Identification of a Likely Radio Counterpart of the Rapid Burster

We have identified a likely radio counterpart to the low-mass X-ray binary MXB 1730-335 (the Rapid Burster). The counterpart has shown 8.4 GHz radio on/off behavior correlated with the X-ray on/off behavior as observed by the RXTE/ASM during six VLA observations. The probability of an unrelated, randomly varying background source duplicating this behavior is 1-3% depending on the correlation time scale. The location of the radio source is RA 17h 33m 24.61s; Dec -33d 23' 19.8" (J2000), +/- 0.1". We do not detect 8.4 GHz radio emission coincident with type II (accretion-driven) X-ray bursts. The ratio of radio to X-ray emission during such bursts is constrained to be below the ratio observed during X-ray persistent emission at the 2.9-sigma level. Synchrotron bubble models of the radio emission can provide a reasonable fit to the full data set, collected over several outbursts, assuming that the radio evolution is the same from outburst to outburst, but given the physical constraints the emission is more likely to be due to ~hour-long radio flares such as have been observed from the X-ray binary GRS 1915+105.Comment: 28 pages, 4 figures; accepted for publication in ApJ (no changes

Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors

Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here, we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7asinhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1, or the more selective YKL-1-116. The effects were allele specific; a CDK7asmutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition. Kalan et al. find that activation of the p53 tumor suppressor protein in human colon cancer-derived cells can induce transcriptional dependency on Cdk7, analogous to constitutive dependencies described in other tumors driven by oncogenic transcription factors. This work provides a proof of concept for combining p53-activating agents with Cdk7 inhibitors to elicit synthetic lethality. Keywords: Cdk7; p53; colon cancer; synthetic lethality; transcription; 5-fluorouracil; nutlin-3; apoptosis; chemical genetics; CDK inhibitorNational Institutes of Health (U.S.) (Grant HG002668

Multifrequency spectra of solar brightness temperature derived from eclipse observations

Changes in solar radio-brightness temperature were derived at 2.8,19.3 and 22.2 GHz from the observations of radio flux during the total eclipse of 1980 February 16. High-resolution MEM spectra of the brightness temperature fluctuations at the three frequencies showed periodicities ranging from 3.5 min to 128 min. Between 3.5 min and 14.6 min there are several periodicities of comparable significance common to the three operating frequencies. If the corresponding variations in brightness temperature are assumed to result from spatial variations in the solar radio emission, the observed periodicities imply scale sizes in the range 76000 km to 320000 km

Archaeological evidence of anthropogenic burning for food production in forested uplands of the Grand Canyon province, northern Arizona

Despite convincing archaeological arguments about the global effects of human pyrogeography and their evolutionary significance, many of the implicated data sources are unavailable in research contexts that lack significant accumulations of charcoal or stands of fire-scarred trees. In view of the strong likelihood that hominins routinely ignited small, low-intensity landscape fires for millennia, we explore the role of cultural burning for food-production in an area of the American Southwest where anthropogenic fire has not been considered. To illustrate the virtues of a multidisciplinary approach, informed by Formation Theory and time perspectivism, we focus on the returns from macrobotanical and palynological analyses of samples recovered from a variety of archaeological and geoarchaeological contexts in the Upper Basin, a landform located south of the Grand Canyon in northern Arizona. Previous archaeobotanical studies of samples recovered from archaeological sites (ca. AD 500–1500) in the basin's pinyon-juniper woodlands are dominated by amaranth, chenopodium, and other economic ruderals. These findings support the “fire foodway” model that posits prehistoric Indigenous populations of the Upper Basin depended on these fire-following wild plants, rather than maize, by harvesting their abundant seeds and leaves from production locations that were created by low-intensity understory fires. In this paper, we present the results of new studies of archaeobotanical remains recovered from cut-back terraces and sedimentary contexts that (i) expand the evidence base for the fire-foodway model, (ii) provide a basis for proposing several types of prehistoric cultural burning practices, and (iii) introduce the outlines of the ruderal seed-bed hypothesis. Combined, these findings provide a new archaeological perspective on upland subsistence practices in the northern American Southwest. Our study also highlights biases of modern vegetation surveys that do not include archaeological data, and contributes to an appreciation of the extent to which biodiversity has declined because of widespread fire exclusion

