Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behcet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position ). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ~40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

24 March 2020

Seventy years after the adoption of the Geneva Conventions, there are challenges that remain to be addressed. This briefing takes three pertinent examples, and discusses possibilities for addressing them.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, definitive treatment usually requiring surgical removal of the offending parathyroid glands. To perform focused surgical approaches, it is necessary to localize all hyperfunctioning glands. The aim of the study was to compare the efficiency of established conventional scintigraphic imaging modalities with emerging ¹⁸F-fluorocholine PET/CT imaging in preoperative localization of hyperfunctioning parathyroid glands in a larger series of PHPT patients. Methods: In total, 103 patients with PHPT were imaged preoperatively with ¹⁸F-fluorocholine PET/CT and conventional scintigraphic imaging methods, consisting of ^99mTc-sestamibi SPECT/CT, ^99mTc-sestamibi/pertechnetate subtraction imaging, and ^99mTc-sestamibi dual-phase imaging. The results of histologic analysis, as well as intact parathyroid hormone and serum calcium values obtained 1 d after surgery and on follow-up, served as the standard of truth for evaluation of imaging results. Results: Diagnostic performance of ¹⁸F-fluorocholine PET/CT surpassed conventional scintigraphic methods (separately or combined), with calculated sensitivity of 92% for PET/CT and 39%–56% for conventional imaging (65% for conventional methods combined) in the entire patient group. Subgroup analysis, differentiating single and multiple hyperfunctioning parathyroid glands, showed PET/CT to be most valuable in the group with multiple hyperfunctioning glands, with sensitivity of 88%, whereas conventional imaging was significantly inferior, with sensitivity of 22%–34% (44% combined). Conclusion: ¹⁸F-fluorocholine PET/CT is a diagnostic modality superior to conventional imaging methods in patients with PHPT, allowing for accurate preoperative localization.

Paris : J. Cherbuliez, 1870.

Bertrand Clarke, Jennifer Clarke

Source: Statist. Surv., Volume 6, 1--73.

Abstract:
We review predictive techniques from several traditional branches of statistics. Starting with prediction based on the normal model and on the empirical distribution function, we proceed to techniques for various forms of regression and classification. Then, we turn to time series, longitudinal data, and survival analysis. Our focus throughout is on the mechanics of prediction more than on the properties of predictors.

Despite declines in cigarette smoking, smokeless tobacco use among youth has remained unchanged in the United States. Modified or novel smokeless tobacco products are being increasingly promoted to youth in the United States as an alternative to smoking.

Among US students in grades 6 through 12, 5.0% used snuff or chewing or dipping tobacco, whereas 2.2% used snus or dissolvable tobacco products. Approximately two-thirds of smokeless tobacco users concurrently smoked combustible tobacco; risk perception of all tobacco products was protective of smokeless tobacco use. (Read the full article)

Use of complementary and alternative medicine (CAM) is increasingly common among American youth; however, information on use of CAM among youth with recurrent headache (HA) is limited.

Youth across a range of chronic conditions experience HA. These youth are more likely to use CAM. Use and expenditures for conventional medical care, and increased difficulties in activity and functioning are greater for youth with HA who use CAM. (Read the full article)

Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis.

Realme has been successful because of our focus on the product; many brands don’t focus on the product anymore. We have grown 850% y-o-y; from the second quarter of the year until August, our sales have increased 300%.

The Court of Appeal’s decision in The South West Strategic Health Authority v Bay Island Voyages [2015] EWCA Civ 708 provides guidance on the application of the Athens Convention 1974 in contribution claims against carriers. The Facts On 26 Au...

LOS ANGELES, CA – HARMAN International Industries, Inc. (NYSE:HAR), the premium audio and infotainment group, will have a major presence at the 137th Audio Engineering Society Convention as it returns to the Los Angeles Convention Center Thursday, October 9 through Sunday, October 12 for the first time in twelve years. HARMAN, the premiere sponsor of both the annual AES President’s Reception and the AES Student Zone, will present several research papers, highlight new Professional audio equipment, and demonstrate the company’s latest innovative music restoration technology, Clari-Fi, throughout the week.

A large-scale update of the file names used for articles available via the PMC FTP service for bulk download was undertaken in early January 2017. The new file naming convention is PMCID-based (e.g., PMC4855680.tar.gz) rather than being built from article citation data (i.e., journal abbreviation_pub date_volume_issue_page). This update was made following user reports that the previous naming convention was resulting in missing contents in cases where citation data was duplicated across multiple articles. The new convention will ensure that file names are unique and that the corpus available via the FTP service is complete.

