[Iodine nutritional status and intake levels in adult from different water iodine content areas of Xinjiang Uygur Autonomous Region in 2017].

OBJECTIVE: To understand the iodine nutrition status of adults in Xinjiang Uygur Autonomous Region under the effective control of iodine deficiency disease. METHODS: Using stratified cluster random sampling method, in the district to determine water iodine median<10 µg/L and ≥10 µg/L of urban and rural areas, a total of 10 survey points, deals from the collecting water deals of extracting water iodine content detection. Adults over 18 years old were randomly selected from 30 households at each survey site to carry out a survey on dietary iodine intake, and the contents of dietary salt iodine and adult urine iodine were tested. RESULTS: The median iodine content in water in Xinjiang Uygur Autonomous Region was 4. 4(2. 3, 13. 6)µg/L. The median iodine content of household salt was 27(24, 30) mg/kg. The median urinary iodine content in adults was 168(103, 259)µg/L. The average dietary iodine intake of adults in the region was 312 µg/d. CONCLUSION: The water iodine content in the environment outside Xinjiang Uygur Autonomous Region is relatively low, and the iodine nutritional status and dietary iodine intake of adults are generally at the appropriate level. However, urban adults with relatively low water iodine content and good economic status have a higher risk of iodine deficiency. Iodized salt is the main source of dietary iodine for adults in Xinjiang Uygur Autonomous Region. Adults in poorer rural and urban areas rely more heavily on iodized salt.

Telomerase-null survivor screening identifies novel telomere recombination regulators.

Telomeres are protein-DNA structures found at the ends of linear chromosomes and are crucial for genome integrity. Telomeric DNA length is primarily maintained by the enzyme telomerase. Cells lacking telomerase will undergo senescence when telomeres become critically short. In Saccharomyces cerevisiae, a very small percentage of cells lacking telomerase can remain viable by lengthening telomeres via two distinct homologous recombination pathways. These "survivor" cells are classified as either Type I or Type II, with each class of survivor possessing distinct telomeric DNA structures and genetic requirements. To elucidate the regulatory pathways contributing to survivor generation, we knocked out the telomerase RNA gene TLC1 in 280 telomere-length-maintenance (TLM) gene mutants and examined telomere structures in post-senescent survivors. We uncovered new functional roles for 10 genes that affect the emerging ratio of Type I versus Type II survivors and 22 genes that are required for Type II survivor generation. We further verified that Pif1 helicase was required for Type I recombination and that the INO80 chromatin remodeling complex greatly affected the emerging frequency of Type I survivors. Finally, we found the Rad6-mediated ubiquitination pathway and the KEOPS complex were required for Type II recombination. Our data provide an independent line of evidence supporting the idea that these genes play important roles in telomere dynamics.

EZH2 engages TGFß signaling to promote breast cancer bone metastasis via integrin ß1-FAK activation.

Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFß) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin ß1. Integrin ß1 activates focal adhesion kinase (FAK), which phosphorylates TGFß receptor type I (TGFßRI) at tyrosine 182 to enhance its binding to TGFß receptor type II (TGFßRII), thereby activating TGFß signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin ß1-FAK axis cooperates with the TGFß signaling pathway to promote bone metastasis of breast cancer.

Vitamin E Enhances Cancer Immunotherapy by Reinvigorating Dendritic Cells via Targeting Checkpoint SHP1.

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and DC-derived extracellular vesicles (DC-EV), triggering systemic antigen-specific T-cell antitumor immunity. Combining VitE with DC-recruiting cancer vaccines or immunogenic chemotherapies greatly boosted ICT efficacy in animals. Therefore, combining VitE supplement or SHP1-inhibited DCs/DC-EVs with DC-enrichment therapies could substantially augment T-cell antitumor immunity and enhance the efficacy of cancer immunotherapies. SIGNIFICANCE: The impacts of nutritional supplements on responses to immunotherapies remain unexplored. Our study revealed that dietary vitamin E binds to and inhibits DC checkpoint SHP1 to increase antigen presentation, prime antitumor T-cell immunity, and enhance immunotherapy efficacy. VitE-treated or SHP1-silenced DCs/DC-EVs could be developed as potent immunotherapies. This article is highlighted in the In This Issue feature, p. 1599.

Boosting immune surveillance by low-dose PI3K inhibitor facilitates early intervention of breast cancer.

