Miracle-dz/UniFAR-FTUs huggingface dataset:
Population genomics of the honey bee reveals strong signatures of positive selection on worker traits

Significance Most hypotheses explaining the evolution of sociality in insects assume that positive selection drives the evolution of worker traits. Yet we know little about the extent of natural selection acting on social insects. We produced a map of positive selection for the honey bee through analysis of 40 individual genomes. We found strong evidence of positive selection acting on genes and regulatory sequences, and we discovered that mutations in worker-biased proteins tend to have greater fitness effects than mutations in queen-biased proteins. We also found many instances of positive selection acting on genes that influence worker traits, suggesting that worker phenotypes represent a major vector for adaptation in social insects. Most theories used to explain the evolution of eusociality rest upon two key assumptions: mutations affecting the phenotype of sterile workers evolve by positive selection if the resulting traits benefit fertile kin, and that worker traits provide the primary mechanism allowing social insects to adapt to their environment. Despite the common view that positive selection drives phenotypic evolution of workers, we know very little about the prevalence of positive selection acting on the genomes of eusocial insects. We mapped the footprints of positive selection in Apis mellifera through analysis of 40 individual genomes, allowing us to identify thousands of genes and regulatory sequences with signatures of adaptive evolution over multiple timescales. We found Apoidea- and Apis-specific genes to be enriched for signatures of positive selection, indicating that novel genes play a disproportionately large role in adaptive evolution of eusocial insects. Worker-biased proteins have higher signatures of adaptive evolution relative to queen-biased proteins, supporting the view that worker traits are key to adaptation. We also found genes regulating worker division of labor to be enriched for signs of positive selection. Finally, genes associated with worker behavior based on analysis of brain gene expression were highly enriched for adaptive protein and cis-regulatory evolution. Our study highlights the significant contribution of worker phenotypes to adaptive evolution in social insects, and provides a wealth of knowledge on the loci that influence fitness in honey bees.
Preclinical Assessment of the Absorption and Disposition of the Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor GDC-0980 and Prediction of Its Pharmacokinetics and Efficacy in Human

(S)-1-{4-[2-(2-Amino-pyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazin-1-yl}-2-hydroxy-propan-1-one (GDC-0980) is a potent and selective inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin, two key components of the PI3K pathway, the deregulation of which is associated with the development of many cancers. The objectives of these studies were to characterize the absorption and disposition of GDC-0980 and assess its efficacy in an MCF7-neo/HER2 human breast cancer xenograft model in immunocompromised mice. Studies in parental Madin-Darby canine kidney cells indicated that GDC-0980 had high permeability (Papp = 18 × 10−6 cm/s), suggesting good absorption potential. However, it was found to be a P-glycoprotein and breast cancer resistance protein substrate in transfected cells and in knockout mice studies. Plasma protein binding was low, with the fraction unbound ranging from 29 to 52% across species. GDC-0980 hepatic clearance (CL) was predicted to be low in all of the species tested from hepatocyte incubations. The plasma CL of GDC-0980 was low in mouse (6.30 ml · min−1 · kg−1), rat (15.4 ml · min−1 · kg−1), and dog (6.37 ml · min−1 · kg−1) and moderate in cynomolgus monkey (18.9 ml · min−1 · kg−1). Oral bioavailability ranged from 14.4% in monkey to 125% in dog. Predicted human plasma CL and volume of distribution using allometry were 5.1 ml · min−1 · kg−1 and 1.8 l/kg, respectively. Parameters estimated from the pharmacokinetic/pharmacodynamic modeling of the MCF7-neo/HER2 xenograft data indicated that the GDC-0980 plasma concentration required for tumor stasis was approximately 0.5 μM. These parameters, combined with the predicted human pharmacokinetic profile, suggested that 55 mg once daily may be a clinically efficacious dose. GDC-0980 preclinical characterization and the predictions of its human properties supported its clinical development; it is currently in Phase II clinical trials.
A light in dark times : Maxine Greene and the unfinished conversation

