The essential Mcm7 protein PROLIFERA is localized to the nucleus of dividing cells during the G(1) phase and is required maternally for early Arabidopsis development

PROLIFERA (PRL) encodes a homologue of the DNA replication licensing factor Mcm7, a highly conserved protein found in all eukaryotes. Insertions in the PROLIFERA gene are lethal, resulting in decreased transmission through the female gametophyte, and homozygous embryonic lethality. We show here that PROLIFERA is specifically expressed in populations of dividing cells in sporophytic tissues of the plant body, such as the palisade layer of the leaf and founder cells of initiating flower primordia, Gene fusions with the green fluorescent protein (GFP) reveal that the PROLIFERA protein accumulates during the G(1) phase of the cell cycle, and is transiently localized to the nucleus. During mitosis, the fusion protein rapidly disappears, returning to daughter nuclei during G(1), PROLIFERA::GUS fusions are strongly expressed in the central cell nucleus of mature megagametophytes, which have a variety of arrest points reflecting a leaky lethality. Expression is also observed in the endosperm of mutant prl embryo sacs that arrest following fertilization. Crosses with wild-type pollen result in occasional embryonic lethals that also stain for GUS activity, In contrast, embryos resulting from crosses of wild-type carpels with PRL::GUS pollen do not stain and are phenotypically normal. In situ hybridization of GUS fusion RNA indicates transcription is equivalent from maternally and paternally derived alleles, so that accumulation of maternally derived gametophytic protein is likely to be responsible for the 'maternal' effect

Efficacy of depth jumps to elicit a post-activation performance enhancement in junior endurance runners

Objectives: To determine the effect of performing depth jumps (DJ) pre-exercise on running economy (RE) and time to exhaustion (TTE) at the speed associated with maximal oxygen uptake (sV˙O2max) in a group of high-performing junior middle-distance runners. Design: Randomized crossover study. Methods: Seventeen national- and international-standard male distance runners (17.6 ± 1.2 years, 63.4 ± 6.3 kg, 1.76 ± 0.06 m, 70.7 ± 5.2 mL kg−1 min−1) completed two trials. Following a 5 min warm-up at 60% V˙O2max, participants performed a 5 min run at 20%Δ below oxygen uptake corresponding with lactate turn-point to determine pre-intervention RE. Participants then completed either six DJ from a box equivalent to their best counter-movement jump (CMJ) or a control condition (C) involving body weight quarter squats. After a 10 min passive recovery, another 5 min sub-maximal run was performed followed by a run to exhaustion at sV˙O2max. Results: Compared to the C trial, DJ produced moderate improvements (−3.7%, 95% confidence interval for effect size: 0.25–1.09) in RE, which within the context of minimal detectable change is considered possibly beneficial. Differences in TTE and other physiological variables were most likely trivial (ES: <0.2). Individual responses were small, however a partial correlation revealed a moderate relationship (r = −0.55, p = 0.028) between change in RE and CMJ height. Conclusions: The inclusion of a set of six DJ in the warm-up routine of a well-trained young male middle-distance runner is likely to provide a moderate improvement in RE

Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium

Introduction: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumour necrosis factor (TNF) family member capable of inducing apoptosis in many cell types. Methods: Using immunohistochemistry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) and real-time PCR we investigated the expression of TRAIL, TRAIL receptors and several key molecules of the intracellular apoptotic pathway in human synovial tissues from various types of arthritis and normal controls. Synovial tissues from patients with active rheumatoid arthritis (RA), inactive RA, osteoarthritis (OA) or spondyloarthritis (SpA) and normal individuals were studied. Results Significantly higher levels of TRAIL, TRAIL R1, TRAIL R2 and TRAIL R4 were observed in synovial tissues from patients with active RA compared with normal controls (p < 0.05). TRAIL, TRAIL R1 and TRAIL R4 were expressed by many of the cells expressing CD68 (macrophages). Lower levels of TUNEL but higher levels of cleaved caspase-3 staining were detected in tissue from active RA compared with inactive RA patients (p < 0.05). Higher levels of survivin and x-linked inhibitor of apoptosis protein (xIAP) were expressed in active RA synovial tissues compared with inactive RA observed at both the protein and mRNA levels. Conclusions: This study indicates that the induction of apoptosis in active RA synovial tissues is inhibited despite stimulation of the intracellular pathway(s) that lead to apoptosis. This inhibition of apoptosis was observed downstream of caspase-3 and may involve the caspase-3 inhibitors, survivin and xIAP.Anak ASSK Dharmapatni, Malcolm D Smith, David M Findlay, Christopher A Holding, Andreas Evdokiou, Michael J Ahern, Helen Weedon, Paul Chen, Gavin Screaton, Xiao N Xu and David R Hayne

OceanSODA-UNEXE: a multi-year gridded Amazon and Congo River outflow surface ocean carbonate system dataset

