A quantitative metric of pioneer activity reveals that HNF4A has stronger in vivo pioneer activity than FOXA1

BACKGROUND: We and others have suggested that pioneer activity - a transcription factor\u27s (TF\u27s) ability to bind and open inaccessible loci - is not a qualitative trait limited to a select class of pioneer TFs. We hypothesize that most TFs display pioneering activity that depends on the TF concentration and the motif content at their target loci. RESULTS: Here, we present a quantitative in vivo measure of pioneer activity that captures the relative difference in a TF\u27s ability to bind accessible versus inaccessible DNA. The metric is based on experiments that use CUT&Tag to measure the binding of doxycycline-inducible TFs. For each location across the genome, we determine the concentration of doxycycline required for a TF to reach half-maximal occupancy; lower concentrations reflect higher affinity. We propose that the relative difference in a TF\u27s affinity between ATAC-seq labeled accessible and inaccessible binding sites is a measure of its pioneer activity. We estimate binding affinities at tens of thousands of genomic loci for the endodermal TFs FOXA1 and HNF4A and show that HNF4A has stronger pioneer activity than FOXA1. We show that both FOXA1 and HNF4A display higher binding affinity at inaccessible sites with more copies of their respective motifs. The quantitative analysis of binding suggests different modes of binding for FOXA1, including an anti-cooperative mode of binding at certain accessible loci. CONCLUSIONS: Our results suggest that relative binding affinities are reasonable measures of pioneer activity and support the model wherein most TFs have some degree of context-dependent pioneer activity

Structure of the RNA-dependent RNA polymerase of poliovirus

AbstractBackground: The central player in the replication of RNA viruses is the viral RNA-dependent RNA polymerase. The 53 kDa poliovirus polymerase, together with other viral and possibly host proteins, carries out viral RNA replication in the host cell cytoplasm. RNA-dependent RNA polymerases comprise a distinct category of polymerases that have limited sequence similarity to reverse transcriptases (RNA-dependent DNA polymerases) and perhaps also to DNA-dependent polymerases. Previously reported structures of RNA-dependent DNA polymerases, DNA-dependent DNA polymerases and a DNA-dependent RNA polymerase show that structural and evolutionary relationships exist between the different polymerase categories.Results: We have determined the structure of the RNA-dependent RNA polymerase of poliovirus at 2.6 Å resolution by X-ray crystallography. It has the same overall shape as other polymerases, commonly described by analogy to a right hand. The structures of the ‘fingers’ and ‘thumb’ subdomains of poliovirus polymerase differ from those of other polymerases, but the palm subdomain contains a core structure very similar to that of other polymerases. This conserved core structure is composed of four of the amino acid sequence motifs described for RNA-dependent polymerases. Structure-based alignments of these motifs has enabled us to modify and extend previous sequence and structural alignments so as to relate sequence conservation to function. Extensive regions of polymerase–polymerase interactions observed in the crystals suggest an unusual higher order structure that we believe is important for polymerase function.Conclusions: As a first example of a structure of an RNA-dependent RNA polymerase, the poliovirus polymerase structure provides for a better understanding of polymerase structure, function and evolution. In addition, it has yielded insights into an unusual higher order structure that may be critical for poliovirus polymerase function

A test of the pioneer factor hypothesis using ectopic liver gene activation

The pioneer factor hypothesis (PFH) states that pioneer factors (PFs) are a subclass of transcription factors (TFs) that bind to and open inaccessible sites and then recruit non-pioneer factors (non-PFs) that activate batteries of silent genes. The PFH predicts that ectopic gene activation requires the sequential activity of qualitatively different TFs. We tested the PFH by expressing the endodermal PF FOXA1 and non-PF HNF4A in K562 lymphoblast cells. While co-expression of FOXA1 and HNF4A activated a burst of endoderm-specific gene expression, we found no evidence for a functional distinction between these two TFs. When expressed independently, both TFs bound and opened inaccessible sites, activated endodermal genes, and \u27pioneered\u27 for each other, although FOXA1 required fewer copies of its motif for binding. A subset of targets required both TFs, but the predominant mode of action at these targets did not conform to the sequential activity predicted by the PFH. From these results, we hypothesize an alternative to the PFH where \u27pioneer activity\u27 depends not on categorically different TFs but rather on the affinity of interaction between TF and DNA

Heritability of Clinical Mastitis Incidence and Relationships with Sire Transmitting Abilities for Somatic Cell Score, Udder Type Traits, Productive Life, and Protein Yield

