Two-Dimensional Crystallography of TFIIB– and IIE–RNA Polymerase II Complexes: Implications for Start Site Selection and Initiation Complex Formation

AbstractTranscription factors IIB (TFIIB) and IIE (TFIIE) bound to RNA polymerase II have been revealed by electron crystallography in projection at 15.7 Å resolution. The results lead to simple hypotheses for the roles of these factors in the initiation of transcription. TFIIB is suggested to define the distance from TATA box to transcription start site by bringing TATA DNA in contact with polymerase at that distance from the active center of the enzyme. TFIIE is suggested to participate in a key conformational switch occurring at the active center upon polymerase–DNA interaction

Searching speeds and the energetic feasibility of an obligate whale-scavenging fish

Two recently published models reach opposite conclusions on the energetic feasibility of a scavenging fish that specialises oil whale carcasses. We argue that the key difference between these models lies in their estimate of the likely searching speed of such a hypothetical scavenger. Neither of the previous models considers that although faster searching will allow food sites to be found more quickly, it will also reduce the time between meals that the fish can survive on its reserves. Hence, we present a novel model that encapsulates this trade-off, and use this model to predict the optimal searching speed for Such a hypothetical scavenger. The model predicts that the optimal speed should increase with mass and be in the range 0.1-0.2 m s(-1) for fish of the range of sizes found for the ubiquitous grenadier Coryphaenoides armatus. These values accord with most estimates of the swimming speeds for this species. Hence, we conclude that rejection of a whale-carcass feeding specialist fish on energetic grounds is premature. Although, we see no reason to dismiss Such a specialist oil energetic grounds, we argue that such a fish will be unlikely oil ecological grounds, although a deep-sea fish that gathered much of its energy from scavenging at relatively large food packages oil the ocean floor should be feasible

Horizontal And Vertical Movements Of Juvenile Bluefin Tuna (Thunnus Thynnus), In Relation To Oceanographic Conditions Of The Western North Atlantic, Determined With Ultrasonic Telemetry

We employed ultrasonic transmitters to follow (for up to 48 h) the horizontal and vertical movements of five juvenile (6.8-18.7 kg estimated body mass) bluefin tuna (Thunnus thynnus) in the western North Atlantic (off the eastern shore of Virginia). Our objective was to document the fishes\u27 behavior and distribution in relation to oceanographic conditions and thus begin to address issues that currently limit population assessments based on aerial surveys. Estimation of the trends in adult and juvenile Atlantic bluefin tuna abundance by aerial surveys, and other fishery-independent measures, is considered a priority. Juvenile bluefin tuna spent the majority of their time over the continental shelf in relatively shallow water (generally less then 40 m deep). Fish used the entire water column in spite of relatively steep vertical thermal gradients (approximate to24degreesC at the surface and approximate to12degreesC at 40 m depth), but spent the majority of their time (approximate to90%) above 15 m and in water warmer then 20degreesC, Mean swimming speeds ranged from 2.8 to 3.3 knots, and total distance covered from 152 to 289 km (82-156 nmi). Because fish generally remained within relatively confined areas, net displacement was only 7.7-52.7 km (4.1-28.4 nmi). Horizontal movements were not correlated with sea surface temperature. We propose that it is unlikely that juvenile bluefin tuna in this area can detect minor horizontal temperature gradients (generally less then 0.5degreesC/km) because of the steep vertical temperature gradients (up to approximate to0.6degreesC/m) they experience during their regular vertical movements. In contrast, water clarity did appear to influence behavior because the fish remained in the intermediate water mass between the turbid and phytoplankton-rich plume exiting Chesapeake Bay (and similar coastal waters) and the clear oligotrophic water east of the continental shelf

Different forms of TFIIH for transcription and DNA repair: Holo-TFIIH and a nucleotide excision repairosome

AbstractYeast TFIIH that is active in transcription can be dissociated into three components: a 5-subunit core, the SSL2 gene product, and a complex of 47 kDa, 45 kDa, and 33 kDa polypeptides that possesses protein kinase activity directed towards the C-terminal repeat domain of RNA polymerase II. These three components can reconstitute fully functional TFIIH, and all three are required for transcription in vitro. By contrast, TFIIH that is highly active in nucleotide excision repair (NER) lacks the kinase complex and instead contains the products of all other genes known to be required for NER in yeast: RAD1, RAD2, RAD4, RAD10, and RAD14. This repairosome is not active in reconstituted transcription in vitro and is significantly more active than any of the constituent polypeptides in correcting defective repair in extracts from strains mutated in NER genes

