It’s not that spicy.

Paulette Jiles delighted with her convention-breaking western romance, 'News of the World.' Her follow-up, 'Simon the Fiddler,' is just old-fashioned.

Convicted rapist Roman Polanski wins a César, France's equivalent of the Oscar, for directing "An Officer and a Spy," sparking immediate backlash.

"The film will not be screened in theatres in the predominantly Muslim UAE, a desert country of around 10 million people where gay sex is illegal," said filmmaker Hitesh Kewalya.

The Netflix documentary "A Secret Love" recounts the 72-year relationship between Pat Henschel and Terry Donahue, who had to hide their true selves from the world.

AS I SIT at the bar looking out across the best, white-sand beach in Jamaica, the chilled beats of reggae's latest superstar bounce across the breeze. The chorus to local boy Chronixx's "Skankin' Sweet" kicks in. An ode to parking the stresses of life and appreciating the good things, his lyrics "forget your troubles and rock with me," certainly resonate throughout this laid-back Caribbean island nation.

WHEN the orange gold blossoms that a boyfriend chose as a gift for his sweetheart arrived they were less the glorious bouquet he had been expecting and more a bunch of buds.

A DOG was thrown over a bridge into a river to drown in Romania during the coronavirus lockdown, an animal charity has revealed.

KATE, DUCHESS of Cambridge and Prince William have been married for nine years, but how did the Cambridge's wedding day echo the Queen and Prince Philip's romance?

PRINCESS Beatrice was to join her sister, Princess Eugenie, in entering married life this month before the coronavirus pandemic hit. Now, the couple will have to wait before they can finally tie the knot, similarly to Beatrice and her husband, Jack Brooksbank.

Dramatic, fiery and different every night, you'll never tire of looking at them. You'll bore everyone with photos of them. One of your friends proposed underneath one, while another made them the backdrop to her honeymoon. One thing's for sure, Santorini sure does a good sunset.

Chilean midfielder David Pizarro joins Manchester City on loan from Roma for the rest of the season.

A chronology of key events

Key facts, figures and dates

Parodist Andrew Shaffer's new mystery "Hope Rides Again" (a sequel to 2018's "Hope Never Dies"), reunites the literary and real-life duo.

The Amateur Traveler talks to Shawn about his trip to Transylvania in Romania. We talk, of course, about Vlad III the Impaler (Dracula) but also about the green rolling hills, walled towns, castles and people of this beautiful country.

Hear about travel to Bucharest as the Amateur Traveler talks to Wandering Earl about visiting and living in that city. Earl calls Bucharest one of the most under-rated cities in all of Europe, certainly eastern Europe.

Hear about travel to Northern Romania as the Amateur Traveler talks to Ralph Velasco of photoenrichment.com about the region that he visited leading a recent photo tour.

We talk about the regions of Maramureş and Bukovina, north of Transylvania.

Hear about travel to the Danube Delta in Romania as the Amateur Traveler talks to Christian Cummins about traveling to this UNESCO biosphere in Europe.

Claudio P. Albuquerque
Jul 1, 2008; 7:1389-1396
Research

(Impact Journals LLC) Volume 11, Issue 18 of @Oncotarget Clinical implications of chromatin accessibility assessed by ATAC-seq profiling in human cancers especially in a large patient cohort is largely unknown.

Introduction: Aromatase inhibitors are the mainstay of hormonal therapy in estrogen receptor positive, postmenopausal breast cancer, although response rate is just over 50%. The goal of the present study was to validate and optimize positron emission tomography (PET) with ¹¹C-vorozole for measuring aromatase expression in postmenopausal breast cancer. Methods: Ten newly diagnosed, postmenopausal women with biopsy confirmed breast cancer were administered ¹¹C-vorozole intravenously and PET emission data collected between 40 – 90 minutes post-injection. Tracer injection and scanning were repeated 2 hours after ingestion of 2.5mg letrozole p.o. Mean and maximal standard uptake values and ratios to non-tumor tissue (SUVs, SUVRs) were calculated for tumor and non-tumor regions at baseline and after letrozole. Biopsy specimens from the same tumors were stained for aromatase using immunohistochemistry and evaluated for stain intensity and the percentage of immune-positive cells. Results: Seven of the 10 women (70%) demonstrated increased focal uptake of tracer (SUVR>1.1) coinciding with the mammographic location of the lesion. The other 3 women (30%) did not show increased uptake in the tumor (SUVR <1.0). All of the cases with SUVR above 1.1 had SUVs above 2.4 and there was no overlap in SUV between the two groups, with mean SUV in tumors overexpressing aromatase (SUVR>1.1) ranging from 2.47 to 13.6, while tumors not overexpressing aromatase (SUVR<1) ranged from 0.8 to 1.8. Pretreatment with letrozole reduced tracer uptake in the majority of subjects; although the %blocking varied across and within tumors. Tumors with high SUV in vivo also showed high staining intensity on IHC. Conclusion: PET with ¹¹C-vorozole is a useful technique for measuring aromatase expression in individual breast lesions, enabling a non-invasive quantitative measurement of baseline and post-treatment aromatase availability in primary tumors and metastatic lesions.