"A Light in Dark Times" features a list of contributors who have been deeply influenced by Professor Greene's progressive philosophies. While Maxine Greene is the focus for this collection, each chapter is an encounter with her ideas by an educator concerned with his or her own works and projects. In essence, each featured author takes off from Maxine Greene and then moves forward. This collection of essays should - as Maxine Greene has - influence a wide range of worlds: arts and aesthetics, literature and literacy studies, cultural studies, school change and improvement, the teaching of literacy, teacher education, philosophy of education, peace and social justice, women's studies and civil rights. Contributors include: William Ayers; Jean Anyon and Louise Berman; Leon Botstein; Deborah P. Britzman; Linda Darling-Hammond; Karen Ernst; Michelle Fine; Norm Fruchter; Madeleine R. Grumet; Sandra Hollingsworth; Mary-Ellen Jacobs; Herbert Kohl; Wendy Kohli; Craig Kridel; Peter McLaren; Maureen Miletta; Janet L. Miller; Sonia Nieto; Nel Noddings; Jo Anne Pagano; Frank Pignatelli; William F. Pinar; Kathleen Reilly; Jonathan G. Silin; Sheila Slater; Candy Systra; Carlos Alberto Torres; and Mark Weiss.
Symposium II: Idiopathic parkinsonism: From pathohistology to molecular pathology Neurotoxicity of MPTP

was reported. In 1982 several young adults in northern California mysteriously developed a profound parkinsonian syndrome after intravenous use of what was purported to be ‘synthetic heroin’. Assay of the drugs identified 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as the probable toxin. This compound is a by-product in the synthesis of 1-methyl-4-phenyl-4-propionoxypiperidine (MPPP), a potent meperidine analog.
Antisense‐Induced Reduction of Presenilin 1 Expression Selectively Increases the Production of Amyloid β42 in Transfected Cells

Abstract : Autosomal dominant mutations in the presenilin 1 (PS1) gene are associated with familial, early‐onset Alzheimer's disease. Although the pathogenic mechanism of these mutations is unclear, their common feature is that they lead to an increased concentration of amyloid β‐peptide (Aβ) 42 in the plasma of early‐onset patients, in the conditioned media of transfected cells, and in the brains of transgenic mice that overexpress mutant PS1. To address the mechanism(s) by which the pathogenic PS1 mutations increase Aβ42, we constructed human cell lines expressing a doxycyclin (dox)‐inducible antisense PS1 RNA and measured its effects on the levels of PS1, amyloid precursor protein (APP), and Aβ. In time course experiments, we observed a statistically significant (p = 0.0038) more than twofold elevation in secreted Aβ42 as early as 12 days after addition of dox. This correlated with an 80% decrease in the 46‐kDa PS1 holoprotein and a 30% decrease in the 26‐kDa N‐terminal fragment (NTF). Furthermore, there was a significant fivefold (p = 0.002) increase in Aβ42 after 14‐day dox treatment ; this correlated with a >90% decrease in PS1 holoprotein and 60% decrease in NTF. At no time point did we observe significant changes in Aβ40, APP holoprotein, presenilin 2, or tubulin. Ten days after the removal of dox, we observed a return to constitutive levels for Aβ42, PS1 holoprotein, and NTF. These results suggest that in human cell lines, the reduction of normal PS1 activity results in the increased production of Aβ42. Furthermore, our results are consistent with a loss of function or dominant negative mechanism for the pathogenic PS1 mutations.
Active reduction of audible noise exciting radial force-density waves in induction motors

This paper presents an approach to the active reduction of radial force-density waves. Additional flux-density waves are generated by the injection of additional and particular low-power current harmonics. With these flux-density waves a force-density countershaft to an acoustic annoying radial force density wave is generated. In this contribution a mathematical model to estimate the amplitude, frequency and phase shift of the required current harmonic is presented. The prediction of the phase-shift is strongly dependent on saturation effects and on the interaction of the additionally imposed and existing flux-density waves. Therefore, a finite element (FE) experiment set is proposed to increase the accuracy of the analytically predicted phase angle. The active injection of force-density countershafts is performed, analyzed and evaluated. The assessment is performed based on FE simulations. The authors found that the injection of force-density countershafts is applicable for force-density waves with any circumferential oscillation modes and frequency in general. However, the consideration of oscillation modes is limited to r = 0, ±2p, ±3p and ±4p in order to keep the additional losses in the machine within an acceptable limit. The proposed approach is robust concerning the accuracy of the phase shift of the additionally imposed current harmonic.
Changes in phytophagous insect host ranges following the invasion of their community: Long‐term data for fruit flies

