Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.

National 400m hurdles champion Rushell Clayton is concerned about what she says are inequalities between men and women in track and field. Clayton was speaking at a Women in Sports Conference in Kingston recently and discussed issues of inequality...

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

In an effort to advance the Association’s diversity and inclusion efforts, the ADA House of Delegates voted at its meeting in September to rescind the policy titled “The Dentist’s Prayer,” used by some state and local dental societies during their meetings, and amend its policy on recognition of religious diversity.

The ADA Council on Dental Practice is encouraging dentists to acknowledge the dedication and contributions of their dental assistants during Dental Assistants Recognition Week.

Painted images of intriguing human-animal hybrids are signs of modern thought

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Stuttgart : Franz Steiner Verlag, 2019.

The fear is that instead of using it to prevent crime and catch terrorists, facial recognition is instead used for political purposes. But we won't stop it or protect privacy by freaking out.

Micronutrients are essential for brain development during gestation and infancy. Few randomized trials of maternal multiple micronutrient supplementation during pregnancy and postpartum have examined child outcomes beyond the neonatal period or tested which cognitive domains show long-term effects.

Children of undernourished mothers given multiple micronutrients performed as well as children of well-nourished mothers in motor and visual attention/spatial ability at age 42 months; children of undernourished mothers given iron/folic acid showed 4- to 5-month delays in these abilities. (Read the full article)

Maternal obesity is an increasingly important public health concern and may adversely affect central nervous system development in offspring. However, few studies have explored the relationship between maternal prepregnancy BMI and neurodevelopmental outcomes in children, with conflicting results.

Using data from a large and contemporary UK birth cohort, we found that maternal prepregnancy BMI is negatively associated with children’s cognitive performance. The relationship appears to become stronger as children get older, although the overall effect size is modest. (Read the full article)

Low birth weight (LBW) infants (<2500 g) are at risk for cognitive and behavioral problems later in life. During infancy, they are also at risk for iron deficiency, which has been associated with impaired neurodevelopment in other high-risk groups.

Iron supplementation during the first 6 months of life to LBW infants reduces the risk of behavioral problems at 3.5 years. Mild iron deficiency in infancy may be an important, preventable contributor to behavioral problems in children born with LBW. (Read the full article)

Suboptimal brain development and increased risk of cognitive deficits are well documented in very low birth weight children. Supplementation with docosahexaenoic acid and arachidonic acid has been associated with positive cognitive effects.

This follow-up study of a randomized controlled trial of supplementation with docosahexaenoic acid and arachidonic acid to very low birth weight infants is the first report on both cognition and brain macrostructure measured with MRI. No cognitive or neuroanatomical effects were detected at 8 years. (Read the full article)

Permanent neuronal deletion and neurocognitive impairment after anesthetic exposure in animals raised substantial concern that similar effects occur in children. Human studies were equivocal but have not combined structural and intelligence tests in otherwise healthy children after childhood anesthesia.

Anesthetic exposure for surgery did not lead to measurable neuronal elimination in brain regions previously identified in animals. However, language comprehension and performance IQ were decreased in exposed children and associated with decreased gray matter, primarily in posterior brain regions. (Read the full article)

Multi-drug resistance among Gram-negative bacteria is a major global public health threat. Metallo-β-lactamases (MBLs) target the most widely-used antibiotic class, the β-lactams, including the most recent-generation carbapenems. Interspecies spread renders these enzymes a serious clinical threat and there are no clinically-available inhibitors. We present crystal structures of IMP-13, a structurally-uncharacterized MBL from Gram-negative Pseudomonas aerugionasa found in clinical outbreaks globally, and characterize the binding using solution NMR-spectroscopy and molecular-dynamics simulations. Crystal structures of apo IMP-13 and bound to four clinically-relevant carbapenem antibiotics (doripenem, ertapenem, imipenem and meropenem) are presented. Active site plasticity and the active-site loop, where a tryptophan residue stabilizes the antibiotic core scaffold, are essential to the substrate-binding mechanism. The conserved carbapenem scaffold plays the most significant role in IMP-13 binding, explaining the broad substrate specificity. The observed plasticity and substrate-locking mechanism provide opportunities for rational drug design of novel metallo-β-lactamase inhibitors, essential in the fight against antibiotic resistance.

