THE INCIDENCE, NATURE, AND IMPLICATIONS OF PRICE-FIXING LITIGATION IN U.S. FOOD INDUSTRIES

Demand and Price Analysis, Political Economy,

Can changes in education alter future population ageing in Asia and Europe?

While population ageing is rising, the educational composition of the elderly remains rather heterogeneous. This study assesses the educational differences in future population ageing in Asia and Europe, and how future population ageing in Asia and Europe would change if the educational composition of its populations changed. A comparative population ageing measure (the Comparative Prospective Old-Age Threshold [CPOAT]) was used, which recalculates old-age thresholds after accounting for differences in life expectancy, and the likelihood of adults surviving to higher ages. Combined data from projected age- and sex-specific life-tables (from the United Nations) and projected age- and sex-specific survival ratios by different levels of education (from the Wittgenstein Centre for Demography and Global Human Capital) were used to construct projected life-tables (2015-2020, ..., 2045-2050) by educational level and sex for different regions of Asia and Europe. Based on these life-tables, future comparative prospective old-age thresholds by educational level and sex were calculated. It was found that in both Asia and Europe, and among both men and women, the projected old-age thresholds are higher for higher educated people than for less-educated people. While Europe has a larger projected share of elderly in the population than Asia, Europe's older population is better educated. In alternative future scenarios in which populations hypothetically have higher levels of education, the projected shares of elderly in the population decrease across all regions of Asia and Europe, but more so in Asia. The results highlight the effectiveness of investing in education as a policy response to the challenges associated with population ageing in Asia and Europe. Such investments are more effective in the Asian regions, where the educational infrastructure is less developed.</p

Time course metabolome of Roux-en-Y gastric bypass confirms correlation between leptin, body weight and the microbiome

Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 dia- betes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabet- ics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to dia- betes. Only leptin and IL-6 had a significant association with the measured metabolites. Lep- tin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes

On the origin of non-monotonic doping dependence of the in-plane resistivity anisotropy in Ba(Fe1−xTx_{1-x}T_x)2_2As2_2, TT = Co, Ni and Cu

The in-plane resistivity anisotropy has been measured for detwinned single crystals of Ba(Fe$_{1-x}$Ni$_x$)$_2$As$_2$ and Ba(Fe$_{1-x}$Cu$_x$)$_2$As$_2$. The data reveal a non-monotonic doping dependence, similar to previous observations for Ba(Fe$_{1-x}$Co$_x$)$_2$As$_2$. Magnetotransport measurements of the parent compound reveal a non-linear Hall coefficient and a strong linear term in the transverse magnetoresistance. Both effects are rapidly suppressed with chemical substitution over a similar compositional range as the onset of the large in-plane resistivity anisotropy. It is suggested that the relatively small in-plane anisotropy of the parent compound in the spin density wave state is due to the presence of an isotropic, high mobility pocket of reconstructed Fermi surface. Progressive suppression of the contribution to the conductivity arising from this isotropic pocket with chemical substitution eventually reveals the underlying in-plane anisotropy associated with the remaining FS pockets.Comment: 12 pages, 9 figure

Cellular IP₆ Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP₆ Are Attenuated for Infection and Replication

Summary: HIV-1 hijacks host proteins to promote infection. Here we show that HIV is also dependent upon the host metabolite inositol hexakisphosphate (IP6) for viral production and primary cell replication. HIV-1 recruits IP6 into virions using two lysine rings in its immature hexamers. Mutation of either ring inhibits IP6 packaging and reduces viral production. Loss of IP6 also results in virions with highly unstable capsids, leading to a profound loss of reverse transcription and cell infection. Replacement of one ring with a hydrophobic isoleucine core restores viral production, but IP6 incorporation and infection remain impaired, consistent with an independent role for IP6 in stable capsid assembly. Genetic knockout of biosynthetic kinases IPMK and IPPK reveals that cellular IP6 availability limits the production of diverse lentiviruses, but in the absence of IP6, HIV-1 packages IP5 without loss of infectivity. Together, these data suggest that IP6 is a critical cofactor for HIV-1 replication

RING domains act as both substrate and enzyme in a catalytic arrangement to drive self-anchored ubiquitination.