Abstract The invasion of an established community by new species can trigger changes in community structure. Invasions often occur in phytophagous insect communities, the dynamics of which are driven by the structure of the host assemblage and the presence of competitors. In this study, we investigated how a community established through successive invasions changed over time, taking the last invasion as the reference. The community included four generalist and four specialist species of Tephritidae fruit flies. We analyzed a long‐term database recording observed numbers of flies per fruit for each species on 36 host plants, over 18 years, from 1991 to 2009. Community structure before the last invasion by Bactrocera zonata in 2000 was described in relation to host plant phylogeny and resource availability. Changes in the host range of each species after the arrival of B. zonata were then documented by calculating diversity indices. The flies in the community occupied three types of niches defined on the basis of plant phylogeny (generalists, Solanaceae specialist, and Cucurbitaceae specialists). After the arrival of B. zonata, no change in the host range of specialist species was observed. However, the host ranges of two generalist species, Ceratitis quilicii and Ceratitis capitata, tended to shrink, as shown by the decreases in species richness and host plant α‐diversity. Our study shows increased host specialization by generalist phytophagous insects in the field following the arrival of an invasive species sharing part of their resources. These findings could be used to improve predictions of new interactions between invaders and recipient communities.
Integrative proteomics and biochemical analyses define Ptc6p as the Saccharomyces cerevisiae pyruvate dehydrogenase phosphatase

The pyruvate dehydrogenase complex (PDC) is the primary metabolic checkpoint connecting glycolysis and mitochondrial oxidative phosphorylation and is important for maintaining cellular and organismal glucose homeostasis. Phosphorylation of the PDC E1 subunit was identified as a key inhibitory modification in bovine tissue ∼50 years ago, and this regulatory process is now known to be conserved throughout evolution. Although Saccharomyces cerevisiae is a pervasive model organism for investigating cellular metabolism and its regulation by signaling processes, the phosphatase(s) responsible for activating the PDC in S. cerevisiae has not been conclusively defined. Here, using comparative mitochondrial phosphoproteomics, analyses of protein–protein interactions by affinity enrichment–mass spectrometry, and in vitro biochemistry, we define Ptc6p as the primary PDC phosphatase in S. cerevisiae. Our analyses further suggest additional substrates for related S. cerevisiae phosphatases and describe the overall phosphoproteomic changes that accompany mitochondrial respiratory dysfunction. In summary, our quantitative proteomics and biochemical analyses have identified Ptc6p as the primary—and likely sole—S. cerevisiae PDC phosphatase, closing a key knowledge gap about the regulation of yeast mitochondrial metabolism. Our findings highlight the power of integrative omics and biochemical analyses for annotating the functions of poorly characterized signaling proteins.
Mycobacterium avium Subspecies paratuberculosis Cultured from Locally and Commercially Pasteurized Cow's Milk in the Czech Republic

ABSTRACT Between November 2002 and April 2003, 244 bottles and cartons of commercially pasteurized cow's milk were obtained at random from retail outlets throughout the Czech Republic. During the same period, samples of raw milk and of milk that was subsequently subjected to a minimum of 71.7°C for 15 s in a local pasteurization unit were also obtained from two dairy herds, designated herds A and B, with low and high levels, respectively, of subclinical Mycobacterium avium subsp. paratuberculosis infection, and from one herd, herd C, without infection. Infection in individual cows in each herd was tested by fecal culturing. Milk samples were brought to the Veterinary Research Institute in Brno, Czech Republic, processed, inoculated onto Herrold's egg yolk slants, and incubated for 32 weeks. Colonies were characterized by morphology, Ziehl-Neelsen staining, mycobactin J dependency, and IS900 PCR results. M. avium subsp. paratuberculosis was cultured from 4 of 244 units (1.6%) of commercially pasteurized retail milk. M. avium subsp. paratuberculosis was also cultured from 2 of 100 (2%) cartons of locally pasteurized milk derived from infected herds A and B and from 0 of 100 cartons of milk from uninfected herd C. Raw milk from 1 of 10 (10%) fecal culture-positive cows in herd A and from 13 of 66 (19.7%) fecal culture-positive cows in herd B was culture positive for M. avium subsp. paratuberculosis. These findings confirm that M. avium subsp. paratuberculosis is present in raw milk from subclinically infected dairy cows. The culture of M. avium subsp. paratuberculosis in the Czech Republic from retail milk that had been pasteurized locally or commercially to the required national and European Union standards is in agreement with similar research on milk destined for consumers in the United Kingdom and the United States and shows that humans are being exposed to this chronic enteric pathogen by this route.
Switching kinetic mechanism and putative proton donor by directed mutagenesis of glutathione reductase.

