Do Political Protests Matter? Evidence from the Tea Party Movement

Can protests cause political change, or are they merely symptoms of underlying shifts in policy preferences? We address this question by studying the Tea Party movement in the United States, which rose to prominence through coordinated rallies across the country on Tax Day, April 15, 2009. We exploit variation in rainfall on the day of these rallies as an exogenous source of variation in attendance. We show that good weather at this initial, coordinating event had significant consequences for the subsequent local strength of the movement, increased public support for Tea Party positions, and led to more Republican votes in the 2010 midterm elections. Policy making was also affected, as incumbents responded to large protests in their district by voting more conservatively in Congress. Our estimates suggest significant multiplier effects: an additional protester increased the number of Republican votes by a factor well above 1. Together our results show that protests can build political movements that ultimately affect policy making and that they do so by influencing political views rather than solely through the revelation of existing political preference

Nitrification and growth of autotrophic nitrifying bacteria and Thaumarchaeota in the coastal North Sea

Nitrification and the associated growth of autotrophic nitrifiers, as well as the contributions of bacteria and Thaumarchaeota to total autotrophic C-fixation by nitrifiers were investigated in the Dutch coastal North Sea from October 2007 to March 2008. Rates of nitrification were determined by incubation of water samples with ¹⁵N-ammonium and growth of autotrophic nitrifiers was measured by incubation with ¹³C-DIC (dissolved inorganic carbon) in the presence and absence of nitrification inhibitors (nitrapyrin and chlorate) in combination with compound-specific stable isotope (¹³C) analysis of bacterial and Thaumarchaeotal lipid biomarkers. Net nitrification during the sampling period was evident from the concentration dynamics of ammonium, nitrite and nitrate. Measured nitrification rates were high (41–221 nmol N L^-1 h^-1). Ammonium assimilation was always substantially lower than nitrification – with nitrification on average contributing 89% (range 73–97%) to total ammonium consumption.¹³C-DIC fixation into bacterial and Thaumarchaeotal lipids was strongly reduced by the nitrification inhibitors (27–95 %). The inhibitor-sensitive ¹³C-PLFA (phospholipid-derived fatty acid) pool was dominated by the common PLFAs 16:0, 16:1?7c and 18:1?7c throughout the whole sampling period and occasionally also included the polyunsaturated fatty acids 18:2?6c and18:3?3. ¹³C-DIC fixation activity of the nitrifying bacteria was much higher than that of the nitrifying Thaumarchaeota throughout the whole sampling period, even during the peak in Thaumarchaeotal abundance and activity. This suggests that the contribution of autotrophic Thaumarchaeota to nitrification during winter in the coastal North Sea may have been smaller than expected from their gene abundance (16S rRNA and <i>amoA</i> (ammonia monooxygenase)). These results emphasize the importance of direct measurements of the actual activity of bacteria and Thaumarchaeota, rather than abundance measurements only, in order to elucidate their biogeochemical importance. The ratio between rates of nitrification versus DIC fixation by bacterial nitrifiers was higher or even much higher than typical values for autotrophic nitrifiers, indicating that little DIC was fixed relative to the amount of energy that was generated by nitrification

Economic Policy in a More Uncertain World

The Aspen Economic Strategy Group's Annual Policy Volume Economic Policy in a More Uncertain World marks the group's 5th anniversary and is released against a backdrop historic economic and strategic uncertainty. The book's seven chapters, each written by leading experts and edited by AESG Director Melissa S. Kearney and Deputy Director Amy Ganz, provide a deep-dive on long-term economic headwinds confronting the country, including demographic changes—declining fertility and population aging—and what a smaller worker to population ratio means in terms of slower economic growth, reduced revenue, and lower productivity growth. Additional chapters on the US immigration system and US innovation policy highlight potential solutions for countering these trends.  Another chapter explores potential adverse impacts on local labor markets from the green energy transition and highlights policies to avoid repeating painful mistakes of the past, including the response to the decline of the coal industry and rise of globalization and automation. A final chapter highlights lessons learned from the unprecedented federal aid to state and local governments during the COVID-19 pandemic

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 μM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg−1, NU7026 underwent rapid plasma clearance (0.108 l h−1) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg−1 was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg−1 i.p. in order to obtain the drug exposure required for radiosensitisation

