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Here Christina Wolbrecht boldly demonstrates how the Republican and Democratic parties have helped transform, and have been transformed by, American public debate and policy on women's rights. She begins by showing the evolution of the positions of both parties on women's rights over the past five decades. In the 1950s and early 1960s, Republicans were slightly more favorable than Democrats, but by the early 1980s, the parties had polarized sharply, with Democrats supporting, and Republicans opposing, such policies as the Equal Rights Amendment and abortion rights. Wolbrecht not only traces the development of this shift in the parties' relative positions--focusing on party platforms, the words and actions of presidents and presidential candidates, and the behavior of the parties' delegations in Congress--but also seeks to explain the realignment. The author considers the politically charged developments that have contributed to a redefinition and expansion of the women's rights agenda since the 1960s--including legal changes, the emergence of the modern women's movement, and changes in patterns of employment, fertility, and marriage. Wolbrecht explores how party leaders reacted to these developments and adopted positions in ways that would help expand their party's coalition. Combined with changes in those coalitions--particularly the rise of social conservatism within the GOP and the affiliation of social movement groups with the Democratic party--the result was the polarization characterizing the parties' stances on women's rights today.

A generation ago, scholars saw interest groups as the single most important element in the American political system. Today, political scientists are more likely to see groups as a marginal influence compared to institutions such as Congress, the presidency, and the judiciary. Frank Baumgartner and Beth Leech show that scholars have veered from one extreme to another not because of changes in the political system, but because of changes in political science. They review hundreds of books and articles about interest groups from the 1940s to today; examine the methodological and conceptual problems that have beset the field; and suggest research strategies to return interest-group studies to a position of greater relevance. The authors begin by explaining how the group approach to politics became dominant forty years ago in reaction to the constitutional-legal approach that preceded it. They show how it fell into decline in the 1970s as scholars ignored the impact of groups on government to focus on more quantifiable but narrower subjects, such as collective-action dilemmas and the dynamics of recruitment. As a result, despite intense research activity, we still know very little about how groups influence day-to-day governing. Baumgartner and Leech argue that scholars need to develop a more coherent set of research questions, focus on large-scale studies, and pay more attention to the context of group behavior. Their book will give new impetus and direction to a field that has been in the academic wilderness too long.

Is it ever legitimate to redraw electoral districts on the basis of race? In its long struggle with this question, the U.S. Supreme Court has treated race-conscious redistricting either as a requirement of political fairness or as an exercise in corrosive racial quotas. Cutting through these contradictory positions, Keith Bybee examines the theoretical foundations of the Court's decisions and the ideological controversy those decisions have engendered. He uncovers erroneous assumptions about political identity on both sides of the debate and formulates new terms on which minority representation can be pursued. As Bybee shows, the Court has for the last twenty years encouraged a division between individualist and group concepts of political identity. He demonstrates convincingly that both individualist and group proponents share the misguided notion that political identity is formed prior to and apart from politics itself. According to Bybee, this \"mistaken identity\" should be abandoned for a more flexible, politically informed understanding of who the \"people\" really are. Thus, a misdirected debate will be replaced by a more considered discussion in which the people can speak for themselves, even as the Court speaks on their behalf. Engaged in the politics of minority representation, the Court will be able to help citizens articulate and achieve more fruitful forms of political community.

Describes Italy as an \"ideal type\" for the presidentialization of a political system. Although the changing role of the state has contributed to the presidentialization of Italy's political system, greater attention is given to the crucial role played by the deterioration of traditional social cleavage politics & the media's proactive campaign for institutional reform. Although these elements came to a head during the 1990s, the process toward presidentialization has been under way in the executive arena for more than 20 years. The gradual strengthening of the executive; the emergence of prime ministerial dominance; the movement for electoral reform; & the shift from a partified to a presidentialized polity are described. A stronger executive, together with a media-dominated political arena & the new electoral law, resulted in a majoritarian form of politics that was unlike anything the reformers expected. However, it is concluded that the trend towards presidentialization in Italy does not necessarily indicate that a definite regime change has occurred. Prospects for the future are discussed. 40 References. J. Lindroth

