The 5'-3' exoribonuclease Pacman (Xrn1) regulates expression of the heat shock protein Hsp67Bc and the microRNA miR-277-3p in Drosophila wing imaginal discs

Pacman/Xrn1 is a highly conserved exoribonuclease known to play a critical role in gene regulatory events such as control of mRNA stability, RNA interference and regulation via miRNAs. Although Pacman has been well studied in Drosophila tissue culture cells, the biologically relevant cellular pathways controlled by Pacman in natural tissues are unknown. This study shows that a hypomorphic mutation in pacman (pcm5) results in smaller wing imaginal discs. These tissues, found in the larva, are known to grow and differentiate to form wing and thorax structures in the adult fly. Using microarray analysis, followed by quantitative RT-PCR, we show that eight mRNAs were increased in level by >2 fold in the pcm5 mutant wing discs compared to the control. The levels of pre mRNAs were tested for five of these mRNAs; four did not increase in the pcm5 mutant, showing that they are regulated at the post-transcriptional level and therefore could be directly affected by Pacman. These transcripts include one that encodes the heat-shock protein Hsp67Bc, which is upregulated 11.9-fold at the post-transcriptional level and 2.3-fold at the protein level. One miRNA, miR-277-3p, is 5.6-fold downregulated at the post-transcriptional level in mutant discs, suggesting that Pacman affects its processing in this tissue. Together, these data show that a relatively small number of mRNAs and miRNAs substantially change in abundance in pacman mutant wing imaginal discs. Since Hsp67Bc is known to regulate autophagy and protein synthesis, it is possible that Pacman may control the growth of wing imaginal discs by regulating these processes

Xrn1/Pacman affects apoptosis and regulates expression of hid and reaper

Programmed cell death, or apoptosis, is a highly conserved cellular process that is crucial for tissue homeostasis under normal development as well as environmental stress. Misregulation of apoptosis is linked to many developmental defects and diseases such as tumour formation, autoimmune diseases and neurological disorders. In this paper, we show a novel role for the exoribonuclease Pacman/Xrn1 in regulating apoptosis. Using Drosophila wing imaginal discs as a model system, we demonstrate that a null mutation in pacman results in small imaginal discs as well as lethality during pupation. Mutant wing discs show an increase in the number of cells undergoing apoptosis, especially in the wing pouch area. Compensatory proliferation also occurs in these mutant discs, but this is insufficient to compensate for the concurrent increase in apoptosis. The phenotypic effects of the pacman null mutation are rescued by a deletion that removes one copy of each of the pro-apoptotic genes reaper, hid and grim, demonstrating that pacman acts through this pathway. The null pacman mutation also results in a significant increase in the expression of the pro-apoptotic mRNAs, hid and reaper, with this increase mostly occurring at the post-transcriptional level, suggesting that Pacman normally targets these mRNAs for degradation. Our results uncover a novel function for the conserved exoribonuclease Pacman and suggest that this exoribonuclease is important in the regulation of apoptosis in other organisms

A randomized, prospective open labeled study of oral amoxicillin-clavulanate and levofloxacin with intravenous ceftriaxone and amikacin in chemotherapy induced low risk febrile neutropenia

Background : We compared the efficacy of oral antibiotics with intravenous antibiotics in low risk febrile neutropenia. Design : A prospective, randomized study Methods: Between April 2004 - December 2005, 55 patients with low risk febrile neutropenia (expected neutropenia duration < 7 days with no co-morbid features) between 15 and 75 years of age, were randomized to receive either oral amoxicillin-clavulanate 625mg twice daily and levofloxacin -500mg once daily OR intravenous (i.v.) ceftriaxone 2g and amikacin 15mg/kg once daily. Most patients were treated on out patient basis. The primary end point was response to therapy, defervescence of fever within 72 hours with improvement in any clinical manifestation of infection and no recurrence of fever for 48 hours without use of antipyretics. Use of growth factors was not permitted except in treatment failure. Results: A total of 64 febrile episodes were recorded (mean 1.20 ); 33 in the IV group and 31 in the oral antibiotics group. Both groups were equally matched for age (median 25 years in the IV group and 19 years in the oral group), gender, type of cancer, baseline absolute neutrophil count (median 200/cmm in both arms) and duration of neutropenia (5 days and 4 days in the IV and oral groups, respectively). A focus of infection was identified clinically in 15% of episodes and microbiologically in 11% of episodes; 57% of which were Gram positive organisms and the rest Gram negative. 72% in the IV arm and 77% in the oral arm responded to therapy (p=ns). One patient in IV group had one episode of seizure. Non-responding patients received second line IV antibiotics. There was no mortality in either group. Age > 60 years, neutropenia lasting > 7 days after the onset of fever and positive blood culture were predictors for lack of response to antibiotics on multivariate analysis. Conclusion: Oral antibiotics have comparable efficacy as IV antibiotics in the management of low risk febrile neutropenia