Background

Fluid overload in patients undergoing hemodialysis contributes to cardiovascular morbidity and mortality. There is a global trend to lower dialysate sodium with the goal of reducing fluid overload.

Midori Ishii and Bungo Akiyoshi

The kinetochore is a macromolecular protein complex that drives chromosome segregation in eukaryotes. Unlike most eukaryotes that have canonical kinetochore proteins, evolutionarily divergent kinetoplastids, such as Trypanosoma brucei, have unconventional kinetochore proteins. T. brucei also lacks a canonical spindle checkpoint system, and it therefore remains unknown how mitotic progression is regulated in this organism. Here, we characterized, in the procyclic form of T. brucei, two paralogous kinetochore proteins with a CLK-like kinase domain, KKT10 and KKT19, which localize at kinetochores in metaphase but disappear at the onset of anaphase. We found that these proteins are functionally redundant. Double knockdown of KKT10 and KKT19 led to a significant delay in the metaphase to anaphase transition. We also found that phosphorylation of two kinetochore proteins, KKT4 and KKT7, depended on KKT10 and KKT19 in vivo. Finally, we showed that the N-terminal part of KKT7 directly interacts with KKT10 and that kinetochore localization of KKT10 depends not only on KKT7 but also on the KKT8 complex. Our results reveal that kinetochore localization of KKT10 and KKT19 is tightly controlled to regulate the metaphase to anaphase transition in T. brucei.

This article has an associated First Person interview with the first author of the paper.

Figuring out how to stage the nation’s largest and most important political gatherings will be tricky in the COVID-19 era. And while officials in both parties say they’re still planning for in-person conventions, pulling that off will be a lot easier said than done. 

Ugly makeup is imperfect, sloppy, chaotic – and only worn to please the wearer, against social expectations

In 2018, Rosanna Meikle felt like a failure. She was toiling through beauty school, and she hadn’t been able to find much work nor garner much attention for her creations online. She was exhausted from the sameness she saw around her, “a sea of beautiful girls, smoky eyes and plumped lips”, she remembers. “My school was in an expensive area of Auckland, which made me feel so out of place. I couldn’t afford the products or the clothes, my kit wasn’t ‘professional’ enough and neither was my look.”

Related: ‘It makes me feel human’: 11 women share their lockdown beauty regimens

Up for reelection this fall, North Carolina Gov. Roy Cooper has to decide whether to allow Trump's coronation to proceed amid a pandemic.

Canceled Wednesday, this year's E3 was particularly anticipated because new consoles from Sony and Microsoft are due to be released by the end of the year.

(MedPage Today) -- Subcutaneous implantable cardioverter defibrillators (S-ICDs) performed on par with conventional transvenous ICDs (TV-ICDs) in the first head-to-head randomized trial. The overall primary composite endpoint of inappropriate...

With major sporting competitions on hold because of coronavirus, now is the time to reassess how we approach the sport-lifestyle balance of professional athletes and even how they are recruited, writes Richard Hinds.

Get the inside information on what industry does and does NOT want from their academic counterparts: Join us June 16, 3-4 p.m. EDT for Insider’s Guide to Effective Partnering at BIO 2011, a FREE AUTM webinar to help you prepare for the BIO convention in Washington, DC, June 27-30.

BIO is hosting a Translation Research Forum at the BIO International Convention.  NIH Director Collins keynotes an event that will explore how private, public and academic sectors can leverage meaningful partnerships, highlight emerging best practices, explore risk-sharing at the clinical research stage, and explore ways to bridge the gap in funding and know-how necessary to take […]

"It’s a special honor to be part of this anniversary and to continue one of our nation’s most important conversations – the crucial, ongoing dialogue between law enforcement and members of the Arab-American community," said Attorney General Holder.

"I believe our criminal defense system can, and will, become a source of tremendous national pride. I look forward to working with you all in achieving this goal. And I am grateful for your guidance, your engagement, and for your commitment," said Attorney General Holder.

"...for two decades now, the National Action Network has been on the front lines of our nation’s fight to ensure security, opportunity, and justice for all. Today, this work goes on in your demands to those in power and in your aspirations for those in need."

"This Administration is moving in a direction that is guided, not by fear – but by fact, by reason, and by a commitment to advancing the cause of justice and to upholding our nation’s most essential and enduring values."