Spectinomycin is a ribosome-binding antibiotic that blocks the translocation step of translation. A prevalent resistance mechanism is the modification of the drug by aminoglycoside nucleotidyl transferase (ANT) enzymes of the spectinomycin-specific ANT (9) family or by the dual-specificity ANT(3") (9) family that also acts on streptomycin. We previously reported the structural mechanism of streptomycin modification by the ANT(3") (9) AadA from Salmonella enterica. ANT (9) from Enterococcus faecalis adenylates the 9-hydroxyl of spectinomycin. We here present the first structures of spectinomycin bound to an ANT enzyme. Structures were solved for ANT (9) in apo form, in complex with ATP, spectinomycin and magnesium or in complex with only spectinomycin. ANT (9) shows similar overall structure as AadA with an N-terminal nucleotidyltransferase domain and a C-terminal α-helical domain. Spectinomycin binds close to the entrance of the interdomain cleft, while ATP is buried at the bottom. Upon drug binding, the C-terminal domain rotates by 14 degrees to close the cleft, allowing contacts of both domains with the drug. Comparison with AadA shows that spectinomycin specificity is explained by a straight α₅ helix and a shorter α_5-α₆ loop that would clash with the larger streptomycin substrate. In the active site, we observe two magnesium ions, one of them in a previously un-observed position that may activate the 9-hydroxyl for deprotonation by the catalytic base Glu-86. The observed binding mode for spectinomycin suggests that also spectinamides and aminomethyl spectinomycins, recent spectinomycin analogues with expansions in position 4 of the C ring, will be subjected to modification by ANT (9) and ANT(3") (9) enzymes.

The Multicultural Resource Center at Penn State has announced this year’s Senior and Faculty/Staff Diversity Recognition Awards recipients. The 2020 awards honor multicultural University Park graduating seniors who excel in academics, leadership, and service, as well as faculty and staff throughout Penn State who demonstrate a commitment to diversity, equity and inclusion efforts beyond the responsibilities of their position.

Six accomplished seniors will celebrate the culmination of their collegiate involvement and success by representing the Donald P. Bellisario College of Communications as student marshals for the Class of 2020.

Penn State New Kensington announced its academic, teaching and extracurricular award winners on May 1, and shared a dedicated, virtual recognition web page, including video messages, photos and award winners.

Biometrics are generally a good alternative to passwords, but authentication via face-scanning is a terrible idea, according to security expert Max Eddy.

Regulation moves at a snail's pace, so it's up to CEOs, executives, and employees to reject projects that put profit over privacy. Clearview AI facial-recognition tech is just the latest example of 'innovation' that could quickly get out of hand.

In keeping with Penn State Scranton's current continuing adjustment to an all-virtual environment, the annual Student Recognition Dinner will be held virtually at 6 p.m. on Wednesday, April 22.

In an inspiring show of support, a large contingent of Penn State Scranton’s campus community logged onto their computers the evening of April 22 to celebrate the accomplishments of the student body.

After more than 10 years of European legal protection for employees in the event of a relevant transfer, many aspects of the Transfer of Undertakings Directive 2001 (Council Directive 2001/23/EC) and its predecessor have by now been litigated over a...

The Court in AA v Persons Unknown [2019] EWHC 3556 (Comm) (17 January 2020) ordered injunctive relief against unknown persons accused of extorting ransom payments in the form of Bitcoin worth $950,000 from an insurance company, following a cyber-att...

AN3433 - Touchpad With Built-In Surface Gesture Recognition Using Peripheral Touch Controller

ABSTRACT

The UV-inducible pili system of Sulfolobales (Ups) mediates the formation of species-specific cellular aggregates. Within these aggregates, cells exchange DNA to repair DNA double-strand breaks via homologous recombination. Substitution of the Sulfolobus acidocaldarius pilin subunits UpsA and UpsB with their homologs from Sulfolobus tokodaii showed that these subunits facilitate species-specific aggregation. A region of low conservation within the UpsA homologs is primarily important for this specificity. Aggregation assays in the presence of different sugars showed the importance of N-glycosylation in the recognition process. In addition, the N-glycan decorating the S-layer of S. tokodaii is different from the one of S. acidocaldarius. Therefore, each Sulfolobus species seems to have developed a unique UpsA binding pocket and unique N-glycan composition to ensure aggregation and, consequently, also DNA exchange with cells from only the same species, which is essential for DNA repair by homologous recombination.

IMPORTANCE Type IV pili can be found on the cell surface of many archaea and bacteria where they play important roles in different processes. The UV-inducible pili system of Sulfolobales (Ups) pili from the crenarchaeal Sulfolobales species are essential in establishing species-specific mating partners, thereby assisting in genome stability. With this work, we show that different Sulfolobus species have specific regions in their Ups pili subunits, which allow them to interact only with cells from the same species. Additionally, different Sulfolobus species have unique surface-layer N-glycosylation patterns. We propose that the unique features of each species allow the recognition of specific mating partners. This knowledge for the first time gives insights into the molecular basis of archaeal self-recognition.