After a decade of crisis management, the democratic implications of emergency modes of governance in the European Union (EU) are under the spotlight. The prevailing analysis is critical. Scholars point to an emergent, distinctly European trend of transnational crisis exploitation where elite appeals to exceptional pressures serve asymmetric power and influence, overriding democratic norms and potentially fuelling Eurosceptic backlash. However, the literature does not ask whether citizens consider themselves disempowered by the EU’s emergency politics, with its alleged emphasis on urgency and technocratic problem-solving. The relative symmetry and simultaneity of the Covid-19 crisis across Europe offers an opportunity for an empirical examination of public opinion on traits of emergency politics. We juxtapose the implications of emergency politics for public opinion with the transnational cleavages literature and use survey data from 15 member states on EU- and national-level pandemic responses to examine the competing hypotheses. Our findings indicate perceptions of crisis management are largely determined by prior views on EU integration and democracy. More generally, the results suggest that the transnational cleavage remains overall a key driver and delimiter of Euroscepticism in crisis times. Though there is some variance between emergency politics dimensions, we do not detect a widespread perception of disillusionment motivated by EU emergency rule.

Background The accumulation of amyloid‐β (Aβ) in the form of neurotoxic aggregates is widely recognized as a central pathological hallmark in Alzheimer’s disease (AD). Recent progress in immunotherapeutic strategies has validated the efficacy of Aβ clearance in treating Alzheimer’s disease, thereby establishing Aβ deposits as a promising target for therapeutic intervention. Given the numerous reports emphasizing the importance of sulfonic acid group in targeting Aβ, we aim to synthesize sulfonated trimer peptides for later evaluation of therapeutic efficacy. Method Trimer peptides were synthesized via standard Fmoc‐based solid‐phase peptide synthesis (SPPS). After the completion of synthesis of trimer, global deprotection and cleavage from the resin were performed using trifluoroacetic acid (TFA) to release the peptides. Following peptide synthesis, O‐sulfonation of the serine hydroxyl group was carried out using chlorosulfonic acid as the sulfonating agent. Then, the sulfonated trimer peptides were purified using reverse‐phase high‐performance liquid chromatography (RP‐HPLC). Result A total of 27 sulfonated trimer peptides were rationally designed and successfully synthesized. The library included trimers containing sulfonated serine at different positions. The peptides were synthesized with an average crude yield of approximately 50%. Subsequently, all peptides were purified using reverse‐phase high‐performance liquid chromatography (RP‐HPLC), yielding final products with an average purity of approximately 90%. Conclusion As a result, a total of 27 sulfonated trimer peptides were successfully synthesized and purified. Through subsequent efficacy validation of the synthesized trimer peptides, the essential contribution of sulfonation to amyloid‐β targeting will be elucidated.

