Physical environment, man-made pollution, nutrition and their mutual interactions can be major causes of human diseases. These disease determinants have distinct spatial distributions across geographical units, so that their adequate study involves the investigation of the associated geographical strata. We propose four geographical detectors based on spatial variation analysis of the geographical strata to assess the environmental risks of health: the risk detector indicates where the risk areas are; the factor detector identifies factors that are responsible for the risk; the ecological detector discloses relative importance between the factors; and the interaction detector reveals whether the risk factors interact or lead to disease independently. In a real-world study, the primary physical environment (watershed, lithozone and soil) was found to strongly control the neural tube defects (NTD) occurrences in the Heshun region (China). Basic nutrition (food) was found to be more important than man-made pollution (chemical fertilizer) in the control of the spatial NTD pattern. Ancient materials released from geological faults and subsequently spread along slopes dramatically increase the NTD risk. These findings constitute valuable input to disease intervention strategies in the region of interest.

Ubiquitination and deubiquitination of receptor-interacting protein 1 (RIP1) play an important role in the positive and negative regulation of the tumor necrosis factor ␣ (TNF␣)-induced nuclear factor B (NF-B) activation. Using a combination of functional genomic and proteomic approaches, we have identified ubiquitin-specific peptidase 21 (USP21) as a deubiquitinase for RIP1. USP21 is constitutively associated with RIP1 and deubiquitinates RIP1 in vitro and in vivo. Notably, knockdown of USP21 in HeLa cells enhances TNF␣-induced RIP1 ubiquitination, IB kinase ␤ (IKK␤), and NF-B phosphorylation, inhibitor of NF-B ␣ (IB␣) phosphorylation and ubiquitination, as well as NF-B-dependent gene expression. Therefore, our results demonstrate that USP21 plays an important role in the down-regulation of TNF␣-induced NF-B activation through deubiquitinating RIP1. Transcription factor nuclear factor B (NF-B)3 plays an important role in controlling the expression of survival factors, cytokines, and proinflammatory molecules in a broad range of cellular responses (1-3). NF-B is sequestered in the cytoplasm by a family of inhibitory proteins called inhibitor of NF-B (IB) proteins in inactivated cells. Many intercellular stimuli are capable of triggering the activation of a signal transduction pathway that leads to the degradation of IB proteins through the 26 S proteasome (4 -6). Degradation of the IB proteins allows NF-B translocation from cytoplasm to the nucleus and activates the expression of the target genes (7).Upon binding of tumor necrosis factor ␣ (TNF␣), TNF receptor 1 (TNFR1) recruits several adaptor proteins, including receptorinteracting protein 1 (RIP1/RIPK1) and TNF receptor-associated factor 2 (TRAF2), to form a complex (8, 9). This TNFR1-associated complex initiates the activation of IB kinase (IKK), which phosphorylates IB protein and activates NF-B (10 -17).Protein ubiquitination is a crucial regulatory mechanism in various cellular processes, including cell cycle progression, the DNA damage response, and immune responses (18 -20). In the TNF␣-induced NF-B signal transduction pathway, the Lys 63 -linked polyubiquitination of RIP1 protein mediated by TRAF2 E3 ligase is essential for TNF␣-induced IKK/NF-B activation, whereas phosphorylation of the IB proteins by activated IKK leads to their Lys 48 -linked polyubiquitination, which labels it for its degradation by the 26 S proteasome (21).Several deubiquitinating enzymes, including CYLD, A20, Cezanne, ubiquitin-specific peptidase 15 (USP15), and USP31, have been suggested to be involved in the down-regulation of TNF␣-induced NF-B activation (22-26). However, it remains unclear how deubiquitination plays a role in the down-regulation of TNF␣-induced NF-B activation.The USPs belong to a subclass of the protein-deubiquitinating enzyme (DUB) superfamily that are categorized into five subclasses based on their ubiquitin-protease domains in the human genome and have been shown to be involved in a broad range of biological activities (27). Even though the USP subclass o...

BACKGROUND: Shanxi Province has historically reported a high prevalence of NTDs. In order to establish baseline rates for NTDs and discuss the risk factors associated with sociodemographic, maternal characteristics, and geographic factors, we performed the present study using an approach combining population and hospital-based methodologies. METHODS: We used v 2 and Fisher's exact tests to evaluate variation in the prevalence by selected covariates and computed crude ORs and 95% CIs. Adjusted odds ratios (AORs) were performed using logistic regression with all the covariates included in the model. RESULTS: The overall NTD prevalence during the 3 year study period was 199.38 per 10,000 births, with a higher NTD prevalence clustered in 46 villages within this geographic area. However, no statistical significance was found between NTD prevalence and the elevation of the villages or their distance from coal plants. AORs revealed women aged 20 and above had a lower risk of NTDs compared to those younger than 20 (AOR range 0.4-0.5). A higher risk of NTDs was observed among female infants (AOR 1.50; 95% CI: 1.04-2.17), women with four or more previous births (AOR 2.80; 95% CI: 1.20-6.52), and a previous history of birth defects (AOR 3.23; 95% CI: 1.46-7.12).

