Proteins in the α-macroglobulin (αM) superfamily use thiol esters to form covalent conjugation products upon their proteolytic activation. αM protease inhibitors use theirs to conjugate proteases and preferentially react with primary amines (e.g. on lysine side chains), whereas those of αM complement components C3 and C4B have an increased hydroxyl reactivity that is conveyed by a conserved histidine residue and allows conjugation to cell surface glycans. Human α2-macroglobulin–like protein 1 (A2ML1) is a monomeric protease inhibitor but has the hydroxyl reactivity–conveying histidine residue. Here, we have investigated the role of hydroxyl reactivity in a protease inhibitor by comparing recombinant WT A2ML1 and the A2ML1 H1084N mutant in which this histidine is removed. Both of A2ML1s' thiol esters were reactive toward the amine substrate glycine, but only WT A2ML1 reacted with the hydroxyl substrate glycerol, demonstrating that His-1084 increases the hydroxyl reactivity of A2ML1's thiol ester. Although both A2ML1s conjugated and inhibited thermolysin, His-1084 was required for the conjugation and inhibition of acetylated thermolysin, which lacks primary amines. Using MS, we identified an ester bond formed between a thermolysin serine residue and the A2ML1 thiol ester. These results demonstrate that a histidine-enhanced hydroxyl reactivity can contribute to protease inhibition by an αM protein. His-1084 did not improve A2ML1's protease inhibition at pH 5, indicating that A2ML1's hydroxyl reactivity is not an adaption to its acidic epidermal environment.

Juntuo Zhou
Nov 30, 2020; 0:RA120.002384v1-mcp.RA120.002384
Research

Oktawia Nilsson
Nov 17, 2020; 0:jlr.RA120000920v1-jlr.RA120000920
Research Articles

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) is essential for the transportation of cholesterol between peripheral tissues and the liver. However, specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis, the pathological accumulation of protein fibrils in tissues and organs. Carriers of these mutations do not exhibit increased cardiovascular disease risk despite displaying reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of patients carrying either L75P or L174S ApoA-I amyloidogenic variants a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.

The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n=492) and tissue microarrays composed of early-stage LUADs (n=228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.

How do Eurasian kleptocracies earn and use their money? 9 November 2021 — 1:00PM TO 2:30PM Anonymous (not verified) 22 October 2021 Chatham House and Online

This event explores the presence of corrupt funds from Eurasia in Western democracies, what they are used for, and how they can be constrained.

The Pandora Papers once again shone the spotlight on the UK being home to corrupt funds from kleptocracies, where the ruling elite abuse their political power for private gain.

In recent years much focus has been placed on this term, and the possible effects such money could have on Western democracies.

• How do such states create this wealth in the first place?
• How do these funds make their way to the UK?
• Is the term kleptocracy appropriate for the majority of countries in Eurasia?
• What evidence is there that such funds are ‘weaponized’ to achieve foreign policy goals?

This event discusses the term, how it can be applied, and the differences between how ’grey’ funds are used by various countries. It also highlights how the UK and the wider international community can counteract these flows, both from a legal point of view, and via other methods.

After much anticipation, the National Institute of Standards and Technology (NIST) issued its first Post Quantum Cryptography (PQC) standards today. They are intended to defeat efforts by quantum computers powerful […]

The post NIST Issues Post Quantum Cryptography Standards and Calls for their Adoption appeared first on HPCwire.

Watch a discussion between three educators who ran for their state legislatures about their experiences on the campaign trail.

Teachers felt that iPads "provide no educational function in the classroom" and are often used to play games in class.

When can we expect the Islanders to get healthy?

Emma Lingan and Eric Cruikshank discuss Washington Capitals center Dylan Strome, the Bruins and Red Wings coaches, Kirill Kaprizov's next contract and much more.

Members of 30 different state and national advocacy groups and unions are meeting in Washington, D.C., for the Grassroots Assembly for Child Care and Early Education.

Many schools that have recently opened their doors are already seeing COVID-19 cases among students and staff. Should that shake the confidence of other school leaders who are planning to reopen?

