Quantifying influences of administrative division adjustment on PM2.5 pollution in China's mega-urban agglomerations.

China's mega-urban agglomerations have experienced severe particulate matter pollution that is accompanied by rapid economic growth and extensive administrative division adjustment (ADA). However, the precise roles of ADA on the environmental quality are unknown. Using the geographical detector and evolution tree model, this study quantifies the effects and mechanisms of ADA on the changes in PM2.5 concentration in three mega-urban agglomerations: Beijing-Tianjin-Hebei (BTH), Yangtze River Delta (YRD), and Pearl River Delta (PRD) during 2000-2017. Our results showed that: (1) ADA had strong positive effects on PM2.5 concentrations in the 0-6 years lag and negative effects in the 7-10 years lag; (2) During 2000-2009, ADA elevated PM2.5 concentration by 5.93% via stimulating the development and transfer of heavy industry and urban sprawl in the BTH; (3) YRD and PRD respectively reduced the ADA's exacerbating effect to 5.26% and 4.98% via reasonable industrial structures and comprehensive cooperation mechanisms; (4) During 2009-2017, BTH and YRD integrated industrial transformation and environmental protection services through ADA, which alleviated 9.51% and 8.49% of PM2.5 pollution. PRD, meanwhile, accomplished orderly population dispersal and urban expansion by combining ADA with urban planning, thus reducing the PM2.5 concentration by 8.01%. We located three agglomerations in the evolution tree, which provide a basis for formulating relevant policies and region-oriented air pollution joint prevention control strategies.

Gut Homeostasis, Microbial Dysbiosis, and Opioids.

Gut homeostasis plays an important role in maintaining animal and human health. The disruption of gut homeostasis has been shown to be associated with multiple diseases. The mutually beneficial relationship between the gut microbiota and the host has been demonstrated to maintain homeostasis of the mucosal immunity and preserve the integrity of the gut epithelial barrier. Currently, rapid progress in the understanding of the host-microbial interaction has redefined toxicological pathology of opioids and their pharmacokinetics. However, it is unclear how opioids modulate the gut microbiome and metabolome. Our study, showing opioid modulation of gut homeostasis in mice, suggests that medical interventions to ameliorate the consequences of drug use/abuse will provide potential therapeutic and diagnostic strategies for opioid-modulated intestinal infections. The study of morphine's modulation of the gut microbiome and metabolome will shed light on the toxicological pathology of opioids and its role in the susceptibility to infectious diseases.

Association of Smoking with Metabolic Volatile Organic Compounds in Exhaled Breath.

Lung cancer (LC) screening will be more efficient if it is applied to a well-defined high-risk population. Characteristics including metabolic byproducts may be taken into account to access LC risk more precisely. Breath examination provides a non-invasive method to monitor metabolic byproducts. However, the association between volatile organic compounds (VOCs) in exhaled breath and LC risk or LC risk factors is not studied. Exhaled breath samples from 122 healthy persons, who were given routine annual exam from December 2015 to December 2016, were analyzed using thermal desorption coupled with gas chromatography mass spectrometry (TD-GC-MS). Smoking characteristics, air quality, and other risk factors for lung cancer were collected. Univariate and multivariate analyses were used to evaluate the relationship between VOCs and LC risk factors. 7, 7, 11, and 27 VOCs were correlated with smoking status, smoking intensity, years of smoking, and depth of inhalation, respectively. Exhaled VOCs are related to smoking and might have a potential to evaluate LC risk more precisely. Both an assessment of temporal stability and testing in a prospective study are needed to establish the performance of VOCs such as 2,5-dimethylfuranm and 4-methyloctane as lung cancer risk biomarkers.

Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection.

We investigated mechanisms by which TLR9 signaling promoted the development of the protective response to Cryptococcus neoformans in mice with cryptococcal pneumonia. The afferent (week 1) and efferent (week 3) phase immune parameters were analyzed in the infected wild-type (TLR9(+/+)) and TLR-deficient (TLR9(-/-)) mice. TLR9 deletion diminished 1) accumulation and activation of CD11b(+) dendritic cells (DCs), 2) the induction of IFN-γ and CCR2 chemokines CCL7, CCL12, but not CCL2, at week 1, and 3) pulmonary accumulation and activation of the major effector cells CD4(+) and CD8(+) T cells, CD11b(+) lung DCs, and exudate macrophages at week 3. The significance of CCL7 induction downstream of TLR9 signaling was investigated by determining whether CCL7 reconstitution would improve immunological parameters in C. neoformans-infected TLR9(-/-) mice. Early reconstitution with CCL7 1) improved accumulation and activation of CD11b(+) DCs at week 1, 2) restored early IFN-γ production in the lungs, and 3) restored the accumulation of major effector cell subsets. CCL7 administration abolished the difference in lung fungal burdens between TLR9(+/+) and TLR9(-/-) mice at week 3; however, significant reduction of fungal burdens between PBS- and CCL7-treated mice has not been observed, suggesting that additional mechanism(s) apart from early CCL7 induction contribute to optimal fungal clearance in TLR9(+/+) mice. Collectively, we show that TLR9 signaling during the afferent phase contributes to the development of protective immunity by promoting the early induction of CCL7 and IFN-γ and the subsequent early recruitment and activation of DCs and additional effector cells in mice with cryptococcal pneumonia.

HMGB1-mediated transcriptional activation of circadian gene TIMELESS contributes to endometrial cancer progression through Wnt-ß-catenin pathway.

TIMELESS (TIM) is a circadian gene which is implicated in the regulation of daily rhythm, DNA replication and repair, and cancer initiation and progression. Nevertheless, the role of TIM in endometrial cancer (EC) development is largely unknown. Bioinformatics analysis showed that TIM was aberrantly up-regulated in EC tissues and positively correlated with clinical or histological grade of EC. Functional studies showed that TIM knockdown reduced EC cell viability and restrained EC cell migration in vitro, as well as blocked xenograft tumor growth in vivo. Mechanistically, HMGB1 transcriptionally up-regulated TIM expression in EC cells. In addition, TIM could activate the transcription of the canonical Wnt ligand WNT8B, and TIM depletion could reduce the malignant potential of EC cells largely by targeting and down-regulating WNT8B. As a conclusion, HMGB1/TIM/WNT8B signal cascade was identified in this study for the first time. HMGB1 exerted its oncogenic role by activating the transcription of TIM, leading to the activation of Wnt signaling and EC progression.

Environmental health, economy, and amenities interactively drive migration patterns among China's older people.

The increasing number of older adult migrants is rapidly changing regional demographic and social structures in China. There is an urgent need to understand the spatial patterns and factors that influence older adults to migrate, especially the role of environmental health. However, this issue has been under-studied. This study focused on intra-provincial and inter-provincial older adult migrants as research subjects, estimated their spatial concentration index based on the iterative proportional fitting approach, and explored the factors influencing their migration using the GeoDetector Model. The results showed the following: (1) In 2015, more than 76% of inter-provincial older adult migrants were distributed in Eastern China, and most intra-provincial older adult migrants were scattered in sub-provincial cities. (2) Compared to factors relating to economy and amenities, environmental health by itself played a relatively weak role in the migration of older adults, but the interaction among environmental health, economy, and amenities was a key driving force of older adult migration. (3) There were significant differences in the dominant environmental health factors between inter-provincial migration and intra-provincial migration, which were temperature and altitude, respectively. Our findings can help policymakers focus on the composition of older adult migrants based on urban environmental health characteristics and rationally optimize older adult care facilities to promote supply-demand matching.

Virulence factors identified by Cryptococcus neoformans mutant screen differentially modulate lung immune responses and brain dissemination.

Deletions of cryptococcal PIK1, RUB1, and ENA1 genes independently rendered defects in yeast survival in human CSF and within macrophages. We evaluated virulence potential of these genes by comparing wild-type Cryptococcus neoformans strain H99 with deletant and complement strains in a BALB/c mouse model of pulmonary infection. Survival of infected mice; pulmonary cryptococcal growth and pathology; immunological parameters; dissemination kinetics; and CNS pathology were examined. Deletion of each PIK1, RUB1, and ENA1 differentially reduced pulmonary growth and dissemination rates of C. neoformans and extended mice survival. Furthermore, pik1Δ induced similar pathologies to H99, however, with significantly delayed onset; rub1Δ was more efficiently contained within pulmonary macrophages and was further delayed in causing CNS dissemination/pathology; whereas ena1Δ was progressively eliminated from the lungs and did not induce pathological lesions or disseminate into the CNS. The diminished virulence of mutant strains was associated with differential modulation of pulmonary immune responses, including changes in leukocyte subsets, cytokine responses, and macrophage activation status. Compared to H99 infection, mutants induced more hallmarks of a protective Th1 immune response, rather than Th2, and more classical, rather than alternative, macrophage activation. The magnitude of immunological effects precisely corresponded to the level of virulence displayed by each strain. Thus, cryptococcal PIK1, RUB1, and ENA1 differentially contribute to cryptococcal virulence, in correlation with their differential capacity to modulate immune responses.