Triple-negative breast cancer (TNBC) is characterized by poor response to therapy and low overall patient survival. Recently, Estrogen Receptor beta (ERβ) has been found to be expressed in a fraction of TNBCs where, because of its oncosuppressive actions on the genome, it represents a potential therapeutic target, provided a better understanding of its actions in these tumors becomes available. To this end, the cell lines Hs 578T, MDA-MB-468 and HCC1806, representing the claudin-low, basal-like 1 and 2 TNBC molecular subtypes respectively, were engineered to express ERβ under the control of a Tetracycline-inducible promoter and used to investigate the effects of this transcription factor on gene activity. The antiproliferative effects of ERβ in these cells were confirmed by multiple functional approaches, including transcriptome profiling and global mapping of receptor binding sites in the genome, that revealed direct negative regulation by ERβ of genes, encoding for key components of cellular pathways associated to TNBC aggressiveness representing novel therapeutic targets such as angiogenesis, invasion, metastasis and cholesterol biosynthesis. Supporting these results, interaction proteomics by immunoprecipitation coupled to nano LC-MS/MS mass spectrometry revealed ERβ association with several potential nuclear protein partners, including key components of regulatory complexes known to control chromatin remodeling, transcriptional and post-transcriptional gene regulation and RNA splicing. Among these, ERβ association with the Polycomb Repressor Complexes 1 and 2 (PRC1/2), known for their central role in gene regulation in cancer cells, was confirmed in all three TNBC subtypes investigated, suggesting its occurrence independently from the cellular context. These results demonstrate a significant impact of ERβ in TNBC genome activity mediated by its cooperation with regulatory multiprotein chromatin remodeling complexes, providing novel ground to devise new strategies for the treatment of these diseases based on ligands affecting the activity of this nuclear receptor or some of its protein partners.

For more than two decades naturally presented, human leukocyte antigen (HLA)-restricted peptides (immunopeptidome) have been eluted and sequenced using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Since, identified disease-associated HLA ligands have been characterized and evaluated as potential active substances. Treatments based on HLA-presented peptides have shown promising results in clinical application as personalized T cell-based immunotherapy. Peptide vaccination cocktails are produced as investigational medicinal products under GMP conditions. To support clinical trials based on HLA-presented tumor-associated antigens, in this study the sensitive LC-MS/MS HLA class I antigen identification pipeline was fully validated for our technical equipment according to the current US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines.

The immunopeptidomes of JY cells with or without spiked-in, isotope labeled peptides, of peripheral blood mononuclear cells of healthy volunteers as well as a chronic lymphocytic leukemia and a bladder cancer sample were reliably identified using a data-dependent acquisition method. As the LC-MS/MS pipeline is used for identification purposes, the validation parameters include accuracy, precision, specificity, limit of detection and robustness.

Famous American poet and singer Maya Angelou shared this about matters pertaining to the heart: “Love recognises no barriers. It jumps hurdles, leaps fences, penetrates walls to arrive at its destination full of hope.” What started out as an...

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life, 12.7 h) and ²²⁵Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than for ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than for ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

"Xander joins his local am-dram group in order to make friends. He certainly doesn't expect to fall for the group's playboy star. Graeme is confident and easygoing. He believes in fun without commitment. However, all that changes when Xander gets under his skin" -- Pub;isher info.

