Quantum key distribution provides secure keys resistant to code-breaking quantum computers. The continuous-variable version of quantum key distribution offers the advantages of higher secret key rates in metropolitan areas, as well as the use of standard telecom components that can operate at room temperature. However, the transmission distance of these systems (compared with discrete-variable systems) are currently limited and considered unsuitable for long-distance distribution. Herein, we report the experimental results of long distance continuous-variable quantum key distribution over 202.81 km of ultralow-loss optical fiber by suitably controlling the excess noise and employing highly-efficient reconciliation procedures. This record-breaking implementation of the continuous-variable quantum key distribution doubles the previous distance record and shows the road for long-distance and large-scale secure quantum key distribution using room-temperature standard telecom components.

The continuous-variable version of quantum key distribution (QKD) offers the advantages (over discrete-variable systems) of higher secret key rates in metropolitan areas, as well as the use of standard telecom components that can operate at room temperature. An important step in the real-world adoption of continuous-variable QKD is the deployment of field tests over commercial fibers. Here we report two different field tests of a continuousvariable QKD system through commercial fiber networks in Xi'an and Guangzhou over distances of 30.02 km (12.48 dB) and 49.85 km (11.62 dB), respectively. We achieve secure key rates two orders-of-magnitude higher than previous field test demonstrations by employing an efficient calibration model with one-time evaluation. This accomplishment is also realized by developing a fully automatic control system which stabilizes system noise, and by applying a rate-adaptive reconciliation method which maintains high reconciliation efficiency with high success probability in fluctuated environments. Our results pave the way to deploy continuousvariable QKD in metropolitan settings.

There is great medical need for estrogens with favorable pharmacological profiles, that support desirable activities for menopausal women such as metabolic and vascular protection but that lack stimulatory activities on the breast and uterus. Here, we report the development of structurally novel estrogens that preferentially activate a subset of estrogen receptor (ER) signaling pathways and result in favorable target tissue-selective activity. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we obtained “Pathway Preferential Estrogens” (PaPEs) which interacted with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. PaPEs elicited a pattern of gene regulation and cellular and biological processes that did not stimulate reproductive and mammary tissues or breast cancer cells. However, in ovariectomized mice, PaPEs triggered beneficial responses both in metabolic tissues (adipose tissue and liver) that reduced body weight gain and fat accumulation and in the vasculature that accelerated repair of endothelial damage. This process of designed ligand structure alteration represents a novel approach to develop ligands that shift the balance in ER-mediated extranuclear and nuclear pathways to obtain tissue-selective, non-nuclear pathway-preferential estrogens, which may be beneficial for postmenopausal hormone replacement. The approach may also have broad applicability for other members of the nuclear hormone receptor superfamily.

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Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERa)-positive (ER þ) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERa signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER þ breast cancer cells. FFAs activated both the ERa and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERa and mTOR sig-naling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER þ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERa and mTOR signaling cross-talk would be tested to prevent ER þ breast cancers in obese postmenopausal women. Significance: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.

Scope We studied the impact of dietary supplementation with licorice root components on diet-induced obesity, fat accumulation and hepatic steatosis in ovariectomized C57BL/6 mice as a menopause model. Materials and Methods We evaluated the molecular and physiological effects of dietary licorice root administered to ovariectomized C57BL/6 mice as root powder (LRP), extracts (LRE) or isolated isoliquiritegenin (ILQ) on reproductive (uterus and mammary gland) and non-reproductive tissues important in regulating metabolism (liver, perigonadal, perirenal, mesenteric and subcutaneous fat). Quantitative outcome measures including body weight, fat distribution (MRI), food consumption, bone density and weight (DXA) and gene expression were assessed by the degree of restoration to the premenopausal health state. We characterized histological (H&E and oil red O staining) and molecular properties (expression of certain disease markers) of these tissues, and correlated these with metabolic phenotype as well as blood levels of bioactives. Conclusions Although LRE and ILQ provided some benefit, LRP was the most effective in reducing body weight gain, overall fat deposition, liver steatosis, and expression of hepatic lipid synthesis genes following ovariectomy. Our data demonstrate that licorice root provided improvement of multiple metabolic parameters under conditions of menopausal low estrogen and high-fat diets without stimulating reproductive tissues.

Conjugated estrogens (CE) and Bazedoxifene (BZA) combination is used to alleviate menopause-associated symptoms in women. CE+BZA undergo first-pass-metabolism in the liver and deconjugation by gut microbiome via β-glucuronidase (GUS) enzyme inside the distal gut. To date, the impact of long-term exposure to CE+BZA on the gut microbiome or GUS activity has not been examined. Our study using an ovariectomized mouse model showed that CE+BZA administration did not affect the overall cecal or fecal microbiome community except that it decreased the abundance of Akkermansia, which was identified as a fecal biomarker correlated with weight gain. The fecal GUS activity was reduced significantly and was positively correlated with the abundance of Lactobacillaceae in the fecal microbiome. We further confirmed in Escherichia coli K12 and Lactobacillus gasseri ADH that Tamoxifen-, 4-hydroxy-Tamoxifen- and Estradiol-Glucuronides competed for GUS activity. Our study for the first time demonstrated that long-term estrogen supplementation directly modulated gut microbial GUS activity. Our findings implicate that long-term estrogen supplementation impacts composition of gut microbiota and microbial activity, which affects estrogen metabolism in the gut. Thus, it is possible to manipulate such activity to improve the efficacy and safety of long-term administered estrogens for postmenopausal women or breast cancer patients.

Bud-break is an economically and environmentally important process in trees and shrubs from boreal and temperate latitudes, but its molecular mechanisms are poorly understood. Here, we show that two previously reported transcription factors, EARLY BUD BREAK 1 (EBB1) and SHORT VEGETATIVE PHASE-Like (SVL) directly interact to control bud-break. EBB1 is a positive regulator of bud-break, whereas SVL is a negative regulator of bud-break. EBB1 directly and negatively regulates SVL expression. We further report the identification and characterization of the EBB3 gene. EBB3 is a temperature-responsive, epigenetically-regulated, positive regulator of bud-break that provides a direct link to activation of the cell cycle during bud-break. EBB3 is an AP2/ERF transcription factor that positively and directly regulates CYCLIND3.1 gene. Our results reveal the architecture of a putative regulatory module that links temperature-mediated control of bud-break with activation of cell cycle.