Prevention of estrogen receptor-negative (ER-) breast cancer is an unmet challenge, although tamoxifen and aromatase inhibitors can successfully decrease the incidence of ER-positive (ER+) breast cancer. PI3K pathway activation has been detected in tamoxifen-resistant ER- breast lesions of patients. Here, we further ratified that the PI3K pathway is significantly activated in premalignant ER- breast lesions compared with paired normal tissues of patients, which prompted our assessment of targeting PI3K on inhibition of ER- mammary tumor initiation and progression. Both genetic knockdown of PIK3CA or intervention with low-doses of a PI3K inhibitor (GDC-0941) prevented the dysplasia phenotype of semi-transformed human ER- mammary epithelial cells in 3-dimensional culture in vitro. Importantly, low-dose GDC-0941 treatment significantly delayed mammary tumor initiation in the MMTV-neu mouse model without exhibiting discernable adverse effects. Interestingly, increased CD8+/GZMB+ T-cells were detected in mammary tissue after GDC-0941 treatment, suggesting enhanced immune surveillance. Mechanistically, elevated expression of potent T-cell chemo-attractants, including CCL5 and CXCL10, were detected both in vitro and in vivo after GDC-0941 treatment. Furthermore, inhibition of PI3K significantly increased T-cell recruitment in a CCL5/CXCL10-dependent manner. In human ER- breast cancer, PI3K activation is correlated with significantly reduced CCL5, CXCL10 and CD8A expression, suggesting that the decreased CD8+ T-cell recruitment and escape of immune surveillance may contribute to ER- breast cancer development. In summary, our study indicates that low-dose PI3K inhibitor treatment may intervene early stage ER- breast cancer development by enhancing immune surveillance via CCL5/CXCL10.

Molecular dynamics of de novo telomere heterochromatin formation in budding yeast.

In the budding yeast Saccharomyces cerevisiae, heterochromatin structure is found at three chromosome regions, which are homothallic mating-type loci, rDNA regions and telomeres. To address how telomere heterochromatin is assembled under physiological conditions, we employed a de novo telomere addition system, and analyzed the dynamic chromatin changes of the TRP1 reporter gene during telomere elongation. We found that integrating a 255-bp, but not an 81-bp telomeric sequence near the TRP1 promoter could trigger Sir2 recruitment, active chromatin mark(s)' removal, chromatin compaction and TRP1 gene silencing, indicating that the length of the telomeric sequence inserted in the internal region of a chromosome is critical for determining the chromatin state at the proximal region. Interestingly, Rif1 but not Rif2 or yKu is indispensable for the formation of intra-chromosomal silent chromatin initiated by telomeric sequence. When an internal short telomeric sequence (e.g., 81 bp) gets exposed to become a de novo telomere, the herterochromatin features, such as Sir recruitment, active chromatin mark(s)' removal and chromatin compaction, are detected within a few hours before the de novo telomere reaches a stable length. Our results recapitulate the molecular dynamics and reveal a coherent picture of telomere heterochromatin formation.

Tethering telomerase to telomeres increases genome instability and promotes chronological aging in yeast.

Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS). The expression of Cdc13-Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long-term chronological aging. Accordingly, genome instability, manifested by accumulation of extra-chromosomal rDNA circle species, age-dependent CAN1 marker-gene mutation frequency and gross chromosomal rearrangement frequency, was significantly elevated. Importantly, inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13-EST2 expression. Interestingly, loss of the CDC13-EST2 fusion gene in the cells with overlong telomeres restored the regular CLS. Altogether, these data suggest that constitutively active telomerase is detrimental to the maintenance of genome stability, and promotes chronological aging in yeast.

[Changes of rat gastric mucosal barrier under stress conditions].

OBJECTIVE To explore the changes of rat gastric mucosal barrier under conditions of water immersion restraint stress. METHODS Eighty rats were randomly divided into Group A (20 rats), B (40 rats) and C (20 rats) after being fasted for 24 hours. And then Group A was divided into two subgroups with ten rats in each. The two subgroups in Group A were given normal saline or omeprazole respectively while under the stress condition. The changes of gastric acid or bicarbonate secretion were determined. Group B (40 rats) were randomly divided into four subgroups,which were subgroup control, 1h, 2h and 4h after beginning of the stress. The quantity of glandular mucosal adherent mucus, the thickness of mucus gel layer and ulcer index were measured after stress in Group B. The glandular mucosal samples were labeled by Lanthanum and observed by transmission electromicroscopy. Group C was randomly divided into two subgroups in the same way with Group A. And each subgroup received normal saline or omeprazole respectively H(+) loss in gastric lumen was calculated by determining the difference of acidity between lavage and drainage fluid H(+) concentration. RESULTS It was found that gastric alkaline secretion decreased progressively (P < 0.05), while gastric acid secretion increased progressively under stress conditions (P < 0.05). The mucus quantity(A/g) in the four subgroups in Group B were 0.137 +/- 0.030, 0.143 +/- 0.012, 0.066 +/- 0.016 and 0.016 +/- 0.016 respectively. The mucus gel thickness(microm) were 71.08 +/- 5.85, 74.50 +/- 12.85, 57.63 +/- 6.45 and 51.35 +/- 2.84 respectively. The ulcer index were 0.2 +/- 0.1,0.4 +/- 0.1,5.2 +/- 1.3 and 10.0 +/- 0.5 respectively. Statistics showed that the mucus quantity was correlated with the mucus gel thickness positively(r = 0.89), while either of them was correlated with the ulcer index negatively(r = 0.85 and "r = 0.83). And it was also found that Lanthanum rarely stained the glandular mucosa in control subgroup, while heavily in stress subgroups. In the subgroup receiving normal saline in Group C, within 5 hours after the beginning of stress, the amount of H(+) loss per hour(micromol) was 2.03 +/- 0.12, 2.00 +/- 0.20, 1.93 +/- 0.49, 2.70 +/- 0.44 and 3.37 +/- 0.35 respectively. It was demonstrated that the amount of H(+) loss was stable within 2h after stress, then increased obviously in normal saline subgroup significantly (P < 0.01). In omeprazole subgroup, the amount of H(+) loss (micromol) was 7.46 +/- 1.22, 4.56 +/- 0.35, 3.11 +/- 0.81, 2.32 +/- 1.42 and 2.13 +/- 1.60, which decreased progressively, however still higher than those in normal saline subgroup (P "< 0.01). CONCLUSIONS The results suggest that gastric bicarbonate secretion is inhibited; gastric barrier is damaged; and hydrogen permeability through gastric mucosal barrier increases under stress conditions.