By directed mutagenesis of the cloned Escherichia coli gor gene encoding the flavoprotein glutathione reductase, Tyr-177 (the residue corresponding to Tyr-197 in the NADPH-binding pocket of the homologous human enzyme) was changed to phenylalanine (Y177F), serine (Y177S), and glycine (Y177G). The catalytic activity of the Y177F mutant was very similar to that of the wild-type enzyme, but that of the Y177S and Y177G mutants was substantially diminished. However, all three mutants retained the ability to protect the reduced flavin from adventitious oxidation, indicating that Tyr-177 does not act as a simple "lid" on the NADPH-binding pocket and that the protection of the reduced enzyme must be due largely to burial of the isoalloxazine ring in the protein. The wild-type enzyme and Y177F mutant displayed ping-pong kinetics, but the Y177S and Y177G mutants appeared to have switched to an ordered sequential mechanism. This could be explained by supposing that the enzyme normally functions by a hybrid kinetic mechanism and that the Y177S and Y177G mutations diverted flux from the ping-pong loop favored by the wild-type enzyme to an ordered sequential loop. The necessary change in the partitioning of the common E-NADPH intermediate could be caused by a slowing of the formation of the EH2 intermediate on the ping-pong loop, or by the observed concomitant fall in the Km for glutathione favoring flux through the ordered sequential loop. In another experiment, His-439, thought to act as a proton donor/acceptor in the glutathione-binding pocket, was mutated to a glutamine residue. (ABSTRACT TRUNCATED AT 250 WORDS)
Optimal PMU Placement Considering Controlled Islanding of Power System

This paper proposes an optimal phasor measurement unit (PMU) placement model considering power system controlled islanding so that the power network remains observable under controlled islanding condition as well as normal operation condition. The optimization objectives of proposed model are to minimize the number of installed PMUs and to maximize the measurement redundancy. These two objectives are combined together with a weighting variable so that the optimal solution with minimum PMU number and maximum measurement redundancy would be obtained from the model. To reduce the number of required PMUs, the effect of zero-injection bus is considered and incorporated into the model. Furthermore, additional constraints for maintaining observability following single PMU failure or line loss are also derived. At last, several IEEE standard systems and the Polish 2383-bus system are employed to test the presented model. Results are presented to demonstrate the effectiveness of the proposed method.
Postoperative Chylous Ascites in Patients With Gynecologic Malignancies

Objective To evaluate the incidence and the effective treatment of postoperative chylous ascites in patients with gynecologic malignancies. Methods In this report, we retrospectively reviewed the cases of 4119 patients who underwent pelvic and/or para-aortic lymph node dissection for gynecologic malignancies in Fudan University Cancer Hospital. Results Among these 4119 cases, 7 (0.17%) patients had chylous ascites postoperatively. The average age of these patients was 52 years. The mean time interval between operation and the appearance of chylous ascites was 30 days (range, 5–75 days). The incidence of chylous ascites after para-aortic lymphadenectomy was approximately 0.32% (5/1540), whereas the rate after pelvic lymphadenectomy alone was 0.077% (2/2579). All cases with chylous ascites were resolved by conservative treatment. This included placement of a peritoneal drainage tube. The mean time to resolution was 13 days (range, 2–28 days). None of the cases had recurrent chylous ascites during follow-up. Conclusions Para-aortic lymph node dissection may be associated with postoperative chylous ascites. Patients may have their chylous ascites successfully treated with conservative management. An abdominal drainage tube can be a simple and effective approach and should be considered in the treatment.
Transgene Rescue Identifies an Essential Function for Drosophila β Spectrin in the Nervous System and a Selective Requirement for Ankyrin-2–binding Activity

The Gal4-UAS system was used to overexpress or knock down β spectrin with dsRNA in a variety of Drosophila tissues. Unexpectedly, overexpression in most tissues tested was lethal, whereas knockdown failed to produce a detectable phenotype in the same tissues. The lethality of a β spectrin mutation was rescued by expression of β spectrin in neurons.
Mouse embryonic germ (EG) cell lines: transmission through the germline and differences in the methylation imprint of insulin-like growth factor 2 receptor (Igf2r) gene compared with embryonic stem (ES) cell lines.