Identification of novel peptide motifs in the serpin maspin that affect vascular smooth muscle cell function

Maspin is a non-inhibitory member of the serpin family that affects cell behaviours related to migration and survival. We have previously shown that peptides of the isolated G α-helix (G-helix) domain of maspin show bioactivity. Migration, invasion, adhesion and proliferation of vascular smooth muscle cells (VSMC) are important processes that contribute to the build-up of atherosclerotic plaques. Here we report the use of functional assays of these behaviours to investigate whether other maspin-derived peptides impact directly on VSMC; focusing on potential anti-atherogenic properties. We designed 18 new peptides from the structural moieties of maspin above ten amino acid residues in length and considered them beside the existing G-helix peptides. Of the novel peptides screened those with the sequences of maspin strand 4 and 5 of beta sheet B (S4B and S5B) reduced VSMC migration, invasion and proliferation, as well as increasing cell adhesion. A longer peptide combining these consecutive sequences showed a potentiation of responses, and a 7-mer contained all essential elements for functionality. This is the first time that these parts of maspin have been highlighted as having key roles affecting cell function. We present evidence for a mechanism whereby S4B and S5B act through ERK1/2 and AMP-activated protein kinase (AMPK) to influence VSMC responses

ATM regulates proteasome-dependent subnuclear localization of TRF1, which is important for telomere maintenance

Ataxia telangiectasia mutated (ATM), a PI-3 kinase essential for maintaining genomic stability, has been shown to regulate TRF1, a negative mediator of telomerase-dependent telomere extension. However, little is known about ATM-mediated TRF1 phosphorylation site(s) in vivo. Here, we report that ATM phosphorylates S367 of TRF1 and that this phosphorylation renders TRF1 free of chromatin. We show that phosphorylated (pS367)TRF1 forms distinct non-telomeric subnuclear foci and that these foci occur predominantly in S and G2 phases, implying that their formation is cell cycle regulated. We show that phosphorylated (pS367)TRF1-containing foci are sensitive to proteasome inhibition. We find that a phosphomimic mutation of S367D abrogates TRF1 binding to telomeric DNA and renders TRF1 susceptible to protein degradation. In addition, we demonstrate that overexpressed TRF1-S367D accumulates in the subnuclear domains containing phosphorylated (pS367)TRF1 and that these subnuclear domains overlap with nuclear proteasome centers. Taken together, these results suggest that phosphorylated (pS367)TRF1-containing foci may represent nuclear sites for TRF1 proteolysis. Furthermore, we show that TRF1 carrying the S367D mutation is unable to inhibit telomerase-dependent telomere lengthening or to suppress the formation of telomere doublets and telomere loss in TRF1-depleted cells, suggesting that S367 phosphorylation by ATM is important for the regulation of telomere length and stability

Essential Factors for Incompatible DNA End Joining at Chromosomal DNA Double Strand Breaks In Vivo

Non-homologous end joining (NHEJ) is a major pathway for the repair of DNA double strand break (DSBs) with incompatible DNA ends, which are often generated by ionizing irradiation. In vitro reconstitution studies have indicated that NHEJ of incompatible DNA ends requires not only the core steps of synapsis and ligation, employing KU80/DNA-PKcs and LIG4, but also additional DNA end processing steps, such as DNA end resection by Artemis and gap-filling by POLλ and POLμ. It seems that DNA end processing steps are important for joining of incompatible DNA ends rather than compatible ends. Despite the fact that DNA end processing is important for incompatible DNA end joining in vitro, the role of DNA processing in NHEJ of incompatible DSBs in vivo has not yet been demonstrated. Here we investigated the in vivo roles of proteins implicated in each step of NHEJ using an assay in which NHEJ of incompatible DNA ends on chromosomal DNA can be assessed in living human cells. siRNA- or inhibitor-mediated impairment of factors in each NHEJ step resulted in a reduction in joining efficiency. Strikingly, stronger effects were observed when DNA end resection and ligation protein functions were impaired. Disruption of synapsis by KU80 and DNA-PKcs impairment, or the disruption of gap filling by POLλ and POLμ depletion, resulted in higher levels of microhomology-mediated joining. The present study indicates that DNA end resection and ligation factors are critical for the efficient joining of incompatible ends in vivo, further emphasizing the importance of synapsis and gap-filling factors in preventing illegitimate joining