Should whole body cryotherapy sessions be differentiated between women and men? A preliminary study on the role of the body thermal resistance

The aim of this study was to investigate how body thermal resistance between sexes evolves over time in the recovery period after a WBC session and to show how this parameter should be considered as a key parameter in WBC protocols. Eighteen healthy participants volunteered for the study (10 males and 8 females). Temperature (core and skin) were recorded pre- and post (immediately and every 5 min until 35 min post) exposure to a single bout of WBC (30 s at −60 °C, 150 s at −110 °C). From both core and skin temperatures a bio-heat transfer model was applied which led to the analytical formulation of the body thermal resistance. An unsteady behavior presenting a similar time-evolution trend in the body insulative response is shown for both females and males, possibly due to the vasodilatation process following an intense peripheral vasoconstriction during the extreme cold. Females present a 37% higher inner thermal resistance than males when reaching an asymptotical thermal state at rest due to a higher concentration of body fat percentage. Adiposity of tissues inherent in fat mass percentage appears to be a key parameter in the body thermal resistance to be taken into account in the definition of appropriate protocols for males and females. The conclusions of this preliminary study suggest that in order to achieve the same skin effects on temperature and consequently to cool efficiency tissues in the same way, the duration of cryotherapy protocols should be shorter when considering female compared to male

The Primordial Inflation Polarization Explorer (PIPER)

The Primordial Inflation Polarization Explorer (PIPER) is a balloon-borne cosmic microwave background (CMB) polarimeter designed to search for evidence of inflation by measuring the large-angular scale CMB polarization signal. BICEP2 recently reported a detection of B-mode power corresponding to the tensor-to-scalar ratio r = 0.2 on ~2 degree scales. If the BICEP2 signal is caused by inflationary gravitational waves (IGWs), then there should be a corresponding increase in B-mode power on angular scales larger than 18 degrees. PIPER is currently the only suborbital instrument capable of fully testing and extending the BICEP2 results by measuring the B-mode power spectrum on angular scales $\theta$ = ~0.6 deg to 90 deg, covering both the reionization bump and recombination peak, with sensitivity to measure the tensor-to-scalar ratio down to r = 0.007, and four frequency bands to distinguish foregrounds. PIPER will accomplish this by mapping 85% of the sky in four frequency bands (200, 270, 350, 600 GHz) over a series of 8 conventional balloon flights from the northern and southern hemispheres. The instrument has background-limited sensitivity provided by fully cryogenic (1.5 K) optics focusing the sky signal onto four 32x40-pixel arrays of time-domain multiplexed Transition-Edge Sensor (TES) bolometers held at 140 mK. Polarization sensitivity and systematic control are provided by front-end Variable-delay Polarization Modulators (VPMs), which rapidly modulate only the polarized sky signal at 3 Hz and allow PIPER to instantaneously measure the full Stokes vector (I, Q, U, V) for each pointing. We describe the PIPER instrument and progress towards its first flight.Comment: 11 pages, 7 figures. To be published in Proceedings of SPIE Volume 9153. Presented at SPIE Astronomical Telescopes + Instrumentation 2014, conference 915

Late Glacial and Holocene Palaeolake History of the Última Esperanza Region of Southern Patagonia

