Influence of a Guanidine Riboswitch in Bacterial Cells

Bacteria live in environments containing complex ecologies of other microbes that communicate and survive through the action of a variety of small metabolic compounds. One common yet relatively unstudied metabolite is guanidine. Although it can be toxic to cells, recent studies have revealed that guanidine may function as a cellular metabolite through a specialized RNA sequence known as a riboswitch. Within our overall project on improving algal productivity, the focus of this study is to: (a) describe various guanidine riboswitch sequences in bacteria that interact with biofuel producing algae; and (b) determine if guanidine has a positive or negative influence on the growth of the bacteria containing these riboswitches. Over 2,000 species across four phyla of bacteria contain genes that help overcome guanidine toxicity. Recently it was discovered that guanidine, a small molecule with three nitrogen linked to a single carbon, regulates some of these genes by specific interactions with a segment of mRNA called a riboswitch. In this investigation, we used the largely uncharacterized cyanobacterium ESFC-1, and others across the four phyla, that contain the guanidine riboswitch, of which there are two subtypes. Both of these two subtypes regulate expression of proteins involved in the export and modification of guanidine inside the bacterial cell. Genome sequence analysis of our guanidine riboswitches indicate that our test bacteria differ in four key highly conserved residues for a guanidine-binding pocket in the model riboswitch. However, structures of the riboswitches may be similar, indicating their functions and guanidine-binding capabilities may be similar

Dealing with a traumatic past: the victim hearings of the South African truth and reconciliation commission and their reconciliation discourse

In the final years of the twentieth and the beginning of the twenty-first century, there has been a worldwide tendency to approach conflict resolution from a restorative rather than from a retributive perspective. The South African Truth and Reconciliation Commission (TRC), with its principle of 'amnesty for truth' was a turning point. Based on my discursive research of the TRC victim hearings, I would argue that it was on a discursive level in particular that the Truth Commission has exerted/is still exerting a long-lasting impact on South African society. In this article, three of these features will be highlighted and illustrated: firstly, the TRC provided a discursive forum for thousands of ordinary citizens. Secondly, by means of testimonies from apartheid victims and perpetrators, the TRC composed an officially recognised archive of the apartheid past. Thirdly, the reconciliation discourse created at the TRC victim hearings formed a template for talking about a traumatic past, and it opened up the debate on reconciliation. By discussing these three features and their social impact, it will become clear that the way in which the apartheid past was remembered at the victim hearings seemed to have been determined, not so much by political concerns, but mainly by social needs

The use of proactive risk management to reduce emergency service vehicle crashes among firefighters

Introduction: Emergency service vehicle crashes (ESVCs), including rollovers and collisions with other vehicles and fixed objects, are a leading cause of death among U.S. firefighters. Risk management (RM) is a proactive intervention to identifying and mitigating occupational risks and hazards. The goal of this study was to assess the effect of RM in reducing ESVCs. Methods: Three fire departments (A, B and C), representing urban and suburban geographies, and serving medium to large populations, participated in facilitated RM programs to reduce their ESVCs. Interventions were chosen by each department to address their department-specific circumstances and highest risks. Monthly crash rates per 10,000 calls were calculated for each department an average of 28 months before and 23 months after the start of the RM programs. Interrupted time series analysis was used to assess the effect of the RM programs on monthly crash rates. Poisson regression was used to estimate the number of crashes avoided. Economic data from Department A were analyzed to estimate cost savings. Results: Department A had a 15.4% (P = 0.30) reduction in the overall monthly crash rate immediately post-RM and a 1% (P = 0.18) decline per month thereafter. The estimated two-year average cost savings due to 167 crashes avoided was $253,100 (95$192,355 - $313,885). Department B had a 9.7% (P = 0.70) increase in the overall monthly crash rate immediately post-RM and showed no significant changes in their monthly crash rate. Department C had a 28.4% (P = 0.001) reduction in overall monthly crash rate immediately post-RM and a 1.2% (P = 0.09) increase per month thereafter, with an estimated 122 crashes avoided. Conclusions: RM programs have the potential to reduce ESVCs in the fire service and their associated costs; results may vary based on the interventions chosen and how they are implemented. Practical applications: Risk management may be an effective and broadly implemented intervention to reduce ESVCs in the US fire service. (C) 2019 The Author(s). National Safety Council and Elsevier Ltd.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm

Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study

Photometric and Spectroscopic Observations of SN 1990E in NGC 1035 Observational Constraints for Models of Type II Supernovae

We present 126 photometric and 30 spectral observations of SN 1990E spanning from 12 days before B maximum to 600 days past discovery. These observations show that SN 1990E was of type II-P, displaying hydrogen in its spectrum, and the characteristic plateau in its light curve. SN 1990E is one of the few SNe II which has been well observed before maximum light, and we present evidence that this SN was discovered very soon after its explosion. In the earliest spectra we identify, for the first time, several H II lines. We present a new technique for measuring extinction to SNe II based on the evolution of absorption lines, and use this method to estimate the extinction to SN 1990E, A_V_= 1.5+/-0.3 mag. From our photometric data we have constructed a bolometric light curve for SN 1990E and show that, even at the earliest times, the bolometric luminosity was falling rapidly. We use the late-time bolometric light curve to show that SN 1990E trapped a majority of the gamma rays produced by the radioactive decay of ^56^Co, and estimate that SN 1990E ejected 0.073_-0.051_^+0.018^ M_sun_ of ^56^Ni, an amount virtually identical to that of SN 1987A.Supernova research at the Harvard University is supported by NSF Grant No. AST 89-05529 and NASA Grant Nos. NAG 5-841 and NGT-51002. A.V.F acknowledges the support of NSF Grant Nos. AST-8957063 and AST-9115174, as well as NSF Cooperative Agreement AST-8809616 (Center for Particle Astrophysics, U. C. Berkeley). Construction of the SONIC was supported by the Scholarly Studies Fund of the Smithsonian Institution

Intensification differentially affects the delivery of multiple ecosystem services in subtropical and temperate grasslands

Intensification, the process of intensifying land management to enhance agricultural goods, results in “intensive” pastures that are planted with productive grasses and fertilized. These intensive pastures provide essential ecosystem services, including forage production for livestock. Understanding the synergies and tradeoffs of pasture intensification on the delivery of services across climatic regions is crucial to shape policies and incentives for better management of natural resources. Here, we investigated how grassland intensification affects key components of provisioning (forage productivity and quality), supporting (plant diversity) and regulating services (CO2 and CH4 fluxes) by comparing these services between intensive versus extensive pastures in subtropical and temperate pastures in the USDA Long-term Agroecosystem Research (LTAR) Network sites in Florida and Oklahoma, USA over multiple years. Our results suggest that grassland intensification led to a decrease in measured supporting and regulating services, but increased forage productivity in temperate pastures and forage digestibility in subtropical pastures. Intensification decreased the net CO2 sink of subtropical pastures while it did not affect the sink capacity of temperate pastures; and it also increased environmental CH4 emissions from subtropical pastures and reduced CH4 uptake in temperate pastures. Intensification enhanced the global warming potential associated with C fluxes of pastures in both ecoregions. Our study demonstrates that comparisons of agroecosystems in contrasting ecoregions can reveal important drivers of ecosystem services and general or region-specific opportunities and solutions to maintaining agricultural production and reducing environmental footprints. Further LTAR network-scale comparisons of multiple ecosystem services across croplands and grazinglands intensively vs extensively managed are warranted to inform the sustainable intensification of agriculture within US and beyond. Our results highlight that achieving both food security and environmental stewardship will involve the conservation of less intensively managed pastures while adopting sustainable strategies in intensively managed pastures

Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

SummaryBackground Lopinavir–ritonavir has been proposed as a treatment for COVID-19 on the basis of in vitro activity,preclinical studies, and observational studies. Here, we report the results of a randomised trial to assess whether lopinavir–ritonavir improves outcomes in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, platform trial, a range of possible treatments was compared with usual care in patients admitted to hospital with COVID-19. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus lopinavir–ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge (or one of the otherRECOVERY treatment groups: hydroxychloroquine, dexamethasone, or azithromycin) using web-based simple (unstratified) randomisation with allocation concealment. Randomisation to usual care was twice that of any of the active treatment groups (eg, 2:1 in favour of usual care if the patient was eligible for only one active group, 2:1:1 if the patient was eligible for two active groups). The primary outcome was 28-day all-cause mortality. Analyses weredone on an intention-to-treat basis in all randomly assigned participants. The trial is registered with ISRCTN,50189673, and ClinicalTrials.gov, NCT04381936.Findings Between March 19, 2020, and June 29, 2020, 1616 patients were randomly allocated to receive lopinavir–ritonavir and 3424 patients to receive usual care. Overall, 374 (23%) patients allocated to lopinavir–ritonavir and 767 (22%) patients allocated to usual care died within 28 days (rate ratio 1·03, 95% CI 0·91–1·17; p=0·60). Resultswere consistent across all prespecified subgroups of patients. We observed no significant difference in time until discharge alive from hospital (median 11 days [IQR 5 to >28] in both groups) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 0·98, 95% CI 0·91–1·05; p=0·53). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion who met the composite endpoint of invasive mechanical ventilation or death (risk ratio 1·09, 95% CI 0·99–1·20; p=0·092).Interpretation In patients admitted to hospital with COVID-19, lopinavir–ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir–ritonavir for treatment of patients admitted to hospital with COVID-19.Funding Medical Research Council and National Institute for Health Research

A Sub-Microscopic Gametocyte Reservoir Can Sustain Malaria Transmission

Novel diagnostic tools, including PCR and high field gradient magnetic fractionation (HFGMF), have improved detection of asexual Plasmodium falciparum parasites and especially infectious gametocytes in human blood. These techniques indicate a significant number of people carry gametocyte densities that fall below the conventional threshold of detection achieved by standard light microscopy (LM).To determine how low-level gametocytemia may affect transmission in present large-scale efforts for P. falciparum control in endemic areas, we developed a refinement of the classical Ross-Macdonald model of malaria transmission by introducing multiple infective compartments to model the potential impact of highly prevalent, low gametocytaemic reservoirs in the population. Models were calibrated using field-based data and several numerical experiments were conducted to assess the effect of high and low gametocytemia on P. falciparum transmission and control. Special consideration was given to the impact of long-lasting insecticide-treated bed nets (LLIN), presently considered the most efficient way to prevent transmission, and particularly LLIN coverage similar to goals targeted by the Roll Back Malaria and Global Fund malaria control campaigns. Our analyses indicate that models which include only moderate-to-high gametocytemia (detectable by LM) predict finite eradication times after LLIN introduction. Models that include a low gametocytemia reservoir (requiring PCR or HFGMF detection) predict much more stable, persistent transmission. Our modeled outcomes result in significantly different estimates for the level and duration of control needed to achieve malaria elimination if submicroscopic gametocytes are included.It will be very important to complement current methods of surveillance with enhanced diagnostic techniques to detect asexual parasites and gametocytes to more accurately plan, monitor and guide malaria control programs aimed at eliminating malaria

Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice

<p>Abstract</p> <p>Background</p> <p>Duchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy.</p> <p>Methods</p> <p>Using the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R) agonist treatment has on diaphragm function, morphology and gene expression.</p> <p>Results</p> <p>We have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression.</p> <p>Conclusion</p> <p>Together, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.</p