A functional role for Nlrp6 in intestinal inflammation and tumorigenesis.

The nucleotide-binding oligomerization domain-like receptor (NLR) family member, Nlrp6, has been implicated in inflammasome signaling to activate caspase-1, which is essential for the production of mature IL-1ß and IL-18. However, a function for Nlrp6 in vivo has never been demonstrated. Due to the relative high expression of Nlrp6 in intestinal tissue, we hypothesized that Nlrp6 has a role in intestinal homeostasis. Indeed, Nlrp6-deficient mice are more susceptible to chemically induced colitis as well as colitis-induced tumorigenesis than wild-type (WT) mice. Nlrp6-deficient mice exhibited significantly more inflammation within the colon than WT mice after dextran sulfate sodium treatment. Their inability to resolve inflammation and repair damaged epithelium as efficiently as WT mice resulted in prolonged increases in epithelial proliferative activity that likely underlie the increased propensity for tumors in these mice during chronic inflammation. We further show that the activity of Nlrp6 in hematopoietic cells is critical for protection against inflammation-related colon tumorigenesis. This study highlights the importance of NLR function in maintaining intestinal homeostasis to prevent the development of aberrant inflammation and tumor development within the colon.

Can red tourism lead to spiritual transformation? Evidence from tourists visiting the Red Army Long March Xiangjiang Battle Memorial Park.

The mechanism of spiritual transformation in red tourism plays a key role in facilitating the inheritance of red culture. A survey of 385 tourists of Chinese nationality was conducted to explore the path of red tourism's influence on tourists' spiritual transformation. Based on the stimulus-organism-response theory, this paper explores tourists' environmental perceptions of red tourism activities as special external stimuli, introduces a positive emotion factor, and constructs a path model of red tourism for tourists' positive emotions based on educational function and cultural identity, which ultimately leads to their spiritual transformation. The results of the empirical tests using structural equation modelling indicated that environmental perceptions had a significantly positive effect on the stimulation of positive emotions, while positive emotions had an indirect effect on spiritual transformation. The research results enhance people's understanding of the spiritual transformation brought by red tourism and provide management significance for red tourism planning.

Arterial line waveform dampening, during weaning from cardiopulmonary bypass.

Arterial line waveform; Blood pressure; Focal arterial dissection; Aortic dissection; Cardiothoracic surgery.

A new marker of short-term mortality and poor outcome in patients with acute ischemic stroke: Mean platelet volume-to-lymphocyte ratio.

BACKGROUND: The mean platelet volume-to-lymphocyte ratio (MPVLR), as a novel marker of thrombosis and inflammation, has been demonstrated to be closely linked to poor cardiovascular disease prognosis. However, the correlation between MPVLR and acute ischemic stroke (AIS) remains unclear. This study, therefore, aimed to clarify the relationship between MPVLR and the short-term prognosis of AIS. METHODS: A total of 315 patients with first-time AIS diagnoses were recruited and divided into 3 groups based on the tri-sectional quantiles for MPVLR on admission: group 1 (N = 105) with a MPVLR ≤ 4.93, group 2 (N = 105) with a MPVLR of 4.94 to 7.21, and group 3 (N = 105) with a MPVLR ≥ 7.22. All patients were followed-up for 3 months, and death within 3 months was defined as the endpoint. Baseline characteristics, stroke severity, and functional outcomes were evaluated. RESULTS: The Spearman's correlation coefficient test showed that MPVLR was significantly positively correlated with the National Institutes of Health Stroke Scale score (R = 0.517, P < .001). Multivariate analysis revealed that MPVLR was an independent predictor of both short-term mortality (adjusted odds ratio [OR] 1.435, P < .001) and poor outcome (adjusted OR 1.589, P < .001). The receiver operating characteristic (ROC) curve analysis showed that the best cutoff value of MPVLR for short-term mortality and poor outcome were 6.69 (sensitivity: 86.4%, specificity: 68.6%) and 6.38 (sensitivity: 78.8%, specificity: 72.3%), respectively. CONCLUSIONS: MPVLR on admission was positively associated with stroke severity. An elevated MPVLR is an independent predictor of short-term mortality and poor outcome after AIS.

Period circadian regulator 2 suppresses drug resistance to cisplatin by PI3K/AKT pathway and improves chronochemotherapeutic efficacy in cervical cancer.

