A framework to quantitatively assess the influence of land use and land cover on coastal wetland hydrological connectivity from a landscape resistance perspective.

Land use and land cover (LULC) change is one of the dominant factors contributing to coastal wetland degradation and loss. Most studies focused on LULC changes or whether they influenced on ecosystems. However, few studies quantitatively assessed the impact of different LULCs on hydrological connectivity. This study aimed to understand how LULC affected hydrological connectivity in the coastal wetlands in the Yellow River Delta (YRD), China, from 1985 to 2020. A framework from a landscape resistance perspective was used to evaluate the LULC's influence. LULCs were converted into a series of resistance surfaces whose values represent the degree to which LULC facilitated or restricted hydrological connectivity. The LULC's influence was evaluated by parameterizing the resistance surfaces using observed hydrological connectivity. The results showed that human-related LULC had more influence on hydrological connectivity. The critical time of LULC's influence on hydrological connectivity was 1985-1990 and 2010-2015. The critical areas were Zone II, Zone I, and Zone VI. The LULCs of agriculture, industry, town/city, and river had the most significant impact on the hydrological connectivity of the YRD coastal wetland. The result could direct LULC planning to mitigate the negative effect on coastal wetlands and provide support for the environmental impact assessment of coastal development practices. This paper advances the study by assessing LULCs' impact on hydrological connectivity and providing a quantitative method. The framework of this study enriches the coastal wetland conservation theory and policy-making of coastal management.

How to balance land demand conflicts to guarantee sustainable land development.

Severe arable land loss and ecological problems raise attention to protect/develop land for food and ecology demand. Spatial conflict appears in front of multidemand for urbanization, food, and ecology. Our study took China as an example and explicitly outlined spatial preference of urbanization, food, and ecology. From the aspect of land amount, there are enough lands to support multidemand with a surplus of agriculture land of 45.5 × 106 ha. However, spatial conflict widely appears among the multidemands. We tested the impacts of different priorities on urban pattern, crop yield, and ecology and found the priority of food > ecology > urbanization gave the best outcome. Our results verified the importance of including priority of land multidemand to avoid confusion and increase efficiency in the implementation of land policies.

Deriving a high-quality daily dataset of large-pan evaporation over China using a hybrid model.

Global warming is expected to increase the atmospheric evaporative demand and make more surface water for evapotranspiration, aggerating water sources' social and ecological shortage. Pan evaporation, as a routine observation worldwide, is an excellent metric to indicate the response of terrestrial evaporation to global warming. However, several non-climatic effects, such as instrument upgrades, have destroyed the homogenization of pan evaporation and limited its applications. In China, 2400s meteorological stations have observed daily pan evaporation since 1951. The observed records became discontinuous and inconsistent due to the instrument upgrade from micro-pan D20 to large-pan E601. Here, combining the Penpan model (PM) and random forest model (RFM), we developed a hybrid model to assimilate different types of pan evaporation into a consistent dataset. Based on the cross-validation test, on a daily scale, the hybrid model has a lower bias (RMSE=0.41 mm day-1) and better stability (NSE=0.94) than the two sub-models and the conversion coefficient method. Finally, we produced a homogenized daily dataset of E601 across China from 1961 to 2018. Based on this dataset, we analyzed the long-term trend of pan evaporation. Pan evaporation showed a -1.23±0.57 mm a-2 downward trend from 1961-1993, primarily caused by decreased pan evaporation in warm seasons over North China. After 1993, the pan evaporation in South China increased significantly, resulting in a 1.83±0.87 mm a-2 upward trend across China. With better homogeneity and higher temporal resolution, the new dataset is expected to promote drought monitoring, hydrological modeling, and water resources management. Free access to the dataset can be found at https://figshare.com/s/0cdbd6b1dbf1e22d757e.

IGFBP2 Plays an Essential Role in Cognitive Development during Early Life.

Identifying the mechanisms underlying cognitive development in early life is a critical objective. The expression of insulin-like growth factor binding protein 2 (IGFBP2) in the hippocampus increases during neonatal development and is associated with learning and memory, but a causal connection has not been established. Here, it is reported that neurons and astrocytes expressing IGFBP2 are distributed throughout the hippocampus. IGFBP2 enhances excitatory inputs onto CA1 pyramidal neurons, facilitating intrinsic excitability and spike transmission, and regulates plasticity at excitatory synapses in a cell-type specific manner. It facilitates long-term potentiation (LTP) by enhancing N-methyl-d-aspartate (NMDA) receptor-dependent excitatory postsynaptic current (EPSC), and enhances neurite proliferation and elongation. Knockout of igfbp2 reduces the numbers of pyramidal cells and interneurons, impairs LTP and cognitive performance, and reduces tonic excitation of pyramidal neurons that are all rescued by IGFBP2. The results provide insight into the requirement for IGFBP2 in cognition in early life.