MBE grown GaAsBi/GaAs multiple quantum well structures: Structural and optical characterization

A series of GaAsBi/GaAs multiple quantum well p–i–n diodes were grown by molecular beam epitaxy. Nomarski images showed evidence of sub-surface damage in each diode, with an increase in the cross-hatching associated with strain relaxation for the diodes containing more than 40 quantum wells. X-ray diffraction ω–2θ scans of the (004) reflections showed that multiple quantum well regions with clearly defined well periodicities were grown. The superlattice peaks of the diodes containing more than 40 wells were much broader than those of the other diodes. The photoluminescence spectra showed a redshift of 56 meV and an attenuation of nearly two orders of magnitude for the 54 and 63 well diodes. Calculations of the quantum confinement and strain induced band gap modifications suggest that the wells in all diodes are thinner than their intended widths and that both loss of quantum confinement and strain probably contributed to the observed redshift and attenuation in the 54 and 63 well diodes. Comparison of this data with that gathered for InGaAs/GaAs multiple quantum wells, suggests that the onset of relaxation occurs at a similar average strain–thickness product for both systems. Given the rapid band gap reduction of GaAsBi with Bi incorporation, this data suggests that GaAsBi is a promising photovoltaic material candidate

Exploring the evidence base for national and regional policy interventions to combat resistance

The effectiveness of existing policies to control antimicrobial resistance is not yet fully understood. A strengthened evidence base is needed to inform effective policy interventions across countries with different income levels and the human health and animal sectors. We examine three policy domains—responsible use, surveillance, and infection prevention and control—and consider which will be the most effective at national and regional levels. Many complexities exist in the implementation of such policies across sectors and in varying political and regulatory environments. Therefore, we make recommendations for policy action, calling for comprehensive policy assessments, using standardised frameworks, of cost-effectiveness and generalisability. Such assessments are especially important in low-income and middle-income countries, and in the animal and environmental sectors. We also advocate a One Health approach that will enable the development of sensitive policies, accommodating the needs of each sector involved, and addressing concerns of specific countries and regions

Preserved emotional awareness of pain in a patient with extensive bilateral damage to the insula, anterior cingulate, and amygdala

Functional neuroimaging investigations of pain have discovered a reliable pattern of activation within limbic regions of a putative "pain matrix" that has been theorized to reflect the affective dimension of pain. To test this theory, we evaluated the experience of pain in a rare neurological patient with extensive bilateral lesions encompassing core limbic structures of the pain matrix, including the insula, anterior cingulate, and amygdala. Despite widespread damage to these regions, the patient's expression and experience of pain was intact, and at times excessive in nature. This finding was consistent across multiple pain measures including self-report, facial expression, vocalization, withdrawal reaction, and autonomic response. These results challenge the notion of a "pain matrix" and provide direct evidence that the insula, anterior cingulate, and amygdala are not necessary for feeling the suffering inherent to pain. The patient's heightened degree of pain affect further suggests that these regions may be more important for the regulation of pain rather than providing the decisive substrate for pain's conscious experience

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11

Readout of a quantum processor with high dynamic range Josephson parametric amplifiers

We demonstrate a high dynamic range Josephson parametric amplifier (JPA) in which the active nonlinear element is implemented using an array of rf-SQUIDs. The device is matched to the 50 $\Omega$ environment with a Klopfenstein-taper impedance transformer and achieves a bandwidth of 250-300 MHz, with input saturation powers up to -95 dBm at 20 dB gain. A 54-qubit Sycamore processor was used to benchmark these devices, providing a calibration for readout power, an estimate of amplifier added noise, and a platform for comparison against standard impedance matched parametric amplifiers with a single dc-SQUID. We find that the high power rf-SQUID array design has no adverse effect on system noise, readout fidelity, or qubit dephasing, and we estimate an upper bound on amplifier added noise at 1.6 times the quantum limit. Lastly, amplifiers with this design show no degradation in readout fidelity due to gain compression, which can occur in multi-tone multiplexed readout with traditional JPAs.Comment: 9 pages, 8 figure