OBJECTIVE: Chronotherapy, a promising therapy, may build up the chemotherapy efficacy through thinking about timing of therapy. Here, we observed the roles of period circadian regulator 2 (PER2) on cervical cancer progression and the therapeutic efficacy of cisplatin (DDP) based on the circadian rhythm of PER2. METHODS: When Hela/DDP and SiHa/DDP transfected with pcDNA3.1-PER2 and/or treated with human epidermal growth factor (hEGF), viability, apoptosis, migration, and nuclear translocation of NF-κB p65 were detected by CCK-8, flow cytometry, transwell, immunofluorescence and western blot. Furthermore, the expression of circadian rhythm regulators, multidrug resistance, and epithelial-mesenchymal transition (EMT) proteins was detected by western blot. Hela/DDP cells-induced tumor formation in nude mice was constructed. The expression of PER2 was measured at different time point by RT-qPCR. Cisplatin was separately injected into mice with cervical cancer at the highest and lowest expression of PER2. After 5 weeks, tumor volume was measured and tumor proliferation was assessed by immunohistochemistry. RESULTS: Overexpression of PER2 significantly reduced proliferative and migrated capacities and nuclear translocation of NF-κB p65 as well as enhanced apoptosis in Hela/DDP and SiHa/DDP cells. Meanwhile, its overexpression elevated the expression of circadian rhythm regulators as well as lowered the expression of multidrug resistance proteins and EMT pathway activation by suppressing PI3K/AKT pathway. PER2 was rhythmically expressed in cervical cancer tissues. Compared to cisplatin treatment at the lowest expression of PER2, tumor growth and proliferation of tumor cells were distinctly suppressed in mice treated with cisplatin at the highest expression of PER2. CONCLUSION: Our findings confirmed the circadian rhythm of PER2 in cervical cancer and its overexpression restrained the resistance to cisplatin in cervical cancer by PI3K/AKT pathway. It may improve cisplatin efficacy through considering the circadian rhythm of PER2.

Spatiotemporal effects of urban ecological land transitions to thermal environment change in mega-urban agglomeration.

Urban ecological land transitions (UELTs) have far-reaching effects on the thermal environment, but their dynamic effects in urban agglomerations remain poorly understood. This study defines the UELTs concept and quantifies its spatiotemporal effects and driving mechanisms on land surface temperature interdecadal variations (LSTIVs) in the Guangdong-Hong Kong-Macao Greater Bay Area using remote sensing, fuzzy overlay, shape-weighted landscape evolution index, and Geodetector methods. The results showed that UELTs shifted from degradation, increasing pressure, and decreasing vegetation proportion in the central city to scattered restoration, pressure relief, and increasing vegetation proportion in 2010-2020. LSTIVs simultaneously transitioned from rapid growth and contiguous expansion to reduction and dispersion. Moreover, the contribution of UELTs to LSTIVs increased by 19.49% from 2000 to 2020, and gradually shifted from being driven by dominant transition (isolating and adjacent degradation) (mean q = 0.58) to recessive transition (increased population and construction land pressure) (mean q = 0.62), where q is the determinant power. Interactions between edge-expansion and infilling restoration with the blue-green ratio (BGR; i.e., ratio of waterbodies to vegetation), habitat quality, and population layout had significant effects on LSTIVs. In addition, the relative magnitude of the effect of UEL restoration-degradation and BGR on LSTIVs was not fixed, but rather related to their interaction effect and the urban agglomeration development stage. Therefore, in addition to promoting an increase in UEL, optimizing the landscape structure of UEL (e.g., increasing aggregation and connectivity, adjusting BGR) and UEL distribution with other human factors are also crucial to reduce the urban thermal environment.

TLR9 signaling is required for generation of the adaptive immune protection in Cryptococcus neoformans-infected lungs.

To determine whether TLR9 signaling contributes to the development of the adaptive immune response to cryptococcal infection, wild-type (TLR9+/+) and TLR9 knockout (TLR9-/-) BALB/c mice were infected intratracheally with 10(4) C. neoformans 52D. We evaluated 1) organ microbial burdens, 2) pulmonary leukocyte recruitment, 3) pulmonary and systemic cytokine induction, and 4) macrophage activation profiles. TLR9 deletion did not affect pulmonary growth during the innate phase, but profoundly impaired pulmonary clearance during the adaptive phase of the immune response (a 1000-fold difference at week 6). The impaired clearance in TLR9-/- mice was associated with: 1) significantly reduced CD4(+), CD8+ T cell, and CD19+ B cell recruitment into the lungs; 2) defects in Th polarization indicated by altered cytokine responses in the lungs, lymphonodes, and spleen; and 3) diminished macrophage accumulation and altered activation profile, including robust up-regulation of Arg1 and FIZZ1 (indicators of alternative activation) and diminished induction of inducible nitric oxide synthase (an indicator of classical activation). Histological analysis revealed defects in granuloma formation and increased numbers of intracellular yeast residing within macrophages in the lungs of TLR9-/- mice. We conclude that TLR9 signaling plays an important role in the development of robust protective immunity, proper recruitment and function of effector cells (lymphocytes and macrophages), and, ultimately, effective cryptococcal clearance from the infected lungs.

Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation.

BACKGROUND: Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. METHODS: Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1) sham (Group S), which underwent removal of the L6 transverse process; (2) ligated (Group L), which underwent left L5 spinal nerve ligation (SNL); and (3) pretreated (Group P), which underwent L5 SNL and was pretreated with intrathecal 2% lidocaine (50 µl). Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav1.3 and Nav1.8) in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3) and 7 (POD7). RESULTS: Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up-regulation of Nav1.3 and down-regulation of Nav1.8, and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P), as measured on POD3, palliated both mechanical allodynia (p < 0.01) and thermal hyperalgesia (p < 0.001), attenuated Nav1.3 up-regulation (p = 0.003), and mitigated spinal microglial activation (p = 0.026) by inhibiting phosphorylation (activation) of p38 MAP kinase (p = 0.034). p38 activation was also suppressed on POD7 (p = 0.002). CONCLUSIONS: Intrathecal lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav1.3 up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain.

[Homer protein expression after focal brain contusion in rats].

OBJECTIVE: To investigate Homer protein expression after focal brain contusion and explore the relationship between expression and injury time. METHODS: Focal brain contusion in rats was established and Homer protein expression in brain at different injury intervals after contusion was detected by immunohistochemistry and Western blotting. RESULTS: A small amount of Homer positive expression cells were detected in control group, sham operated group and experimental group (0.5 h after contusion). The amount of Homer positive expression cells increased after 3 h and reached peak 12 h after contusion. The amount of positive cells continued to decrease 1 d after contusion and to the base level 7 d after contusion. Homer protein expression based on immunohistochemistry and Western blotting had statistical difference among adjacent groups. CONCLUSION: Expression of Homer protein near the focal contusion area shows time dependence after brain contusion in rats.

Spatial Coupling and Causal Effects between the Recreational Use of Ecological Land and Restoration: A Case Study of the Pearl River Delta Urban Agglomeration.

As the urbanization and industrialization of China's urban agglomerations reach increasingly high levels, residents are voicing a growing demand for improved green public sport and recreational space. The coordination of ecological land restoration (ELR) and recreational use at the regional level is therefore urgent. This study demonstrates the spatiotemporal evolution of coupled ELR and the recreational use of ecological land (RUoEL) in the Pearl River Delta urban agglomeration based on spatial interpretation, remote sensing mapping, and spatial statistical analysis. A geographical and temporally weighted regression is used to test the spatial effects of the RUoEL on the evolution of the ELR patterns. The results show that the RUoEL (mainly greenways and ecological recreational spaces) and ELR exert a certain degree of coupled spatial characteristics, and that the former significantly impacts the latter. These spatial differences are more notable in areas with high-level ecological recreational spaces, or which are located near densely populated built-up areas. Recreation-oriented ELR is therefore relatively easy to develop in these areas. The results provide important guidelines for the development of ecosystem service patterns in urban agglomerations that include the coexistence of ELR and recreational use, which will strengthen the academic support for regional ELR planning and improve public health.

Spatial-temporal patterns and influencing factors of ecological land degradation-restoration in Guangdong-Hong Kong-Macao Greater Bay Area.

Despite the fact that urban agglomerations have undergone extensive ecological land coverage modifications, exploration of the patterns and driving mechanisms associated with ecological land degradation (ELD) and ecological land restoration (ELR) in urban agglomerations is still limited. This study combined remote sensing technology, as well as landscape index and geographical detector to characterize the spatiotemporal patterns of ELD (isolating, adjacent, and enclosing degradation) and ELR (outlying, edge-expansion, and infilling restoration) in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) from 1990 to 2019. Subsequently, the contributions, interactions, and driver changes were quantified. The results showed an ecological land shift from over-exploitation to balanced co-existence, which was facilitated by a spatiotemporal pattern transition from adjacent degradation-led (1990-2010) to edge-expansion restoration-led (2010-2019). Land urbanization rate and population density showed a stronger promoting effect on ELD than natural factors, while tertiary industry, topography, and soil conditions were more significant in ELR. The factors' nonlinear interaction enhanced the degradation-restoration pattern evolution and continued to increase over time-particularly the interaction between construction land expansion and other drivers. Additionally, from 2010 to 2019, 80% of the ELR socio-economic factors turned from negative to positive and gradually became to play a significant role. This study is expected to help ecological protection and restoration planners/managers recognize the factors' interactions and variations, and ultimately improve the ecological network structure that is designed to integrate the city with the ecosystem.

