An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Háztáji tehén- és kecsketejek kémiai összetételének összehasonlítása

A szakdolgozatom központi témája a tehéntej és a kecsketej beltartalmi paramétereinek összehasonlítása. Vizsgálataim kiterjedtek a tejek nyers illetve forralt állapotára is. A változatosság jegyében a tejek két különböző országból, Magyarországból és Romániából származtak. Igyekeztem a tejek legfontosabb beltartalmi mutatóit számszerűsíteni, ezért a dolgozatban megtekinthetőek az általam vizsgált tejek szárazanyag-tartalmának, fehérje (nyersfehérje, kazein, albumin), tejzsír, tejcukor, makro- és mikroelem tartalmainak kimutatása. Szakdolgozatom főleg azok számára hasznos, akik hozzám hasonlóan, családi háztartásból vásárolnak nyerstejet, amit otthon felforralás után fogyasztanak és használnak fel.BSc/BAÉlelmiszermérnök

Gender Equality and Constitutional Interpretation

Hungary’s Constitution, adopted in 1949, provided for the equality of men and women, and its amended version of 1989, which facilitated the country’s accession to the Council of Europe and to the European Union, also included this principle. Political processes, however, have always featured male dominance, and women’s movements have not been influential enough to combat this. The principle of formal equality between men and women is virtually fully respected at the higher levels of legislation, but since affirmative measures for women have always been allowed constitutionally, this situation resulted in several constitutional disputes initiated by men claiming that women were overprivileged. This chapter highlights the fact that alleged instances of discrimination against men have dominated the constitutional interpretation related to gender equality since the political transition of 1989–1990, accompanied by the vague argumentation of the Constitutional Court. As for gender politics, since 2010 the government has committed itself to family mainstreaming rather than gender mainstreaming. The primary objective of family policies is to increase the fertility rates of middle-class women. However, these policies may ultimately not promote a work-life balance for the target group; moreover, this approach may have intersectional implications, as it tends to encourage the fertility of “white” (i.e., non-Roma) women

THE ROLE OF THE CORPORATE MANAGEMENT IN THE CRISIS MANAGEMENT IN BUILDING INDUSTRY

Hungary was reached by the great depression in 2008. The 5-year crisis has not left the building

A comment on Herzog, Baron, and Gibbons (2022)

Herzog, Baron, and Gibbons (2022) explore the effects of exposure to official elite rhetoric and group cues on public support against the international nuclear weapons prohibition norm. The authors find that elite cues, in particular security and institutional cues, increase individuals' opposition to the Treaty on the Prohibition of Nuclear Weapons (TPNW). However, elite cues do not seem to have an effect on changing individuals' broader attitudes towards nuclear weapons, as measured by individuals' existing opposition to nuclear arms. We replicate and expand the authors' methods and results to test the robustness of the effects found in the study. First, we reproduce the main finding using the authors' original data and method. We do not find any coding errors that undermine the authors' analysis or conclusions. Second, we test the robustness of the results by (1) using a different operationalization of party identity, and (2) calculating additional subgroup analysis for gender. We find no significant differences between our replicated and the original results, however females' support for the TPNW is more responsive to security cues, while males' support is more responsive to institutions cues.This paper received a response: Herzog, Stephen, Jonathon Baron, and Rebecca Davis Gibbons. Gender Analysis and the Treaty on the Prohibition of Nuclear Weapons: A Response to Daarstad, Park, and Balogh. I4R Discussion Paper Series No. 98. Institute for Replication

A covalent strategy to target intrinsically disordered proteins: Discovery of novel tau aggregation inhibitors

Intrinsically disordered proteins (IDPs) play important roles in disease pathologies; however, their lack of defined stable 3D structures make traditional drug design strategies typically less effective against these targets. Based on promising results of targeted covalent inhibitors (TCIs) on challenging targets, we have developed a covalent design strategy targeting IDPs. As a model system we chose tau, an endogenous IDP of the central nervous system that is associated with severe neurodegenerative diseases via its aggregation. First, we mapped the tractability of available cysteines in tau and prioritized suitable warheads. Next, we introduced the selected vinylsulfone warhead to the non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders were synthesized and tested in aggregation models, and inhibited tau aggregation effectively. Our results revealed the usefulness of the covalent design strategy against therapeutically relevant IDP targets and provided promising candidates for the treatment of tauopathies