Enhancer control of MicroRNA miR-155 expression in EpsteinBarr virus-infected B cells

The oncogenic microRNA miR-155 is the most frequently upregulated miRNA in Epstein-Barr virus (EBV)-positive B cell malignancies and is upregulated in other non-viral lymphomas. Both the EBV nuclear antigen 2 (EBNA2), and B cell transcription factor, interferon regulatory factor 4 (IRF4) are known to activate transcription of the host cell gene from which miR-155 is processed (miR-155HG, BIC). EBNA2 also activates IRF4 transcription indicating that EBV may upregulate miR-155 through direct and indirect mechanisms. The mechanism of transcriptional regulation of IRF4 and miR-155HG by EBNA2 however has not been defined. We demonstrate that EBNA2 can activate IRF4 and miR-155HG expression through specific upstream enhancers that are dependent on the Notch signaling transcription factor RBPJ, a known binding partner of EBNA2. We demonstrate that in addition to activation of the miR-155HG promoter, IRF4 can also activate miR-155HG via the upstream enhancer also targeted by EBNA2. Gene editing to remove the EBNA2- and IRF4-responsive miR-155HG enhancer located 60 kb upstream of miR-155HG led to reduced miR155HG expression in EBV-infected cells. Our data therefore demonstrate that specific RBPJ-dependent enhancers regulate the IRF4-miR-155 expression network and play a key role in the maintenance of miR-155 expression in EBV-infected B cells. These findings provide important insights that will improve our understanding of miR-155 control in B cell malignancies

Monitoring stormwater contaminants in the Puget Sound nearshore: an active biomonitoring tool using transplanted mussels (Mytilus trossulus)

Stormwater delivers a diverse range of contaminants to receiving waters including Puget Sound. Monitoring stormwater pollutants and their effects on biota is critical to informing best management practices aimed at recovering Puget Sound health. In the winter of 2012/13, the Washington Department of Fish and Wildlife’s Toxics-focused Biological Observation System (TBiOS) team conducted a pilot study using transplanted mussels to characterize the extent and magnitude of contamination in nearshore biota of Puget Sound. Mussels are now a key TBiOS indicator organism for tracking contaminants in the nearshore, and the Stormwater Action Monitoring (SAM) program has adopted mussels for nearshore stormwater monitoring as well. SAM now serves as the primary funder of nearshore mussel monitoring in Puget Sound and the first two SAM mussel monitoring surveys were conducted during the winters of 2015/16 and 2017/18, with future surveys planned on a biennial basis. These mussel surveys utilized native bay mussels (Mytilus trossulus) from a local aquaculture source that were transplanted into anti-predator cages to locations along the Puget Sound shoreline. Monitoring sites covered a broad range of upland land-use types, from rural to highly urban, and concentrations of organic contaminants and metals were measured in the mussels after a two to three-month winter deployment period. Data from the first two years of mussel surveys (2012/13, 2015/16) indicates polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were the most abundant organic contaminants of those tested in the nearshore. Concentrations of both contaminants were significantly higher in the most urbanized areas and were positively correlated with impervious surface in upland watersheds adjacent to the nearshore. Patterns of PAHs (i.e. PAH fingerprints) in mussels from different locations demonstrate how mussels might be useful as indicators of sources for this particular class of stormwater contaminants in Puget Sound

Origins and population genetics of sambar deer (Cervus unicolor) introduced to Australia and New Zealand

Context. Some populations of introduced species cause significant undesirable impacts but can also act as reservoirs for genetic diversity. Sambar deer (Cervus unicolor) are ‘Vulnerable’ in their native range and invasive in Australia and New Zealand. Genetic data can be used to determine whether these introduced populations might serve as genetic reservoirs for declining native populations and to identify spatial units for management. Aims. We aimed to identify the provenance of sambar deer in Australia and New Zealand, and to characterise their genetic diversity and population structure. Methods. We used mitochondrial control region sequences and 18 nuclear microsatellite loci of 24 New Zealand and 63 Australian sambar deer collected across continuous habitat in each location. We estimated genetic diversity and population differentiation by using pairwise FST, AMOVA, and STRUCTURE analyses. We compared our data with 27 previously published native and invasive range sequences to identify phylogenetic relationships. Key results. Sambar deer in Australia and New Zealand are genetically more similar to those in the west of the native range (South and Central Highlands of India, and Sri Lanka), than to those in the east (eastern India, and throughout Southeast Asia). Nuclear genetic diversity was lower than in the native range; only one mitochondrial haplotype was found in each introduced population. Australian and New Zealand sambar deer were genetically distinct but there was no population structure within either population. Conclusions. The genetic differences we identified between these two introduced populations at putatively neutral loci indicate that there also may be underlying diversity at functional loci. The lack of population genetic structure that we found within introduced populations suggests that individuals within these popula- tions do not experience barriers to dispersal across the areas sampled. Implications. Although genetic diversity is reduced in the introduced range compared with the native range, sambar deer in Australia and New Zealand harbour unique genetic variants that could be used to strengthen genetic diversity in populations under threat in the native range. The apparent high levels of gene flow across the areas we sampled suggest that localised control is unlikely to be effective in Australia and New Zealand