Functional Diversity of p53 in Human and Wild Animals.

The common understanding of p53 function is a genome guardian, which is activated by diverse stresses stimuli and mediates DNA repair, apoptosis, and cell cycle arrest. Increasing evidence has demonstrated p53 new cellular functions involved in abundant endocrine and metabolic response for maintaining homeostasis. However, TP53 is frequently mutant in human cancers, and the mutant p53 (Mut-p53) turns to an "evil" cancer-assistant. Mut-p53-induced epithelial-mesenchymal transition (EMT) plays a crucial role in the invasion and metastasis of endocrine carcinomas, and Mut-p53 is involved in cancer immune evasion by upregulating PD-L1 expression. Therefore, Mut-p53 is a valuable treatment target for malignant tumors. Targeting Mut-p53 in correcting sequence and conformation are increasingly concerned. Interestingly, in wild animals, p53 variations contribute to cancer resistant and high longevity. This review has discussed the multiple functions of p53 in health, diseases, and nature evolution, summarized the frequently mutant sites of p53, and the mechanisms of Mut-p53-mediated metastasis and immune evasion in endocrine cancers. We have provided a new insight for multiple roles of p53 in human and wild animals.

Involvement of Corticotropin-Releasing Factor and Receptors in Immune Cells in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder defined by ROME IV criteria as pain in the lower abdominal region, which is associated with altered bowel habit or defecation. The underlying mechanism of IBS is not completely understood. IBS seems to be a product of interactions between various factors with genetics, dietary/intestinal microbiota, low-grade inflammation, and stress playing a key role in the pathogenesis of this disease. The crosstalk between the immune system and stress in IBS mechanism is increasingly recognized. Corticotropin-releasing factor (CRF), a major mediator in the stress response, is involved in altered function in GI, including inflammatory processes, colonic transit time, contractile activity, defecation pattern, pain threshold, mucosal secretory function, and barrier functions. This mini review focuses on the recently establish local GI-CRF system, its involvement in modulating the immune response in IBS, and summarizes current IBS animal models and mapping of CRF, CRFR1, and CRFR2 expression in colon tissues. CRF and receptors might be a key molecule involving the immune and movement function via brain-gut axis in IBS.

Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia.

BACKGROUND: High-altitude cerebral edema (HACE) is the severe type of acute mountain sickness (AMS) and life threatening. A subclinical inflammation has been speculated, but the exact mechanisms underlying the HACE are not fully understood. METHODS: Human volunteers ascended to high altitude (3860 m, 2 days), and rats were exposed to hypoxia in a hypobaric chamber (5000 m, 2 days). Human acute mountain sickness was evaluated by the Lake Louise Score (LLS), and plasma corticotrophin-releasing hormone (CRH) and cytokines TNF-α, IL-1ß, and IL-6 were measured in rats and humans. Subsequently, rats were pre-treated with lipopolysaccharide (LPS, intraperitoneal (ip) 4 mg/kg, 11 h) to induce inflammation prior to 1 h hypoxia (7000 m elevation). TNF-α, IL-1ß, IL-6, nitric oxide (NO), CRH, and aquaporin-4 (AQP4) and their gene expression, Evans blue, Na(+)-K(+)-ATPase activity, p65 translocation, and cell swelling were measured in brain by ELISA, Western blotting, Q-PCR, RT-PCR, immunohistochemistry, and transmission electron micrography. MAPKs, NF-κB pathway, and water permeability of primary astrocytes were demonstrated. All measurements were performed with or without LPS challenge. The release of NO, TNF-α, and IL-6 in cultured primary microglia by CRH stimulation with or without PDTC (NF-κB inhibitor) or CP154,526 (CRHR1 antagonist) were measured. RESULTS: Hypobaric hypoxia enhanced plasma TNF-α, IL-1ß, and IL-6 and CRH levels in human and rats, which positively correlated with AMS. A single LPS injection (ip, 4 mg/kg, 12 h) into rats increased TNF-α and IL-1ß levels in the serum and cortex, and AQP4 and AQP4 mRNA expression in cortex and astrocytes, and astrocyte water permeability but did not cause brain edema. However, LPS treatment 11 h prior to 1 h hypoxia (elevation, 7000 m) challenge caused cerebral edema, which was associated with activation of NF-κB and MAPKs, hypoxia-reduced Na(+)-K(+)-ATPase activity and blood-brain barrier (BBB) disruption. Both LPS and CRH stimulated TNF-α, IL-6, and NO release in cultured rat microglia via NF-κB and cAMP/PKA. CONCLUSIONS: Preexisting systemic inflammation plus a short severe hypoxia elicits cerebral edema through upregulated AQP4 and water permeability by TLR4 and CRH/CRHR1 signaling. This study revealed that both infection and hypoxia can cause inflammatory response in the brain. Systemic inflammation can facilitate onset of hypoxic cerebral edema through interaction of astrocyte and microglia by activation of TLR4 and CRH/CRHR1 signaling. Anti-inflammatory agents and CRHR1 antagonist may be useful for prevention and treatment of AMS and HACE.

Adaptive methylation regulation of p53 pathway in sympatric speciation of blind mole rats, Spalax.

Epigenetic modifications play significant roles in adaptive evolution. The tumor suppressor p53, well known for controlling cell fate and maintaining genomic stability, is much less known as a master gene in environmental adaptation involving methylation modifications. The blind subterranean mole rat Spalax eherenbergi superspecies in Israel consists of four species that speciated peripatrically. Remarkably, the northern Galilee species Spalax galili (2n = 52) underwent adaptive ecological sympatric speciation, caused by the sharply divergent chalk and basalt ecologies. This was demonstrated by mitochondrial and nuclear genomic evidence. Here we show that the expression patterns of the p53 regulatory pathway diversified between the abutting sympatric populations of S. galili in sharply divergent chalk-basalt ecologies. We identified higher methylation on several sites of the p53 promoter in the population living in chalk soil (chalk population). Site mutagenesis showed that methylation on these sites linked to the transcriptional repression of p53 involving Cut-Like Homeobox 1 (Cux1), paired box 4 (Pax 4), Pax 6, and activator protein 1 (AP-1). Diverse expression levels of p53 between the incipiently sympatrically speciating chalk-basalt abutting populations of S. galili selectively affected cell-cycle arrest but not apoptosis. We hypothesize that methylation modification of p53 has adaptively shifted in supervising its target genes during sympatric speciation of S. galili to cope with the contrasting environmental stresses of the abutting divergent chalk-basalt ecologies.

Inactivation of corticotropin-releasing hormone-induced insulinotropic role by high-altitude hypoxia.

We have shown that hypoxia reduces plasma insulin, which correlates with corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) in rats, but the mechanism remains unclear. Here, we report that hypobaric hypoxia at an altitude of 5,000 m for 8 h enhances rat plasma CRH, corticosterone, and glucose levels, whereas the plasma insulin and pancreatic ATP/ADP ratio is reduced. In islets cultured under normoxia, CRH stimulated insulin release in a glucose- and CRH-level-dependent manner by activating CRHR1 and thus the cAMP-dependent protein kinase pathway and calcium influx through L-type channels. In islets cultured under hypoxia, however, the insulinotropic effect of CRH was inactivated due to reduced ATP and cAMP and coincident loss of intracellular calcium oscillations. Serum and glucocorticoid-inducible kinase 1 (SGK1) also played an inhibitory role. In human volunteers rapidly ascended to 3,860 m, plasma CRH and glucose levels increased without a detectable change in plasma insulin. By contrast, volunteers with acute mountain sickness (AMS) exhibited a marked decrease in HOMA insulin sensitivity (HOMA-IS) and enhanced plasma CRH. In conclusion, hypoxia may attenuate the CRH-insulinotropic effect by reducing cellular ATP/ADP ratio, cAMP and calcium influx, and upregulated SGK1. Hypoxia may not affect HOMA-IS in healthy volunteers but reduces it in AMS volunteers.

Prenatal stress, anxiety and depression: a mechanism involving CRH peptide family.

Prenatal stress (PNS) is associated with increased biological risk for mental disorders such as anxiety and depression later in life, and stress appear to be additive to the PNS influences. Among the most widely cited and accepted alternative hypotheses of anxiety and depression is dysfunction of the HPA axis, a system that is central in orchestrating the stress response. Therefore, understanding how PNS exerts profound effects on the HPA axis and stress-sensitive brain functions including anxiety and depression has significant clinical importance. In this mini-review, we will focus on novel and evolving concepts regarding the potential mechanisms underlying the short and long-term effects of PNS involving CRH peptide family. We present evidence demonstrating prenatal hypoxia exposure induced anxiety-like behavior in adult male rat offspring and CRHR1 in PVN of the hypothalamus is involved.