"Throughout our history, the efforts of journalists have rendered a clear picture of life in this country – of the historic achievements we have made, and the harsh realities that far too many faced. Without your work, we would not have a starting point for progress – or, in many cases, for the pursuit of justice."

"Although 44 years have passed since our nation first mourned the loss of Dr. King, it is clear that his spirit lives on. His enduring contributions have allowed me to stand on this stage as our nation’s first African-American Attorney General, and to serve alongside our first African-American President. And the dream that he shared – on the National Mall that now includes a memorial in his honor – has inspired countless acts of compassion and collaboration, including the creation of the National Action Network more than two decades ago," said Attorney General Holder.

"As Attorney General, it is my obligation – and solemn duty – to ensure that the rights of all Americans are protected. And I’m proud that, under this Administration, our Civil Rights Division – and its Voting Section – have taken meaningful steps to ensure integrity, independence, and transparency in our enforcement of the Voting Rights Act," said Attorney General Holder.

"You’ve proven the power of unity – and the virtues of diversity. And you’ve breathed new life into the old adage that – more than 80 years ago – gave voice to LULAC’s mission and vision: Uno para todos, todos para uno," said Attorney General Holder.

"In short, it is time – yet again – to put our energy and skills to good use – in advocating for the most vulnerable members of society; in protecting the liberty – and the sacred rights – of every single person in this country; in safeguarding the basic infrastructure of our democracy; in ensuring economic and educational opportunities for all of our countrymen – and women; and in carrying forward the fundamental and inclusive ideals upon which this country was founded, and which continue to drive our pursuit of a more perfect Union," said Attorney General Holder.

"I am here to say that the United States Department of Justice will stand with you, and all people of good will, to preserve this great nation and its fundamental values of freedom, equality and justice," said Assistant Attorney General Perez.

"At the Justice Department, we have made enforcing the rights of American Indians a priority," said Assistant Attorney General Perez.

"I promised them I would never forget – just as I know you have not forgotten. On this, of all nights, let us dedicate ourselves, as Dr. King would expect us to do, to this new struggle," said Attorney General Holder.

It is an idea ACS strives to make real in the work this organization does in law schools, with law students, lawyers, policymakers and opinion leaders across the country. As the third-ranking official at the U.S. Department of Justice and one who oversees, among others, the Civil Rights Division, the Office of Justice Programs and the Access to Justice Initiative, I'm grateful for your commitment and honored by your invitation to contribute to today’s discussion about indigent defense.

Since that moment – thanks to the work of groups like this one, and the dedication of passionate advocates like all of you – our nation has experienced remarkable, once-unimaginable progress.

Today – starting here and now – it’s time to commit ourselves to a respectful, responsible dialogue about issues of justice and equality – so we can meet division and confusion with understanding, with compassion, and ultimately with truth.

Every April, our nation pauses to mark the contributions, and the profound sacrifices, of this extraordinary leader. Dr. King dedicated his career to the service of others.

"Because if a government of, by and for the people means anything at all, it means that a ballot has the power to give equal voice to the high and the low; the weak and the strong; those at the bottom as well as the top. It means that in the polling place, the line is just as long for the richest among us as it is for those who often work the hardest but have the least."

Mr. Chairperson, distinguished Members of the committee, and representatives of civil society. My name is Mark Kappelhoff and I serve as a Deputy Assistant Attorney General in the Civil Rights Division of the U.S. Department of Justice. It is an honor to be a member of the U.S. delegation and to share with you some of the Justice Department’s work to address racial discrimination and to fulfill our obligations under the convention.

Mr. Chairperson, distinguished members of the committee, and representatives of civil society, it is an honor to be a part of the U.S. delegation and share some of the highlights of the Department of Justice’s efforts to eliminate racial discrimination and uphold human rights in the area of criminal justice.

Buenas tardes. Muchas gracias por sus emotivas palabras y su calurosa bienvenida. It’s a privilege to help welcome the Hispanic National Bar Association to our nation’s capital for your 39th Annual Convention. And it’s a great pleasure, as always, to be in such distinguished company.

Domenico Lombardi and Sarah Puritz Milsom explore the role of the International Monetary Fund in the eurozone crisis and review the policy options that the international community must consider to strategically and effectively address the current situation.

While preservation of the planet's dwindling biodiversity itself has rightly grabbed the headlines at the ongoing Convention on Biological Diversity in Japan, Science Insider points out an important geoengineering

An estimated 2,000 synthetic chemicals can be used in conventional packaged foods; for organic the number is 40.