this increased efficiency. A national-scale synthesis of public supply withdrawals (“withdrawals”) reveals a strong North–south gradient in public supply water use with the increasing population in the South contributing to increased withdrawal. Contrastingly, a reverse South–north gradient exists in per-capita withdrawals (“efficiency”), with northern states consistently improving the efficiency, while the southern states’ efficiency declined. Our analyses of spatial patterns of per-capita withdrawals further demonstrate that urban counties exhibit improved efficiency over rural counties. Improved efficiency is also demonstrated over high-income and well-educated counties. Given the potential implications of the findings in developing long-term water conservation measures (i.e., increasing block rates), we argue the need for frequent updates, perhaps monthly to annual, of water use data for identifying effective strategies that control the water-use efficiency in various geographic settings under a changing climate.