A Broad-Spectrum Antiviral Molecule, QL47, Selectively Inhibits Eukaryotic Translation

Small-molecule inhibitors of translation are critical tools to study the molecular mechanisms of protein synthesis. In this study, we sought to characterize how QL47, a host-targeted, small-molecule antiviral agent, inhibits steady-state viral protein expression. We demonstrate that this small molecule broadly inhibits both viral and host protein synthesis and targets a translation step specific to eukaryotic cells. We show that QL47 inhibits protein neosynthesis initiated by both canonical cap-driven and noncanonical initiation strategies, most likely by targeting an early step in translation elongation. Our findings thus establish QL47 as a new small-molecule inhibitor that can be utilized to probe the eukaryotic translation machinery and that can be further developed as a new therapeutic agent

Multi-Frequency observations of radio sun during total solar eclipse of February 16, 1980

Measurements of radio flux of the Sun duirng the total solar eclipse on February 16, 1980 were made from the Japal-Rangapur Observatory near Hyderabad, at radio frequencies of 2.8, 10, 19 and 22.2 GHz. Observations for both ingress and egress are available. Residual fluxesat totality for 2.8, 10 and 19 GHz were 23, 3.5 and 3 per cent respectively. The minimum fluxes were observed from 2 to 7 minutes prior to the mid-eclipse

Development and Characterization of a Wee1 Kinase Degrader

The G1/S cell cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Wee1 regulates the G2/M checkpoint by phosphorylating CDK1 at Tyr15 to prevent mitotic entry. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose-limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we developed Wee1 degraders by conjugating AZD1775 to the cereblon (CRBN)-binding ligand, pomalidomide. The resulting lead compound, ZNL-02-096, degrades Wee1 while sparing PLK1, induces G2/M accumulation at 10-fold lower doses than AZD1775, and synergizes with Olaparib in ovarian cancer cells. We demonstrate that ZNL-02-096 has CRBN-dependent pharmacology that is distinct from AZD1775, which justifies further evaluation of selective Wee1 degraders

The social relations of health care and household resource allocation in neoliberal Nicaragua

<p>Abstract</p> <p>Background</p> <p>With the transition to neoliberalism, Nicaragua's once-critically acclaimed health care services have substantially diminished. Local level social formations have been under pressure to try to bridge gaps as the state's role in the provision of health care and other vital social services has decreased. This paper presents a case study of how global and national health policies reverberated in the social relations of an extended network of female kin in a rural community during late 2002 - 2003.</p> <p>Methods</p> <p>The qualitative methods used in this ethnographic study included semi-structured interviews completed during bi-weekly visits to 51 households, background interviews with 20 lay and professional health practitioners working in the public and private sectors, and participant-observation conducted in the region's government health centers. Interviews and observational field notes were manually coded and iteratively reviewed to identify and conceptually organize emergent themes. Three households of extended kin were selected from the larger sample to examine as a case study.</p> <p>Results</p> <p>The ongoing erosion of vital services formerly provided by the public sector generated considerable frustration and tension among households, networks of extended kin, and neighbors. As resource allocations for health care seeking and other needs were negotiated within and across households, longstanding ideals of reciprocal exchange persisted, but in conditions of poverty, expectations were often unfulfilled, exposing the tension between the need for social support, versus the increasingly oppositional positioning of social network members as sources of competition for limited resources.</p> <p>Conclusions</p> <p>In compliance with neoliberal structural adjustment policies mandated by multilateral and bilateral agencies, government-provided health care services have been severely restricted in Nicaragua. As the national safety net for health care has been eroded, the viability of local level social formations and their ability to respond to struggles collectively has been put at risk as well. Bi-lateral and multilateral agencies need to take into account local needs and demands, and implement policies in a manner that respects national laws, and protects both the physical and social well-being of individuals.</p