ABSTRACT

Streptococcus pneumoniae (or pneumococcus) is a highly prevalent human pathogen. Toll-like receptors (TLRs) function as immune sensors that can trigger host defenses against this bacterium. Defects in TLR-activated signaling pathways, including deficiency in the adaptor protein myeloid differentiation factor 88 (MyD88), are associated with markedly increased susceptibility to infection. However, the individual MyD88-dependent TLRs predominantly involved in antipneumococcal defenses have not been identified yet. Here we find that triple knockout mice simultaneously lacking TLR7, TLR9, and TLR13, which sense the presence of bacterial DNA (TLR9) and RNA (TLR7 and TLR13) in the phagolysosomes of phagocytic cells, display a phenotype that largely resembles that of MyD88-deficient mice and rapidly succumb to pneumococcal pneumonitis due to defective neutrophil influx into the lung. Accordingly, TLR7/9/13 triple knockout resident alveolar macrophages were largely unable to respond to pneumococci with the production of neutrophil-attracting chemokines and cytokines. Mice with single deficiencies of TLR7, TLR9, or TLR13 showed unaltered ability to control lung infection but were moderately more susceptible to encephalitis, in association with a decreased ability of microglia to mount cytokine responses in vitro. Our data point to a dominant, tissue-specific role of nucleic acid-sensing pathways in innate immune recognition of S. pneumoniae and also show that endosomal TLRs are largely capable of compensating for the absence of each other, which seems crucial to prevent pneumococci from escaping immune recognition. These results may be useful to develop novel strategies to treat infections by antibiotic-resistant pneumococci based on stimulation of the innate immune system.

IMPORTANCE The pneumococcus is a bacterium that frequently causes infections in the lungs, ears, sinus cavities, and meninges. During these infections, body defenses are triggered by tissue-resident cells that use specialized receptors, such as Toll-like receptors (TLRs), to sense the presence of bacteria. We show here that pneumococci are predominantly detected by TLRs that are located inside intracellular vacuoles, including endosomes, where these receptors can sense the presence of nucleic acids released from ingested bacteria. Mice that simultaneously lacked three of these receptors (specifically, TLR7, TLR9, and TLR13) were extremely susceptible to lung infection and rapidly died after inhalation of pneumococci. Moreover, tissue-resident macrophages from these mice were impaired in their ability to respond to the presence of pneumococci by producing inflammatory mediators capable of recruiting polymorphonuclear leucocytes to infection sites. This information may be useful to develop drugs to treat pneumococcal infections, particularly those caused by antibiotic-resistant strains.

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and...

Fucosylation of the innermost GlcNAc of N-glycans by fucosyltransferase 8 (FUT8) is an important step in the maturation of complex and hybrid N-glycans. This simple modification can dramatically affect the activities and half-lives of glycoproteins, effects that are relevant to understanding the invasiveness of some cancers, development of mAb therapeutics, and the etiology of a congenital glycosylation disorder. The acceptor substrate preferences of FUT8 are well-characterized and provide a framework for understanding N-glycan maturation in the Golgi; however, the structural basis of these substrate preferences and the mechanism through which catalysis is achieved remain unknown. Here we describe several structures of mouse and human FUT8 in the apo state and in complex with GDP, a mimic of the donor substrate, and with a glycopeptide acceptor substrate at 1.80–2.50 Å resolution. These structures provide insights into a unique conformational change associated with donor substrate binding, common strategies employed by fucosyltransferases to coordinate GDP, features that define acceptor substrate preferences, and a likely mechanism for enzyme catalysis. Together with molecular dynamics simulations, the structures also revealed how FUT8 dimerization plays an important role in defining the acceptor substrate-binding site. Collectively, this information significantly builds on our understanding of the core fucosylation process.

Plans to ban face recognition in public places would only halt a tiny fraction of its use. Instead we need to regulate the technology – and fast, says Donna Lu

The US Special Operations Command is developing a portable face-recognition system designed to identify people 1 kilometre away. It could also be used by law enforcement

Michael Kratsios, the fourth U.S. Chief Technology Officer, explains administration policies at the Fall Conference of the Stanford Institute for Human-Centered Artificial Intelligence

Follow all the latest coronavirus updates HERE

Facial recognition surveillance, powered by artificial intelligence, is being used — or misused — in cities worldwide.

Titta Secombe says it's time the origins of Australian Rules football — which she says involved Indigenous mobs playing for pride with a possum-skin ball — are properly recognised.

"My colleagues and I across the Justice Department – and the entire Obama Administration – remain deeply committed to expanding this work through funding grants, training, and other forms of assistance. We’re eager to continue partnering with leading jurists like those who serve this Court, tireless advocates like our allies at the PSA and NADCP, and determined drug court participants like each of you," said Attorney General Holder.

Attorney General Eric Holder issued the following statement today on the status of same-sex marriages performed in the state of Utah.

Attorney General Eric Holder issued the following statement today on the status of same-sex marriages performed in the state of Michigan.

"These groundbreaking efforts [Smart on Crime, Federal Interagency Reentry Council] are enabling us to tear down unnecessary barriers to opportunity and independence – while building up programs and policies that enable returning individuals to successfully reintegrate into their communities."

innoVactiv announces today its study supporting the efficacy of InSea2® to beneficially affect post-meal cognition and mental energy has been accepted for publication.

We wander about the unknown terrains of life, complacent about what we know and oblivious to what we miss

In the futuristic 2002 film “Minority Report,” law enforcement uses a predictive technology that includes artificial intelligence (AI) for risk assessments to arrest possible murderers before they commit crimes. However, a police officer is now one of the accused future murderers and is on the run from the Department of Justice to prove that the…