Large rivers play an important role in transferring water and all of its constituents, including carbon in its various forms, from the land to the ocean, but the seasonal and inter-annual variations in these riverine flows remain unclear. Satellite Earth observation datasets and reanalysis products can now be used to observe synoptic-scale spatial and temporal variations in the carbonate system within large river outflows. Here, we present the University of Exeter (UNEXE) Satellite Oceanographic Datasets for Acidification (OceanSODA) dataset (OceanSODA-UNEXE) time series, a dataset of the full carbonate system in the surface water outflows of the Amazon (2010–2020) and Congo (2002–2016) rivers. Optimal empirical approaches were used to generate gridded total alkalinity (TA) and dissolved inorganic carbon (DIC) fields in the outflow regions. These combinations were determined by equitably evaluating all combinations of algorithms and inputs against a reference matchup database of in situ observations. Gridded TA and DIC along with gridded temperature and salinity data enable the calculation of the full carbonate system in the surface ocean (which includes pH and the partial pressure of carbon dioxide, pCO2). The algorithm evaluation constitutes a Type-A uncertainty evaluation for TA and DIC, in which model, input and sampling uncertainties are considered. Total combined uncertainties for TA and DIC were propagated through the carbonate system calculation, allowing all variables to be provided with an associated uncertainty estimate. In the Amazon outflow, the total combined uncertainty for TA was 36 µmol kg−1 (weighted root-mean-squared difference, RMSD, of 35 µmol kg−1 and weighted bias of 8 µmol kg−1 for n = 82), whereas it was 44 µmol kg−1 for DIC (weighted RMSD of 44 µmol kg−1 and weighted bias of −6 µmol kg−1 for n = 70). The spatially averaged propagated combined uncertainties for the pCO2 and pH were 85 µatm and 0.08, respectively, where the pH uncertainty was relative to an average pH of 8.19. In the Congo outflow, the combined uncertainty for TA was identified as 29 µmol kg−1 (weighted RMSD of 28 µmol kg−1 and weighted bias of 6 µmol kg−1 for n = 102), whereas it was 40 µmol kg−1 for DIC (weighted RMSD of 37 µmol kg−1 and weighted bias of −16 µmol kg−1 for n = 77). The spatially averaged propagated combined uncertainties for pCO2 and pH were 74 µatm and 0.08, respectively, where the pH uncertainty was relative to an average pH of 8.21. The combined uncertainties in TA and DIC in the Amazon and Congo outflows are lower than the natural variability within their respective regions, allowing the time-varying regional variability to be evaluated. Potential uses of these data would be the assessment of the spatial and temporal flow of carbon from the Amazon and Congo rivers into the Atlantic and the assessment of the riverine-driven carbonate system variations experienced by tropical reefs within the outflow regions. The data presented in this work are available at https://doi.org/10.1594/PANGAEA.946888 (Sims et al., 2023).</p

Hypoglycaemia in severe malaria, clinical associations and relationship to quinine dosage

<p>Abstract</p> <p>Background</p> <p>Hypoglycaemia is an independent risk factor for death in severe malaria and a recognized adverse treatment effect of parenteral quinine. In 2006 our hospital changed quinine treatment policy from 15 mg/kg loading (plus 10 mg/kg 12-hourly) to 20 mg/kg loading (plus 10 mg/kg 8-hourly) to comply with new WHO guidelines. This presented us with the opportunity to examine whether there was any dose relationship of quinine and hypoglycaemia occurrence.</p> <p>Methods</p> <p>Retrospective case notes review of all children admitted to hospital with severe falciparum malaria between April 2002 - July 2009, before and after the introduction of the new WHO quinine regimen. Four-hourly bedside glucose levels were measured until intravenous quinine was discontinued. Clinical events immediately preceding or concurrent with each episode of hypoglycaemia (glucose < = 3.0 mmol/l) were recorded.</p> <p>Results</p> <p>954 children received the old quinine regime and 283 received the new regime. We found no evidence of an increased prevalence of hypoglycaemia (< = 3.0 mmol/L) on the new regime compared to former (15% vs. 15%); similar findings were noted for profound hypoglycaemia (< 2.2 mmols/L) 8% v 5%, P = 0.07. Episodes were co-incident with disease severity markers: coma (57%), circulatory failure (38%) and respiratory distress (21%) but less commonly with seizures (10%). Disruption of maintenance fluids and/or blood transfusion concurred with 42% of the hypoglycaemia episodes. Post admission hypoglycaemia increased odds of fatal outcome (24%) compared to euglycaemic counterparts (8%), odds ratio = 3.45 (95% confidence interval = 2.30-5.16) P < 0.01.</p> <p>Conclusion</p> <p>There was no evidence to indicate a dose relationship between quinine and occurrence of hypoglycaemia. Hypoglycaemia concurred with severity features, disruption of glucose infusion and transfusion. Careful glucose monitoring should be targeted to these complications where resources are limited.</p

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer : the ProtecT three-arm RCT

Background Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments. Objectives To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50–69 years. Design A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up. Setting Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK. Participants Between 2001 and 2009, 228,966 men aged 50–69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment. Interventions The interventions were active monitoring, radical prostatectomy and radical radiotherapy. Trial primary outcome measure Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants. Secondary outcome measures Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes. Results There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy’s impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy). Limitations A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed. Conclusions At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years. Trial registration Current Controlled Trials ISRCTN20141297

A Multilevel Approach to Relating Subjective Workload to Performance After Shifts in Task Demand

Objective: The aim of this laboratory experiment was to demonstrate how taking a longitudinal, multilevel approach can be used to examine the dynamic relationship between subjective workload and performance over a given period of activity involving shifts in task demand.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline