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

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

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

Monitoring psychomotor development in a resource-limited setting:An evaluation of the Kilifi Developmental Inventory

Background: Modifications made to the Kilifi Developmental Checklist and the psychometric characteristics of the new measure (The Kilifi Developmental Inventory) which assess the psychomotor functioning of children aged 6– 35 months are described. Methods: Two groups of community children (319 rural and 104 urban dwellers) and nine children with neurodevelopmental disorders were recruited for a cross-sectional study. Results: In both a rural and urban reference population, the inventory showed excellent internal consistency, interobserver agreement, test-retest reliability and sensitivity to maturational changes. Children with neurodevelopmental impairment and those who were underweight had significantly lower scores than the community sample, attesting to the sensitivity of the measure. Mothers found the assessment procedures acceptable and informative. Conclusions: The Kilifi Developmental Inventory is a culturally appropriate measure that can be used to monitor and describe the development of at-risk children in resource-limited settings in Kenya

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

Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial

IMPORTANCE Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. OBJECTIVE To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality. DESIGN, SETTING, AND PARTICIPANTS The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. INTERVENTION An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. MAIN OUTCOMES AND MEASURES Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. RESULTS Among 415 357 randomizedmen(mean [SD] age, 59.0[5.6] years), 189 386 in the intervention group and 219 439 in the control groupwere included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%)attended the PSAtesting clinic and 67 313 (36%) underwent PSAtesting. Of 64 436 with a valid PSAtest result, 6857 (11%) had a PSA level between 3 ng/mLand 19.9 ng/mL, ofwhom5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95%CI, -0.047 to0.022]; rate ratio [RR] ,0.96 [95%CI,0.85 to 1.08]; P = .50). The number diagnosed with prostate cancerwas higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95%CI, 1.14 to 1.25] ; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lowerwere identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%] ) (difference per 1000 men, 6.11 [95%CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, therewere 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR,0.99 [95%CI,0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RRwas0.93 (95%CI,0.67 to 1.29; P = .66). CONCLUSIONS AND RELEVANCE Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. TRIAL REGISTRATION ISRCTN Identifier: ISRCTN92187251