Urban ecological land and natural-anthropogenic environment interactively drive surface urban heat island: An urban agglomeration-level study in China.

The surface urban heat island effect (SUHI) that occurs during rapid urbanization increases the health risks associated with high temperatures. Urban ecological land (UEL) has been shown to play an important role in improving urban heat stress, however, the impact of UEL interactions with the natural-anthropogenic environment on SUHI at the urban agglomeration-scale is less explored. In this study, the Google Earth Engine and GeoDetector were applied to characterize the spatiotemporal patterns of UEL and SUHI in the Guangdong-Hong Kong-Macao Greater Bay Area from 2000 to 2020 by extracting major built-up urban areas and quantifying the impacts of UEL and its interactions with the natural-anthropogenic factors on SUHI. The results show that the evolution of the UEL landscape structure exhibits clear spatiotemporal coupling with SUHI. Specifically, the UEL underwent a dispersion and degradation process in 2000-2015 and a convergence and restoration process in 2015-2020, the SUHI correspondingly transitioned from intensification and continuity to mitigation and contraction. The UEL landscape structure showed a notable impact on the SUHI reduction, and the dominance and richness of the patches explained an average of 19.95% and 16.03% of the SUHI, respectively. Moreover, the interaction between UEL and land urbanization rate and anthropogenic heat release had a dominant effect on SUHI, but this effect significantly declined from 2015 to 2020. With the implementation of ecological restoration projects, the interaction of UEL with topography rapidly increased and the SUHI gradually dominated by the joint interaction of UEL and natural-anthropogenic factors. A synthesis of the varying effects of several factors showed that the dynamic relationship between the development stages of the urban agglomeration's regional system and SUHI may conform to the Environmental Kuznets Curve. SUHI reduction strategies should therefore comprehensively optimize the rational allocation of UEL landscape structures and natural-human elements to promote the well-being of residents.

Impact of injection sites on clinical pharmacokinetics of subcutaneously administered peptides and proteins.

For most approved subcutaneously (SC) administered drug products in the US, the recommended injection sites (i.e., abdomen, thigh, and upper arm) are usually based on experience from phase 3 trials. Relative bioavailability data directly comparing the pharmacokinetics (PK) of different SC injection sites are often not available and the underlying mechanisms that may affect SC absorption have not been systematically investigated. In this study, we surveyed clinical PK data (AUC, Cmax, and Tmax) for SC administered drug products including therapeutic proteins and peptides based on literature and FDA database. The PK data after abdominal injection was used as a reference to determine the relative bioavailability of SC injections to the arm and thigh. The survey retrieved 19 immunoglobulin G (IgGs), 18 peptides/small proteins (molecular weight < 16 kDa), and 8 non-IgG proteins that had available clinical PK data from multiple SC injection sites. Among these, 5 (26%) IgGs, 9 (50%) peptides/small proteins, and 3 (38%) non-IgG proteins, exhibited injection site-dependent PK (i.e. PK differed by injection sites). Correlation analyses revealed that the PK of peptides/small proteins undergoing rapid SC absorption (Tmax ≤ 2 h), elimination (CL/F ≥ 39 L/h) or low plasma protein binding were more sensitive to injection sites. Similarly, non-IgG proteins (molecular weight ≥ 16 kDa) with high CL/F and low Tmax are associated with high risk of injection site-dependent SC absorption. IgGs with T1/2 < 15 days or Tmax < 5 days are more likely to show injection site-dependent SC absorption. Positive charge of the drug molecule (isoelectric point ≥8) may reduce SC absorption from all three injection sites but is not associated with high risk of injection site-dependent SC absorption. In summary, the results suggested that regional differences in pre-systemic catabolism and local SC blood flow potentially contribute injection site-dependent SC absorption of peptides/small proteins while local lymphatic flow and FcRn binding likely contribute to site-dependent SC absorption of IgGs.