Mahsa Altafi
Oct 23, 2024; 44:e0518242024-e0518242024
Systems/Circuits

Neural circuits supporting innate behaviors, such as feeding, exploration, and social interaction, intermingle in the lateral hypothalamus (LH). Although previous studies have shown that individual LH neurons change their firing relative to the baseline during one or more behaviors, the firing rate dynamics of LH populations within behavioral episodes and the coordination of behavior-related LH populations remain largely unknown. Here, using unsupervised graph-based clustering of LH neurons firing rate dynamics in freely behaving male mice, we identified distinct populations of cells whose activity corresponds to feeding, specific times during feeding bouts, or other innate behaviors—social interaction and novel object exploration. Feeding-related cells fired together with a higher probability during slow and fast gamma oscillations (30–60 and 60–90 Hz) than during nonrhythmic epochs. In contrast, the cofiring of neurons signaling other behaviors than feeding was overall similar between slow gamma and nonrhythmic epochs but increased during fast gamma oscillations. These results reveal a neural organization of ethological hierarchies in the LH and point to behavior-specific motivational systems, the dysfunction of which may contribute to mental disorders.

The cheetah cubs will be named after the fastest male and female American Olympic athletes in the 100-meter dash at the London Olympics.

From the moment they arrived at the concentration camp, Jews and other Holocaust victims were treated like animals, and only a lucky group survived the experience.

The science behind going belly up

Gasp! The answer will amaze you. Still Image Credit: MaFelipe / iStock

Paul Raffaele explores gorilla tourism, raising gorillas in captivity and the future of the Congo mountain gorillas

When the blaze in Moscow subsided on September 18, 1812, the French—who had traveled hundreds of miles into Russia—were left without vital resources as a brutal winter approached

Female worker bees, which forage for the whole colony, struggle more to detect scents in the heat than males do, per the recent research

The world’s slowest mammal is at risk of extinction by the end of the century due to their low metabolic rate and climate change

A pair of 3-year-old giant pandas—a male named Bao Li and a female called Qing Bao—have officially arrived at the Zoo, where they will first acclimate to their new home

The notorious predators, nicknamed the “Man-Eaters of Tsavo,” terrorized railway workers in Kenya for roughly nine months

Using advanced imaging techniques, researchers discovered modern glue, drill holes and even a fragment of a drill bit in the pastiches

Two comb jellies can merge their digestive and nervous systems and even sync their bodily functions, according to new research. The discovery could have implications for human medicine

A scientist used at-home experiments to test whether cats hesitated when moving through increasingly shorter or narrower openings

After a years-long restoration, the unique device that recorded hits like "Come Together" and "Here Comes the Sun" is now fully functional

In a rare technique among mammals, the bats burn proteins from blood, rather than carbs or fat, to power their pursuits of prey, according to a new study

Pedestrians in Montreal, Grand Rapids and other locations can time-travel thanks to installations that map historical scenes directly onto the cityscapes

A new exhibition at the British Library explores the public, private and spiritual lives of such figures as Joan of Arc, Christine de Pizan and Hildegard of Bingen

In the Jim Crow South, activists became martyrs at the hands of white racists, all for the just cause of using the vote to fight for equality and freedom

Hospice Northwest Services is inviting people to visit its third annual photography exhibit, "A Personal Lens on Grief." Here's what the project in Thunder Bay, Ont., entails, and why staff say it's important to find creative ways to express loss.

The P.E.I. Woodlot Owners Association is encouraging its members to boost the biodiversity of their woods with different varieties of trees and shrubs. As CBC's Nancy Russell reports, the goal is to provide habitat for endangered species and protect the forests from future disasters like post-tropical storm Fiona.

A recent study out of the University of Calgary estimates that more than 10 million Canadians are being exposed to high levels of radon, an odourless, tasteless radioactive gas that is the second leading cause of lung cancer in the country.

That Figure Skating Show recaps the short program in the pairs event at Canadian Nationals, where the reigning champs are letting their presence be known.

Extensive automation of time-consuming tasks gives designers fast, accurate tools for testing their ideas

Competition sponsored by SOLIDWORKS and

Effie Award Recognizes Marketing Company Small Army and DS SolidWorks for ‘3 Dudes Gone 3D’ Campaign

Team Competing in Race Back to the Moon

Stories Prove Importance of 'Introduce a Girl to Engineering Day'

OMer Richard Sharp teaches practical and relevant methods of sharing the Gospel with Portuguese young people at a youth camp.

A village builds their own school - a big first for the area and a step in transforming the community.

OMers help Hungarian children uncover their gifts through drama camp.

In Europe’s poorest country, national believers take the lead in meeting needs and equipping compatriots to transform their communities, their country and the world.

Veracruz, Mexico :: A team from Logos Hope points homeless people to Christ at a church outreach.

A couple adopts a small, struggling church in North Africa and prays for faithfulness and perseverance: “It’s one step forward, 100 steps back.”

Couple prepares for mission field by working with international students at home, and shares how God’s love impacts Muslims.

Ethnomusicologists visited a North African country to help local singers and a Sudanese Nubian believer write a worship song in his language and style.