We undertook multi-proxy analyses on two sediment cores from Lago Pato, a small lake basin at 51°S topographically separated from Lago del Toro in Torres del Paine (TdP), to provide insights into glacier dynamics and lake-level change in the TdP and Última Esperanza region over the last ∼30,000 cal a BP (30 ka). Lago Pato is situated in a region overridden by the Southern Patagonian Ice Field during the Last Glacial and in a transitional climatic zone of Southern Patagonia sensitive to seasonal- to millennial-scale changes in the Southern Hemisphere Westerly Winds (SWW). Results show that a deep ice-dammed and enlarged palaeolake encompassed Lago del Toro and Lago Pato c. 30–20 ka after the ice had retreated from local-Last Glacial Maximum (l-LGM) limits at c. 48–34 ka and during the build-up to the global-Last Glacial Maximum (g-LGM), c. 26–19 ka. Gaps in both sediment records between c. 20–13.4 ka and c. 20–10 ka suggest hiatuses in sediment accumulation during the g-LGM and Antarctic Cold Reversal (ACR) readvances and/or removal by lake lowering or flushing during the Late Glacial–early Holocene. The palaeolake level dropped from >100 m a.s.l. to ∼40–50 m a.s.l. towards the end of the ACR c. 13.4–13.0 ka, creating a shallower glaciolacustrine environment dammed by an ice tongue in the Estancia Puerto Consuelo–Última Esperanza fjord. Further lowering of the enlarged palaeolake level occurred when the ice thinned to <40 m a.s.l., eventually isolating Lago Pato from Lago del Toro and glaciogenic sediment input at c. 11.7 ka. After isolation, the ecology and water levels in Lago Pato became sensitive to regional climate shifts. The shallow, stable, and highly anoxic environment that developed after c. 11.7 ka is associated with weaker (or poleward shifted) SWW at 51°S and was replaced at c. 10 ka by an increasingly productive shallow-littoral lake with a variable lake-level and periodic shifts in anoxic-oxic bottom water conditions and ratios of benthic-planktonic diatoms. A more open Nothofagus forest, established at c. 8.6–7.5 ka, and more arid conditions c. 7.5–5.7 cal ka BP are linked to another phase of weaker (or poleward shifted) SWW at 51°S. More persistently wet conditions from c. 5.7 ka, with extensive closed Nothofagus forests and planktonic diatoms dominant, are associated with stronger (or equatorward shifted) SWW over 51°S. The abrupt return of benthic-to-tychoplanktonic diatoms after c. 3 ka reflects enhanced SWW at 51°S. Increasingly stable lacustrine and littoral wetland conditions established in the last ∼500 years reflect weaker SWW and lasted until recent decades

Randomized Controlled Pilot Study of Antiretrovirals and a Behavioral Intervention for Persons with Acute HIV Infection: Opportunity for Interrupting Transmission

Background. Persons with acute HIV infection (AHI) have heightened transmission risk. We evaluated potential transmission reduction using behavioral and biomedical interventions in a randomized controlled pilot study in Malawi. Methods. Persons were randomized 1:2:2 to standard counseling (SC), 5-session behavioral intervention (BI), or behavioral intervention plus 12 weeks of antiretrovirals (ARVs; BIA). All were followed for 26-52 weeks and, regardless of arm, referred for treatment according to Malawi-ARV guidelines. Participants were asked to refer partners for testing. Results. Among 46 persons (9 SC, 18 BI, 19 BIA), the average age was 28; 61% were male. The median viral load (VL) was 5.9 log copies/mL at enrollment. 67% (10/15) of BIA participants were suppressed (<1000 copies/mL) at week 12 vs 25% BI and 50% SC (P = .07). Although the mean number of reported condomless sexual acts in the past week decreased from baseline across all arms (1.5 vs 0.3 acts), 36% experienced incident sexually transmitted infection by 52 weeks (12% SC, 28% BI, 18% BIA). Forty-one percent (19/46) of participants referred partners (44% SC, 44% BI, 37% BIA); 15 of the partners were HIV-infected. Conclusions. Diagnosis of AHI facilitates behavioral and biomedical risk reduction strategies during a high-transmission period that begins years before people are typically identified and started on ARVs. Sexually transmitted infection incidence in this cohort suggests ongoing risk behaviors, reinforcing the importance of early intervention with ARVs to reduce transmission. Early diagnosis coupled with standard AHI counseling and early ARV referral quickly suppresses viremia, may effectively change behavior, and could have tremendous public health benefit in reducing onward transmission