Background Tau abnormalities are central to AD and non‐AD tauopathies, including FTD and PSP. Several tau antibodies tested through Phase 2 have not demonstrated clinical benefit. Potential explanations include affinities too weak for effective target engagement and lack of specificity for toxic species driving pathogenesis. By contrast, the humanized monoclonal antibody TBL‐100 targets tauC3, a C‐terminal tau fragment truncated at Asp421, with picomolar affinity and 1000X specificity vs full‐length tau (FLT). TauC3 is highly toxic and has been implicated in multiple aspects of tau pathology. It is also highly enriched in tau oligomers, which arguably drive spreading of pathology. We previously reported that tauC3 is predicted to have a more open conformation than FLT, the microtubule binding region (MTBR) of which is partially buried. Exposure of the MTBR and the phosphatase activating domain in tauC3 could facilitate oligomerization and impair axonal transport, respectively. To understand TBL‐100 binding, we asked whether it binds an epitope inaccessible in FLT or a neoepitope created by cleavage of a peptide bond at Asp421. Method Affinities of TBL‐100 for recombinant tauC3 monomers (in 4M urea) and oligomers (produced by AF‐488‐maleimide conjugation) were determined by ELISA. Plates were coated with tauC3 and, following washing and blocking, treated with TBL‐100 (or the tau oligomer‐selective antibody TOC1) and HRP‐coupled secondary antibody. Synthetic tau peptide affinities were determined by direct or competition surface plasmon resonance. TBL‐100 was passed over immobilized tauC3 at increasing peptide concentrations. For ELISA, TBL‐100 was immobilized and peptides were titrated with tauC3, which was detected using Tau‐13‐HRP. Result By SPR and ELISA, TBL‐100 preferentially bound the tauC3 sequence ending in Asp421, with >100‐fold weaker and negligible binding to peptides containing one and five additional C‐terminal amino acids, respectively. TBL‐100 bound both monomeric and oligomeric tauC3 with similar low picomolar KDs, but did not bind FLT. Conclusion TBL‐100 has exquisite end specificity for tau cleaved at Asp421 (tauC3). It bound oligomeric tauC3 with the same high affinity as it bound monomeric tauC3, supporting TBL‐100’s potential to interrupt oligomer‐driven spreading of pathology. TBL‐100’s high affinity and specificity for pathogenic tau support its development as a treatment for tauopathies.

Background Alzheimer's disease (AD) pathology involves the accumulation of amyloid‐beta (Aβ) peptides into senile plaques generated by Amyloid Precursor Protein (APP) cleavage by β‐secretases. When APP is cleaved by ADAM10 instead, neuroprotective fragments are released. ADAM10 possesses three isoforms: a zymogen (proADAM10), a proteolytically active mature (mADAM10), and a soluble (sADAM10) isoform. Our group has shown that sADAM10 levels and activity are altered in the plasma of persons with AD. Thus, we aimed to investigate the levels and activity of ADAM10 isoforms in neuron‐like cells to understand their central functioning. Methods SH‐SY5Y cells were differentiated into neuron‐like cells using retinoic acid. The media was collected, and the cells were fractionated into cytoplasmic, membrane‐ bound, and nuclear protein‐rich portions. Western blotting (WB) experiments were performed on each fraction to detect ADAM10 isoforms and assess fraction purity using anti‐GAPDH (cytoplasm), anti‐VDAC (membranes), and anti‐Lamin A/C (nuclei) antibodies. Antibodies targeting the N‐terminal and C‐terminal regions of ADAM10 were used to detect the soluble and membrane‐bound isoforms, respectively. Additionally, enzymatic activity assays were conducted. Results The characterization of the fractioning process and preliminary results of the activity assays show feeble sADAM10 activity in the cell medium, compared to mADAM10 in the membrane and cytoplasm fractions and recombinant ADAM10 (p < 0.001). Conclusion These preliminary results show that sADAM10 has feeble activity in neuron‐like cells, which agrees with our previous findings, validating the potential use of plasma ADAM10 as a blood‐based AD biomarker. Funding: São Paulo Research Foundation (FAPESP) grants #2023/00449‐0; #2023/18020‐0 and 2021/01863‐9