Telomere recombination preferentially occurs at short telomeres in telomerase-null type II survivors.

In telomerase negative yeast cells, Rad52-dependent recombination is activated to maintain telomeres. This recombination-mediated telomere elongation usually involves two independent pathways, type I and type II, and leads to generation of type I and type II survivors. It remains elusive whether the recombination-mediated telomere elongation prefers to take place on shorter or longer telomeres. In this study, we exploited the de novo telomere addition system to examine the telomere recombination event in telomerase negative cells. We show that recombination preferentially occurs on shorter rather than longer telomeres in both pre-survivors and established type II survivors. In type II survivors, the short VII-L telomeres could invade either terminal TG1-3 sequence or short tracts of TG1-3 sequence in subtelomeric Y'-X and Y'-Y' junction to initiate recombination. Unexpectedly, short VII-L telomere recombination still takes place in type II survivors lacking either Rad50 or Rad59, which are required for type II survivor generation in senescing telomerase-null cells. Our results support the notion that Rad50 and Rad59 are not essential for the maintenance of type II survivors once established.

Characterization of the intramolecular G-quadruplex promoting activity of Est1.

In the budding yeast Saccharomyces cerevisiae, telomeric DNA includes TG1-3/C1-3A double-stranded DNA and a protruding G-rich overhang. Our previous studies revealed that the telomerase regulatory subunit Est1 promotes telomeric single-stranded DNA to form intermolecular G-quadruplex in vitro, and this activity is required for telomere replication and protection in vivo. In this study, we further characterized the G-quadruplex promoting activity of Est1. Here we report that Est1 is able to promote the single-stranded oligonucleotide of (TGTGTGGG)4, which mimics the natural telomeric DNA, to form intramolecular G-quadruplex. Therefore, it remains possible that the intramolecular G-quadruplex promoting activity of Est1 is biologically relevant in telomere replication in vivo.

Est1 protects telomeres and inhibits subtelomeric y'-element recombination.

In the budding yeast Saccharomyces cerevisiae, the structure and function of telomeres are maintained by binding proteins, such as Cdc13-Stn1-Ten1 (CST), Yku, and the telomerase complex. Like CST and Yku, telomerase also plays a role in telomere protection or capping. Unlike CST and Yku, however, the underlying molecular mechanism of telomerase-mediated telomere protection remains unclear. In this study, we employed both the CDC13-EST1 fusion gene and the separation-of-function allele est1-D514A to elucidate that Est1 provided a telomere protection pathway that was independent of both the CST and Yku pathways. Est1's ability to convert single-stranded telomeric DNA into a G quadruplex was required for telomerase-mediated telomere protection function. Additionally, Est1 maintained the integrity of telomeres by suppressing the recombination of subtelomeric Y' elements. Our results demonstrate that one major functional role that Est1 brings to the telomerase complex is the capping or protection of telomeres.

SWR1 complex poises heterochromatin boundaries for antisilencing activity propagation.

In eukaryotes, chromosomal processes are usually modulated through chromatin-modifying complexes that are dynamically targeted to specific regions of chromatin. In this study, we show that the chromatin-remodeling complex SWR1 (SWR1-C) uses a distinct strategy to regulate heterochromatin spreading. Swr1 binds in a stable manner near heterochromatin to prepare specific chromosomal regions for H2A.Z deposition, which can be triggered by NuA4-mediated acetylation of histone H4. We also demonstrate through experiments with Swc4, a module shared by NuA4 and SWR1-C, that the coupled actions of NuA4 and SWR1-C lead to the efficient incorporation of H2A.Z into chromatin and thereby synergize heterochromatin boundary activity. Our results support a model where SWR1-C resides at the heterochromatin boundary to maintain and amplify antisilencing activity of histone H4 acetylation through incorporating H2A.Z into chromatin.