IκBα serves as a central anchoring molecule in the sequestration of NF-κB transcription factor in the cytoplasm. Ubiquitination-mediated IκBα degradation immediately precedes and is required for NF-κB nuclear translocation and activation. However, the precise mechanism for the deubiquitination of IκBα is still not fully understood. Using a proteomic approach, we have identified Ubiquitin Specific Peptidase 11 (USP11) as an IκBα associated deubiquitinase. Overexpression of USP11 inhibits IκBα ubiquitination. Recombinant USP11 catalyzes deubiquitination of IκBα in vitro. Moreover, knockdown of USP11 expression enhances TNFα-induced IκBα ubiquitination and NF-κB activation. These data demonstrate that USP11 plays an important role in the downregulation of TNFα-mediated NF-κB activation through modulating IκBα stability. In addition, overexpression of a catalytically inactive USP11 mutant partially inhibits TNFα- and IKKβ-induced NF-κB activation, suggesting that USP11 also exerts a non-catalytic function in its negative regulation of TNFα-mediated NF-κB activation. Thus, IκBα ubiquitination and deubiquitination processes function as a Yin-Yang regulatory mechanism on TNFα-induced NF-κB activation.

To quantitatively assess the association between parity and all-cause mortality, we conducted a meta-analysis of cohort studies. Relevant reports were identified from PubMed and Embase databases. Cohort studies with relative risks (RRs) and 95% confidence intervals (CIs) of all-cause mortality in three or more categories of parity were eligible. Eighteen articles with 2,813,418 participants were included. Results showed that participants with no live birth had higher risk of all-cause mortality (RR= 1.19, 95% CI = 1.03–1.38; I2 = 96.7%, P < 0.001) compared with participants with one or more live births. Nonlinear dose-response association was found between parity and all-cause mortality (P for non-linearity < 0.0001). Our findings suggest that moderate-level parity is inversely associated with all-cause mortality.

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Herein, a novel methodology for preparing sequence-controlled polymers is illustrated by using a latent monomer, furan protected maleimide (FMI). At 110 °C, FMI is deprotected by retro Diels-Alder (rDA) reaction, and the released MI is immediately involved in the cross-polymerization with styrene (St) to deliver heterosegments. At 40 °C the rDA reaction does not proceed, therefore homo-poly(styrene) segments are produced. By implementing programmable temperature changes during polymerization of St and FMI, "living" polymers with tailored a sequence are created. A ternary copolymerization produces complex sequences as designed. Alkynyl-functionalized FMI, used as a latent monomer, leads to the desirable placement of functional groups along the polymer chain. This latent-monomer-based strategy opens a new avenue for fabricating sequence-controlled polymers.

Objective: To examine the association between the risk of neural tube defects (NTD) and maternal serum vitamin B 12 , folate and homocysteine in a high-risk area of China. Design: A case-control study was carried out in Luliang mountain area of Shanxi Province. Subjects/setting: A total of eighty-four NTD pregnancies and 110 matched controls were included in the study; their serum vitamin B 12 and folate concentrations were measured by chemiluminescent immunoenzyme assay and total homocysteine concentrations by fluorescent polarisation immunoassay. Results: Serum vitamin B 12 and folate concentrations were lower in NTD-affected pregnant women than in controls (P , 0?01). Serum total homocysteine was higher in the NTD group than in controls at less than 21 weeks of gestation (P , 0?01). Adjusted odds ratios revealed that women with lower vitamin B 12 (adjusted OR54?96; 95 % CI 1?94, 12?67) and folate (adjusted OR53?23; 95 % CI 1?33, 7?85) concentrations had a higher risk of NTD compared to controls. Based on dietary analysis, less consumption of meat, egg or milk, fresh vegetables and fruit intake would increase the risk of NTD. Conclusions: Lower serum concentrations of folate and vitamin B 12 are related to the increased risk of NTD in high-risk populations. Both folate and vitamin B 12 intake insufficiency could contribute to the increased risk of NTD. A dietary supplement, combining folate and vitamin B 12 , might be an effective measure to decrease the NTD incidence in these areas.