Corticotropin-releasing factor receptor type 1 colocalizes with type 2 in corticotropin-releasing factor-containing cellular profiles in rat brain.

OBJECTIVES: To investigate whether CRHR1 and CRHR2 are colocalized in CRH-specific neurons in rat brain. METHODS: Double/triple immunofluorescence, and combined in situ hybridization were performed in the PVN, amygdala and hippocampus, and triple immunofluorescence was applied to the median eminence (ME), dorsal raphe (DR) and locus coeruleus (LC). RESULTS: Both CRHR1 and CRHR2 immunoreactivity were highly coexpressed in the PVN, central nucleus of the amygdala (CeA) and hippocampus. Triple immunofluorescence under confocal microscopy confirmed that CRHR1 and CRHR2 are coexpressed in CRH-producing neurons in these regions. The results of in situ hybridization combined with double immunofluorescence further strengthened the finding that CRHR1 and CRHR2 were coexpressed in CRH-specific neurons in the PVN, CeA and hippocampus. In addition, CRH immunoreactivity signals were evidently distributed in the ME, DR and LC, and were coexpressed with both receptors. CONCLUSION: CRH receptors colocalize in CRH-containing neurons in the PVN, CeA and hippocampus, and CRH, CRHR1, and CRHR2 coexist in the DR and LC. Our results implicate CRHR1 and CRHR2 in coordinating the regulation of CRH neuronal activity in stress and behavioral responses.

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema.

Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca(2+), and PKCε; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1(+) and AQP4(+), we show that transfected CRFR1(+) contributes to edema via transfected AQP4(+). In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.

The local corticotropin-releasing hormone receptor 2 signalling pathway partly mediates hypoxia-induced increases in lipolysis via the cAMP-protein kinase A signalling pathway in white adipose tissue.

Our objective was to investigate the mechanisms by which the endogenous CRHR2 in white adipose tissue (WAT) regulates metabolic activities associated with lipogenesis and lipolysis under continuous exposure to hypoxia. We found that hypobaric hypoxia at a simulated altitude of 5000 m significantly reduced the body weight, food intake, and WAT mass of rats. Hypoxia also accelerated lipolysis and suppressed lipogenesis in WAT. Pretreatment with astressin 2B, a selective CRHR2 antagonist, partly but significantly attenuated the hypoxia-induced reductions in body weight and WAT mass by blocking the cAMP-protein kinase A (PKA)-hormone-sensitive lipase (HSL)/perilipin signalling pathway. Astressin 2B treatment failed to attenuate hypoxia induced lipogenic inhibition. In conclusion, activation of endogenous WAT Ucn2/3 autocrine/paracrine pathway was involved in hypoxia induced lipolysis via CRHR2 - cAMP-PKA signalling pathway. This study provides the novel understanding of local CRHR2 signaling pathway playing important role in WAT loss and lipid metabolism under hypoxia.

Codon 104 variation of p53 gene provides adaptive apoptotic responses to extreme environments in mammals of the Tibet plateau.

Mutational changes in p53 correlate well with tumorigenesis. Remarkably, however, relatively little is known about the role that p53 variations may play in environmental adaptation. Here we report that codon asparagine-104 (104N) and glutamic acid-104 (104E), respectively, of the p53 gene in the wild zokor (Myospalax baileyi) and root vole (Microtus oeconomus) are adaptively variable, meeting the environmental stresses of the Tibetan plateau. They differ from serine-104 (104S) seen in other rodents, including the lowland subterranean zokor Myospalax cansus, and from serine 106 (106S) in humans. Based on site-directed mutational analysis in human cell lines, the codon 104N variation in M. baileyi is responsible for the adaptive balance of the transactivation of apoptotic genes under hypoxia, cold, and acidic stresses. The 104E p53 variant in Microtus oeconomus suppresses apoptotic gene transactivation and cell apoptosis. Neither 104N nor 104E affects the cell-cycle genes. We propose that these variations in p53 codon 104 are an outcome of environmental adaptation and evolutionary selection that enhance cellular strategies for surviving the environmental stresses of hypoxia and cold (in M. baileyi and M. oeconomus) and hypercapnia (in M. baileyi) in the stressful environments of the Qinghai-Tibet plateau.