Background Brain‐derived neurotrophic factor (BDNF) is an important mediator of neuronal function and survival. BDNF levels are elevated in post‐exercise serum extracted from human donors, and we and others have shown that both post‐exercise serum and BDNF alone reduce β‐cleavage of APP within 2 hours of treatment, but the mechanism for this remains unknown. Several other groups have shown that the subcellular location of APP and BACE1 influences APP processing, with α‐cleavage occurring preferentially at the plasma membrane, and β‐cleavage at acidic intracellular compartments, such as endosomes and lysosomes. Method Human neuroblastoma cells (SH‐SY5Y) were differentiated for 7 days with 10µM all‐trans retinoic acid. Cells were treated with 75ng/mL BDNF or vehicle control (DMEM/F‐12) for 2 hours as performed previously, and subsequently imaged live via spinning‐disk confocal fluorescence microscopy or collected for Western blotting. Antibodies against sAPPα, sAPPβ, and full‐length APP were used to assess changes in APP cleavage. For live imaging experiments, cells were transfected using Lipofectamine 3000 24 hours prior to treatment with combinations of fluorescently tagged BACE1 (BACE1‐GFP, BACE1‐mScarlet) and subcellular compartment‐specific markers (YFP‐CAAX, mScarlet‐EEA1, LAMP1‐RFP). Result Compared to vehicle control, BDNF‐treated cells show a reduction in sAPPβ levels and an increase in the ratio of sAPPα/sAPPβ as measured by Western blot. BDNF treatment also increases colocalization of BACE1 with the plasma membrane marker CAAX and decreases BACE1 colocalization with endosomal marker EEA1. Both phosphorylated BACE1 (Ser498) and BACE1 colocalization with lysosomal marker LAMP1 is unchanged following BDNF treatment. Pretreatment of cells with clathrin‐mediated endocytosis inhibitor PitStop2 (20µM) for 10 minutes prior to BDNF treatment shows increased sAPPα cleavage, but no effect on sAPPβ levels. Conclusion Acute treatment with BDNF may decrease β‐cleavage of APP by altering the subcellular distribution of BACE1, increasing recruitment/retention of BACE1 at the plasma membrane and decreasing BACE1 endocytosis. This effect appears to be independent of clathrin‐mediated endocytosis, as PitStop2 treatment increases α‐cleavage of APP but does not reduce β‐cleavage independent of BDNF treatment. Hence, BDNF may reduce production of Aβ by altering BACE1 distribution, decreasing upstream β‐cleavage.

Background Signal peptidyl peptidase 2b (SPPL2b) is an intramembrane peptidase, from the same family of presenilins, and is predominantly expressed in the brain. SPPL2b is involved in the cleavage of various transmembrane proteins linked to the pathophysiology of Alzheimer's disease (AD), such as BRI2, TNFα, Cleac7a, and TMEM106B. Recently, we demonstrated that SPPL2b inhibition reduces the processing of amyloid precursor protein (APP), resulting in decreased production of amyloid‐beta 42 (Aβ42) and amyloid‐beta 40 (Aβ40). In this study, we aimed to explore the therapeutic potential of SPPL2b by deleting the SPPL2b gene in the AppNL‐G‐F knock‐in AD mouse model, and we aimed, since no specific inhibitors of SPPL2b currently exist, to identified potential SPPL2b inhibitory compounds through in silico screening. Method To investigate the therapeutic potential of SPPL2b inhibition, we developed a novel AD mouse model by crossbreeding AppNL‐G‐F knock‐in mice with SPPL2b‐deficient mice. Brain samples from these mice were analyzed using western blotting, immunofluorescence, and Golgi staining. To identify potential inhibitors of SPPL2b we screened the Vitas‐M commercial library. Result We observed a significant reduction in Aβ plaque deposition in the brains of SPPL2b knockout (KO) / AppNL‐G‐F mice at both 4 and 12 months of age. Additionally, cortical and hippocampal gliosis were markedly reduced in these mice (Figure 1). At 12 months, Golgi staining analysis showed that SPPL2b deletion protected against synaptic loss in AppNL‐G‐F mice, as evidenced also by the rescue of the postsynaptic density marker PSD95 in SPPL2b KO / AppNL‐G‐F mice. Moreover, a decrease in phospho‐tau intensity was observed. Importantly, we have identified 100 potential SPPL2b inhibitory compounds. Conclusion Our findings underline the critical role of SPPL2b in the development of Aβ pathology in AD. In a global context where innovative strategies to prevent and mitigate AD progression are urgently needed, this study highlights SPPL2b as a promising therapeutic target. Futhermore, the identified compounds are now undergoing in vitro evaluation and the most promising inhibitors will be tested in vivo to assess their effects on AD pathology.