Primordial germ cells of the mouse cultured on feeder layers with leukemia inhibitory factor, Steel factor and basic fibroblast growth factor give rise to cells that resemble undifferentiated blastocyst-derived embryonic stem cells. These primordial germ cell-derived embryonic germ cells can be induced to differentiate extensively in culture, form teratocarcinomas when injected into nude mice and contribute to chimeras when injected into host blastocysts. Here, we report the derivation of multiple embryonic germ cell lines from 8.5 days post coitum embryos of C57BL/6 inbred mice. Four independent embryonic germ cell lines with normal male karyotypes have formed chimeras when injected into BALB/c host blastocysts and two of these lines have transmitted coat color markers through the germline. We also show that pluripotent cell lines capable of forming teratocarcinomas and coat color chimeras can be established from primordial germ cells of 8.0 days p.c. embryos and 12.5 days p.c. genital ridges. We have examined the methylation status of the putative imprinting box of the insulin-like growth factor type 2 receptor gene (Igf2r) in these embryonic germ cell lines. No correlation was found between methylation pattern and germline competence. A significant difference was observed between embryonic stem cell and embryonic germ cell lines in their ability to maintain the methylation imprint of the Igf2r gene in culture. This may illustrate a fundamental difference between these two cell types.
Genetic variations in magnesium-related ion channels may affect diabetes risk among African American and Hispanic American women.

BACKGROUND Prospective studies consistently link low magnesium intake to higher type 2 diabetes (T2D) risk. OBJECTIVE We examined the association of common genetic variants [single nucleotide polymorphisms (SNPs)] in genes related to magnesium homeostasis with T2D risk and potential interactions with magnesium intake. METHODS Using the Women's Health Initiative-SNP Health Association Resource (WHI-SHARe) study, we identified 17 magnesium-related ion channel genes (583 SNPs) and examined their associations with T2D risk in 7287 African-American (AA; n = 1949 T2D cases) and 3285 Hispanic-American (HA; n = 611 T2D cases) postmenopausal women. We performed both single- and multiple-locus haplotype analyses. RESULTS Among AA women, carriers of each additional copy of SNP rs6584273 in cyclin mediator 1 (CNNM1) had 16% lower T2D risk [OR: 0.84; false discovery rate (FDR)-adjusted P = 0.02]. Among HA women, several variants were significantly associated with T2D risk, including rs10861279 in solute carrier family 41 (anion exchanger), member 2 (SLC41A2) (OR: 0.54; FDR-adjusted P = 0.04), rs7174119 in nonimprinted in Prader-Willi/Angelman syndrome 1 (NIPA1) (OR: 1.27; FDR-adjusted P = 0.04), and 2 SNPs in mitochondrial RNA splicing 2 (MRS2) (rs7738943: OR = 1.55, FDR-adjusted P = 0.01; rs1056285: OR = 1.48, FDR-adjusted P = 0.02). Even with the most conservative Bonferroni adjustment, two 2-SNP-haplotypes in SLC41A2 and MRS2 region were significantly associated with T2D risk (rs12582312-rs10861279: P = 0.0006; rs1056285-rs7738943: P = 0.002). Among women with magnesium intake in the lowest 30% (AA: ≤0.164 g/d; HA: ≤0.185 g/d), 4 SNP signals were strengthened [rs11590362 in claudin 19 (CLDN19), rs823154 in SLC41A1, rs5929706 and rs5930817 in membra; HA: ≥0.313 g/d), rs6584273 in CNNM1 (OR: 0.71; FDR-adjusted P = 0.04) and rs1800467 in potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) (OR: 2.50; FDR-adjusted P = 0.01) were significantly associated with T2D risk. CONCLUSIONS Our findings suggest important associations between genetic variations in magnesium-related ion channel genes and T2D risk in AA and HA women that vary by amount of magnesium intake.