The objective of this study was to determine the relationships among daughter clinical mastitis during first and second lactations and sire transmitting abilities for somatic cell score, udder type traits, productive life, and protein yield. Data on clinical mastitis during first lactation were available for 1795 daughters (in six Pennsylvania herds, one Minnesota herd, and one Nebraska herd) of 283 Holstein sires. Data on clinical mastitis during second lactation were available for 1055 of these daughters. A total of 479 cows had 864 clinical episodes during first lactation, and 230 cows had 384 clinical episodes during second lactation. Clinical mastitis incidence and the total number of clinical episodes during each lactation were regressed on herd-season of calving (a classification variable), age at first calving, lactation length, and sire transmitting abilities taken one at a time. Linear effects, nonlinear effects, and odds ratios were estimated for sire transmitting abilities. Separate analyses were conducted on dependent variables that considered clinical mastitis from: all organisms, coagulase-negative staphylococci, coliform species, streptococci other than Streptococcus agalactiae, and the most common environmental organisms (coliform species and streptococci other than Streptococcus agalactiae). Heritability of clinical mastitis ranged from 0.01 to 0.42. Daughters of sires that transmit the lowest somatic cell score had the lowest incidence of clinical mastitis and the fewest clinical episodes during first and second lactations. Daughters of sires that transmit longer productive life, shallower udders, deeper udder cleft, and strongly attached fore udders had either fewer clinical episodes or lower clinical mastitis incidence during first and second lactations. The incidence of clinical mastitis and the number of clinical episodes per lactation may be reduced by selection for lower somatic cell score, longer productive life, shallower udders, deeper udder cleft, or strongly attached fore udders

Review on abyssomicins:Inhibitors of the chorismate pathway and folate biosynthesis

Antifolates targeting folate biosynthesis within the shikimate-chorismate-folate metabolic pathway are ideal and selective antimicrobials, since higher eukaryotes lack this pathway and rely on an exogenous source of folate. Resistance to the available antifolates, inhibiting the folate pathway, underlines the need for novel antibiotic scaffolds and molecular targets. While para-aminobenzoic acid synthesis within the chorismate pathway constitutes a novel molecular target for antifolates, abyssomicins are its first known natural inhibitors. This review describes the abyssomicin family, a novel spirotetronate polyketide Class I antimicrobial. It summarizes synthetic and biological studies, structural, biosynthetic, and biological properties of the abyssomicin family members. This paper aims to explain their molecular target, mechanism of action, structure–activity relationship, and to explore their biological and pharmacological potential. Thirty-two natural abyssomicins and numerous synthetic analogues have been reported. The biological activity of abyssomicins includes their antimicrobial activity against Gram-positive bacteria and mycobacteria, antitumor properties, latent human immunodeficiency virus (HIV) reactivator, anti-HIV and HIV replication inducer properties. Their antimalarial properties have not been explored yet. Future analoging programs using the structure–activity relationship data and synthetic approaches may provide a novel abyssomicin structure that is active and devoid of cytotoxicity. Abyssomicin J and atrop-o-benzyl-desmethylabyssomicin C constitute promising candidates for such programs

Hydrophilic polymer embolism identified in brain tumor specimens following Wada testing: A report of 2 cases

Hydrophilic polymers are commonly used as coatings on intravascular medical devices. As intravascular pro-cedures continue to increase in frequency, the risk of embolization of this material throughout the body has become evident. These emboli may be discovered incidentally but can result in serious complications includ-ing death. Here, we report the first two cases of hydrophilic polymer embolism (HPE) identified on brain tu-mor resection following Wada testing. One patient experienced multifocal vascular complications and diffuse cerebral edema, while the other had an uneventful postoperative course. Wada testing is frequently per-formed during preoperative planning prior to epilepsy surgery or the resection of tumors in eloquent brain regions. These cases demonstrate the need for increased recognition of this histologic finding to enable fur-ther correlation with clinical outcomes

Pyroelectric detectors

The multi-agency, long-term Global Change programs, and specifically NASA's Earth Observing system, will require some new and advanced photon detector technology which must be specifically tailored for long-term stability, broad spectral range, cooling constraints, and other parameters. Whereas MCT and GaAs alloy based photovoltaic detectors and detector arrays reach most impressive results to wavelengths as long as 12 microns when cooled to below 70 K, other materials, such as ferroelectrics and pyroelectrics, appear to offer special opportunities beyond 12 microns and above 70 K. These materials have found very broad use in a wide variety of room temperature applications. Little is known about these classes of materials at sub-room temperatures and no photon detector results have been reported. From the limited information available, researchers conclude that the room temperature values of D asterisk greater than or equal to 10(exp 9) cm Hz(exp 1/2)/W may be improved by one to two orders of magnitude upon cooling to temperatures around 70 K. Improvements of up to one order of magnitude appear feasible for temperatures achievable by passive cooling. The flat detector response over a wavelength range reaching from the visible to beyond 50 microns, which is an intrinsic advantage of bolometric devices, makes for easy calibration. The fact that these materials have been developed for reduced temperature applications makes ferro- and pyroelectric materials most attractive candidates for serious exploration

哀乎？乐乎？

2004年是反倾销（AD）政策诞辰100周年。虽然各国都在进行旨在达成广泛的自由贸易协定的谈判，但是，反倾销措施日益广泛的应用说明：各国实际上是将反倾销措施作为保护特定行业的手段。本文旨在介绍和探讨反倾销政策作为一种与贸易自由化相对抗的战略在世界范围内的应用和发展。译者单位：东北财经大学商务英语学院（116023