Composite Fermion Wavefunctions Derived by Conformal Field Theory

The Jain theory of hierarchical Hall states is reconsidered in the light of recent analyses that have found exact relations between projected Jain wavefunctions and conformal field theory correlators. We show that the underlying conformal theory is precisely given by the W-infinity minimal models introduced earlier. This theory involves a reduction of the multicomponent Abelian theory that is similar to the projection to the lowest Landau level in the Jain approach. The projection yields quasihole excitations obeying non-Abelian fractional statistics. The analysis closely parallels the bosonic conformal theory description of the Pfaffian and Read-Rezayi states.Comment: 4 pages, 1 figur

On the infrared behaviour of 3d Chern-Simons theories in N=2 superspace

We discuss the problem of infrared divergences in the N=2 superspace approach to classically marginal three-dimensional Chern-Simons-matter theories. Considering the specific case of ABJM theory, we describe the origin of such divergences and offer a prescription to eliminate them by introducing non-trivial gauge-fixing terms in the action. We also comment on the extension of our procedure to higher loop order and to general three-dimensional Chern-Simons-matter models.Comment: 26 pages, 6 figures, JHEP3; v2: minor corrections and references added; v3: introduction expanded, presentation of section 3.3.1 improved, references added, version to appear in JHE

Long-term chromospheric activity in southern M dwarfs: Gl 229 A and Gl 752 A

Several late-type stars present activity cycles similar to that of the Sun. However, these cycles have been mostly studied in F to K stars. Due to their small intrinsic brightness, M dwarfs are not usually the targets of long-term observational studies of stellar activity, and their long-term variability is generally not known. In this work, we study the long-term activity of two M dwarf stars: Gl 229 A (M1/2) and Gl 752 A (M2.5). We employ medium resolution echelle spectra obtained at the 2.15 m telescope at the Argentinian observatory CASLEO between the years 2000 and 2010 and photometric observations obtained from the ASAS database. We analyzed Ca \II K line-core fluxes and the mean V magnitude with the Lomb-Scargle periodogram, and we obtain possible activity cycles of $\sim$4 yr and $\sim$7 yr for Gl 229 A and Gl 752 A respectively.Comment: Accepted for publication by Astronomical Journal (AJ

High Intensity Interval Training As A Novel Treatment For Impaired Awareness Of Hypoglycaemia In People With Type 1 Diabetes (Hit4hypos):a randomised parallel-group study

Aims/hypothesis: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH. Methods: HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18–55 years with type 1 diabetes of at least 5 years’ duration and HbA 1c levels &lt;75 mmol/mol (&lt;9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic–hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT. Results: Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75–32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic–hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: −988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (–298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: −4 [2] vs 0 [2], p&lt;0.05). Conclusions/interpretation: In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia. Trial registration: ISRCTN15373978. Funding: Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation. Graphical Abstract: [Figure not available: see fulltext.].</p

High Intensity Interval Training As A Novel Treatment For Impaired Awareness Of Hypoglycaemia In People With Type 1 Diabetes (Hit4hypos):a randomised parallel-group study

Aims/hypothesis: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH. Methods: HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18–55 years with type 1 diabetes of at least 5 years’ duration and HbA 1c levels &lt;75 mmol/mol (&lt;9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic–hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT. Results: Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75–32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic–hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: −988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (–298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: −4 [2] vs 0 [2], p&lt;0.05). Conclusions/interpretation: In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia. Trial registration: ISRCTN15373978. Funding: Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation. Graphical Abstract: [Figure not available: see fulltext.].</p

Renewal processes and fluctuation analysis of molecular motor stepping

We model the dynamics of a processive or rotary molecular motor using a renewal processes, in line with the work initiated by Svoboda, Mitra and Block. We apply a functional technique to compute different types of multiple-time correlation functions of the renewal process, which have applications to bead-assay experiments performed both with processive molecular motors, such as myosin V and kinesin, and rotary motors, such as F1-ATPase

Assessing the threat of toxic contaminants to early marine survival of Chinook salmon in the Salish Sea

Human development of the Salish Sea has resulted in loss and modification of salmonid habitats, including reduced habitat quality due to contaminant inputs, particularly in the lower reaches of rivers and estuaries of the central Puget Sound. Chemical contaminants released into the Salish Sea from anthropogenic sources can reduce the health and productivity of salmon. Juvenile salmon are exposed to contaminants in freshwater, estuarine, and marine habitats but they are particularly vulnernable as they transition from fresh to saltwater because this life history stage is especially sensitive to stressors that may reduce their early marine survival. Reduced growth and disease resistance have been demonstrated for juvenile Chinook salmon exposed to environmentally relevant contaminant levels; however, synoptic, Puget Sound-wide surveys to assess the extent and magnitude of contaminant exposure are lacking. In this study we measured exposure of juvenile Chinook salmon to chemicals of concern that enter Puget Sound via stormwater, wastewater treatment facilities, atmospheric deposition to marine waters, and groundwater. During the spring and summer of 2013, outmigrating fish were sampled from the river mouthes and two adjacent marine shorelines at each of five Puget Sound river-estuary systems: Skagit, Snohomish, Green/Duwamish, Puyallup/Hylebos, and Nisqually. We (1) report the extent and magnitude of exposure, (2) compare exposure in outmigrants across five major river-estuary systems, and (3) evaluate potential effects on marine survival. Results will be used to establish a time series of contaminant conditions in juvenile Chinook salmon to measure the effectiveness of current toxics reductions strategies and actions, inform future pollution reduction efforts, and enhanced recovery of Chinook salmon