Funder: Boehringer Ingelheim Fonds (Stiftung für medizinische Grundlagenforschung); doi: https://doi.org/10.13039/501100001645Attachment of ubiquitin (Ub) to proteins is one of the most abundant and versatile of all posttranslational modifications and affects outcomes in essentially all physiological processes. RING E3 ligases target E2 Ub-conjugating enzymes to the substrate, resulting in its ubiquitination. However, the mechanism by which a ubiquitin chain is formed on the substrate remains elusive. Here we demonstrate how substrate binding can induce a specific RING topology that enables self-ubiquitination. By analyzing a catalytically trapped structure showing the initiation of TRIM21 RING-anchored ubiquitin chain elongation, and in combination with a kinetic study, we illuminate the chemical mechanism of ubiquitin conjugation. Moreover, biochemical and cellular experiments show that the topology found in the structure can be induced by substrate binding. Our results provide insights into ubiquitin chain formation on a structural, biochemical and cellular level with broad implications for targeted protein degradation

A tri-ionic anchor mechanism drives Ube2N-specific recruitment and K63-chain ubiquitination in TRIM ligases.

The cytosolic antibody receptor TRIM21 possesses unique ubiquitination activity that drives broad-spectrum anti-pathogen targeting and underpins the protein depletion technology Trim-Away. This activity is dependent on formation of self-anchored, K63-linked ubiquitin chains by the heterodimeric E2 enzyme Ube2N/Ube2V2. Here we reveal how TRIM21 facilitates ubiquitin transfer and differentiates this E2 from other closely related enzymes. A tri-ionic motif provides optimally distributed anchor points that allow TRIM21 to wrap an Ube2N~Ub complex around its RING domain, locking the closed conformation and promoting ubiquitin discharge. Mutation of these anchor points inhibits ubiquitination with Ube2N/Ube2V2, viral neutralization and immune signalling. We show that the same mechanism is employed by the anti-HIV restriction factor TRIM5 and identify spatially conserved ionic anchor points in other Ube2N-recruiting RING E3s. The tri-ionic motif is exclusively required for Ube2N but not Ube2D1 activity and provides a generic E2-specific catalysis mechanism for RING E3s

Sequences in the cytoplasmic tail of SARS-CoV-2 Spike facilitate expression at the cell surface and syncytia formation.

The Spike (S) protein of SARS-CoV-2 binds ACE2 to direct fusion with host cells. S comprises a large external domain, a transmembrane domain, and a short cytoplasmic tail. Understanding the intracellular trafficking of S is relevant to SARS-CoV-2 infection, and to vaccines expressing full-length S from mRNA or adenovirus vectors. Here we report a proteomic screen for cellular factors that interact with the cytoplasmic tail of S. We confirm interactions with the COPI and COPII vesicle coats, ERM family actin regulators, and the WIPI3 autophagy component. The COPII binding site promotes exit from the endoplasmic reticulum, and although binding to COPI should retain S in the early Golgi where viral budding occurs, there is a suboptimal histidine residue in the recognition motif. As a result, S leaks to the surface where it accumulates and can direct the formation of multinucleate syncytia. Thus, the trafficking signals in the tail of S indicate that syncytia play a role in the SARS-CoV-2 lifecycle

A Method for the Acute and Rapid Degradation of Endogenous Proteins.

Methods for the targeted disruption of protein function have revolutionized science and greatly expedited the systematic characterization of genes. Two main approaches are currently used to disrupt protein function: DNA knockout and RNA interference, which act at the genome and mRNA level, respectively. A method that directly alters endogenous protein levels is currently not available. Here, we present Trim-Away, a technique to degrade endogenous proteins acutely in mammalian cells without prior modification of the genome or mRNA. Trim-Away harnesses the cellular protein degradation machinery to remove unmodified native proteins within minutes of application. This rapidity minimizes the risk that phenotypes are compensated and that secondary, non-specific defects accumulate over time. Because Trim-Away utilizes antibodies, it can be applied to a wide range of target proteins using off-the-shelf reagents. Trim-Away allows the study of protein function in diverse cell types, including non-dividing primary cells where genome- and RNA-targeting methods are limited