Structural bases for the interaction and stabilization of the human amino acid transporter LAT2 with its ancillary protein 4F2hc.

Heteromeric amino acid transporters (HATs) are the unique example, known in all kingdoms of life, of solute transporters composed of two subunits linked by a conserved disulfide bridge. In metazoans, the heavy subunit is responsible for the trafficking of the heterodimer to the plasma membrane, and the light subunit is the transporter. HATs are involved in human pathologies such as amino acidurias, tumor growth and invasion, viral infection and cocaine addiction. However structural information about interactions between the heavy and light subunits of HATs is scarce. In this work, transmission electron microscopy and single-particle analysis of purified human 4F2hc/L-type amino acid transporter 2 (LAT2) heterodimers overexpressed in the yeast Pichia pastoris, together with docking analysis and crosslinking experiments, reveal that the extracellular domain of 4F2hc interacts with LAT2, almost completely covering the extracellular face of the transporter. 4F2hc increases the stability of the light subunit LAT2 in detergent-solubilized Pichia membranes, allowing functional reconstitution of the heterodimer into proteoliposomes. Moreover, the extracellular domain of 4F2hc suffices to stabilize solubilized LAT2. The interaction of 4F2hc with LAT2 gives insights into the structural bases for light subunit recognition and the stabilizing role of the ancillary protein in HATs.

Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral fractures: Results of a randomized controlled ancillary study of HORIZON

BACKGROUND In postmenopausal women, yearly intravenous zoledronate (ZOL) compared to placebo (PLB) significantly increased bone mineral density (BMD) at lumbar spine (LS), femoral neck (FN), and total hip (TH) and decreased fracture risk. The effects of ZOL on BMD at the tibial epiphysis (T-EPI) and diaphysis (T-DIA) are unknown. METHODS A randomized controlled ancillary study of the HORIZON trial was conducted at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. Women with ≥1 follow-up DXA measurement who had received ≥1 dose of either ZOL (n=55) or PLB (n=55) were included. BMD was measured at LS, FN, TH, T-EPI, and T-DIA at baseline, 6, 12, 24, and 36 months. Morphometric vertebral fractures were assessed. Incident clinical fractures were recorded as adverse events. RESULTS Baseline characteristics were comparable with those in HORIZON and between groups. After 36 months, BMD was significantly higher in women treated with ZOL vs. PLB at LS, FN, TH, and T-EPI (+7.6%, +3.7%, +5.6%, and +5.5%, respectively, p<0.01 for all) but not T-DIA (+1.1%). The number of patients with ≥1 incident non-vertebral or morphometric fracture did not differ between groups (9 ZOL/11 PLB). Mean changes in BMD did not differ between groups with and without incident fracture, except that women with an incident non-vertebral fracture had significantly higher bone loss at predominantly cortical T-DIA (p=0.005). CONCLUSION ZOL was significantly superior to PLB at T-EPI but not at T-DIA. Women with an incident non-vertebral fracture experienced bone loss at T-DIA.

Border tax adjustments: Can energy and carbon taxes be adjusted at the border?

Will die Schweiz mit unilateralen energie- und klimapolitischen Massnahmen ambitionierte Ziele verfolgen, dann erfahren energieintensive Sektoren Nachteile im internationalen Wett- bewerb. Produktionsverlagerungen und „carbon leakage“ sind die Folgen, was nicht im Sinne der Schweizer Wirtschaft und der globalen Klimaziele ist. Mit Grenzausgleichsmassnahmen (BAM) kann die Schweiz ihre energieintensiven Betriebe nicht vor internationalen Wettbe- werbsnachteilen schützen. Weiter kommt hinzu, dass die Einführung von BAM aus rechtli- cher Sicht „riskant“ ist und bei einem Schweizer Alleingang mit hohen Vollzugshürden ge- rechnet werden muss. Für die Schweiz macht eine Einführung von BAM nur im Rahmen ei- ner grösseren Klimakoalition Sinn (bspw. zusammen mit der EU). Alternativen zu BAM sind die einfacher und autonom umsetzbaren Ausnahmeregelungen für energieintensive Betriebe oder Output-based-allocation-Systeme.

The Determinants of Personal Income Tax Progressivity Around the Globe

This paper utilizes a novel database collected by the authors to document features of the progressivity of personal income tax systems across 209 countries for the years 1980-2009. We measure progressivity in several ways. First, we associate it with the increase in effective average (marginal) tax rates between a wage of zero and ten times the average wage in a country. Second, we consider the curvature of the tax schedule expressed as the difference between the effective average (marginal) tax schedule from a wage of zero to ten times the average wage and a linear average tax schedule and, alternatively, the diference between the effective average (marginal) tax schedule from the minimum positive taxable income, to ten times the average wage as opposed to a linear average tax schedule. Moreover, the paper assesses patterns regarding the conditional correlation of country-specifc tax progressivity measures with a host of economic and political country-specific characteristics and find the labor supply elasticity and the income replacement rates for the unemployed to be key determinants of progressivity around the globe, in line with economic theory.

Second-Personal Reasons and Special Obligations

The paper discusses the second-personal account of moral obligation as put forward by Stephen Darwall. It argues that on such an account, an important part of our moral practice cannot be explained, namely special obligations that are grounded in special relationships between persons. After highlighting the problem, the paper discusses several strategies to accommodate such special obligations that are implicit in some of Darwall’s texts, most importantly a disentanglement strategy and a reductionist strategy. It argues that neither one of these strategies is entirely convincing. The last part of the papers sketches a novel account of how to accommodate special obligations in a second-personal framework: According to this suggestion, special obligations might be due to the fact that relationships change the normative authority that persons have over each other.