A group of Vermont high school students backed by a powerful conservative Christian legal organization is accusing the state of religious discrimination.

[19--?]

A Paris (rue St Jacques au dessus de celle des Mathurins au Gd. St. Remy) : ches Huquier fils, graveur, [between 1700 and 1799]

We study the identity testing problem in the context of spin systems or undirected graphical models, where it takes the following form: given the parameter specification of the model $M$ and a sampling oracle for the distribution $mu_{M^*}$ of an unknown model $M^*$, can we efficiently determine if the two models $M$ and $M^*$ are the same? We consider identity testing for both soft-constraint and hard-constraint systems. In particular, we prove hardness results in two prototypical cases, the Ising model and proper colorings, and explore whether identity testing is any easier than structure learning. For the ferromagnetic (attractive) Ising model, Daskalakis et al. (2018) presented a polynomial-time algorithm for identity testing. We prove hardness results in the antiferromagnetic (repulsive) setting in the same regime of parameters where structure learning is known to require a super-polynomial number of samples. Specifically, for $n$-vertex graphs of maximum degree $d$, we prove that if $|eta| d = omega(log{n})$ (where $eta$ is the inverse temperature parameter), then there is no polynomial running time identity testing algorithm unless $RP=NP$. In the hard-constraint setting, we present hardness results for identity testing for proper colorings. Our results are based on the presumed hardness of #BIS, the problem of (approximately) counting independent sets in bipartite graphs.

Zhixiang Lin, Mahdi Zamanighomi, Timothy Daley, Shining Ma, Wing Hung Wong.

Source: Statistical Science, Volume 35, Number 1, 2--13.

Abstract:
Unsupervised methods, including clustering methods, are essential to the analysis of single-cell genomic data. Model-based clustering methods are under-explored in the area of single-cell genomics, and have the advantage of quantifying the uncertainty of the clustering result. Here we develop a model-based approach for the integrative analysis of single-cell chromatin accessibility and gene expression data. We show that combining these two types of data, we can achieve a better separation of the underlying cell types. An efficient Markov chain Monte Carlo algorithm is also developed.

The city's residents sorted waste materials for reuse in future projects, according to new research

The pilum, a vital weapon in Rome’s imperial ambitions, was a simple iron spear fixed with two bolts onto a heavy wooden post. It was remarkably effective against an attacker charging at high speed.

Hadrian’s Wall was a 73 mile barrier stretching from coast to coast, splitting the warlike north of Britain from the more docile south. It was the Roman Empire’s way of imposing peace in a hostile land

This rapid and efficient method to prepare highly purified recombinant adeno-associated viruses (rAAVs) is based on binding of negatively charged rAAV capsids to an anion-exchange resin that is pH dependent.

Speech by Mr Mugur Isărescu, Governor of the National Bank of Romania, Bucharest, 29 April 2020.

This summer nearly 1,000 Roma children in Roma villages throughout Central and Eastern Europe heard the Gospel.

Volker (OM Montenegro) describes how their outdoor lessons for Roma kids were threatened by bad weather. Then God provided not only the solution - building a carport as a shelter - but also the funds and manpower needed to build it.

Roma pastors and leaders from across Eastern Europe and the Balkans gather together for a Roma conference.

This summer nearly 1,000 Roma children in Roma villages throughout Central and Eastern Europe heard the Gospel.

We find out about the importance of equal opportunities for Roma players in Slovenian football.

Macromastia is associated with severe physical and emotional symptoms and negatively impacts health-related quality of life in adult women. Reduction mammaplasty is the most effective treatment for adults. Little is known regarding the impact of macromastia during adolescence.

Adolescents with macromastia have impaired health-related quality of life, lower self-esteem, more breast-related symptoms, and are at higher risk for disordered eating in comparison with their peers. These negative health outcomes have implications for early intervention in this patient population. (Read the full article)

NF1 is the commonest single-gene neurodevelopmental disorder with known neurobiology and developmental impact on attention and cognition. Its impact on social functioning is described but poorly understood, with no population-based study of autism spectrum disorder (ASD) prevalence in the disorder.

This epidemiological study shows high prevalence of 25% ASD in NF1 not explained by learning difficulties. ASD should be considered during clinical practice with NF1. Further research into NF1 as a single-gene model of ASD is warranted. (Read the full article)