The centromeric histone 3 variant (CENH3, aka CENP-A) is essential for the segregation of sister chromatids during mitosis and meiosis. To better define CENH3 functional constraints, we complemented ...a null allele in Arabidopsis with a variety of mutant alleles, each inducing a single amino acid change in conserved residues of the histone fold domain. Many of these transgenic missense lines displayed wild-type growth and fertility on self-pollination, but exhibited frequent post-zygotic death and uniparental inheritance when crossed with wild-type plants. The failure of centromeres marked by these missense mutation in the histone fold domain of CENH3 reproduces the genome elimination syndromes described with chimeric CENH3 and CENH3 from diverged species. Additionally, evidence that a single point mutation is sufficient to generate a haploid inducer provide a simple one-step method for the identification of non-transgenic haploid inducers in existing mutagenized collections of crop species. As proof of the extreme simplicity of this approach to create haploid-inducing lines, we performed an in silico search for previously identified point mutations in CENH3 and identified an Arabidopsis line carrying the A86V substitution within the histone fold domain. This A87V non-transgenic line, while fully fertile on self-pollination, produced postzygotic death and uniparental haploids when crossed to wild type.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or ...repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI - from initial triggers to chronic neuroinflammation - we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.
Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ...ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases.
Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa (-/-) mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture.
This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Prostate development follows a common pattern between species and depends on the actions of androgens to induce and support ductal branching morphogenesis of buds emerging from the urogenital sinus. ...The human prostate has a compact zonal anatomy immediately surrounding the urethra and below the urinary bladder. Rodents have a lobular prostate with lobes radiating away from the urethra. The human prostate is the site of benign hyperplasia, prostate cancer, and prostatitis. The rodent prostate has little naturally occurring disease. Rodents can be used to model aspects of human benign hyperplasia, but care should be taken in data interpretation and extrapolation to the human condition.
In phylogenetic analyses of molecular sequence data, partitioning involves estimating independent models of molecular evolution for different sets of sites in a sequence alignment. Choosing an ...appropriate partitioning scheme is an important step in most analyses because it can affect the accuracy of phylogenetic reconstruction. Despite this, partitioning schemes are often chosen without explicit statistical justification. Here, we describe two new objective methods for the combined selection of best-fit partitioning schemes and nucleotide substitution models. These methods allow millions of partitioning schemes to be compared in realistic time frames and so permit the objective selection of partitioning schemes even for large multilocus DNA data sets. We demonstrate that these methods significantly outperform previous approaches, including both the ad hoc selection of partitioning schemes (e.g., partitioning by gene or codon position) and a recently proposed hierarchical clustering method. We have implemented these methods in an open-source program, PartitionFinder. This program allows users to select partitioning schemes and substitution models using a range of information-theoretic metrics (e.g., the Bayesian information criterion, akaike information criterion AIC, and corrected AIC). We hope that PartitionFinder will encourage the objective selection of partitioning schemes and thus lead to improvements in phylogenetic analyses. PartitionFinder is written in Python and runs under Mac OSX 10.4 and above. The program, source code, and a detailed manual are freely available from www.robertlanfear.com/partitionfinder.
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for ...developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10
), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5-3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.
In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer ...patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status.
Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis.
After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms.
Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.
•First PARPi trial to show clinically meaningful OS benefit in HRD+ (BRCA/non-BRCA) newly diagnosed advanced ovarian cancer.•5-Year OS rate in HRD+ disease was 66% with olaparib + bevacizumab versus 48% with placebo + bevacizumab.•Forty-six percent of HRD+ patients receiving olaparib + bevacizumab were progression free at 5 years, versus 19% on bevacizumab alone.•No new safety signals were observed, and the incidence of myelodysplastic syndrome/acute myeloid leukemia remained low.•Maintenance olaparib + bevacizumab as a standard of care may enhance potential for cure for HRD+ disease in this setting.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Optical access networks connect multiple endpoints to a common network node via shared fibre infrastructure. They will play a vital role to scale up the number of users in quantum key distribution ...(QKD) networks. However, the presence of power splitters in the commonly used passive network architecture makes successful transmission of weak quantum signals challenging. This is especially true if QKD and data signals are multiplexed in the passive network. The splitter introduces an imbalance between quantum signal and Raman noise, which can prevent the recovery of the quantum signal completely. Here we introduce a method to overcome this limitation and demonstrate coexistence of multi-user QKD and full power data traffic from a gigabit passive optical network (GPON) for the first time. The dual feeder implementation is compatible with standard GPON architectures and can support up to 128 users, highlighting that quantum protected GPON networks could be commonplace in the future.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Banded iron formations were a prevalent feature of marine sedimentation ~3.8-1.8 billion years ago and they provide key evidence for ferruginous oceans. The disappearance of banded iron formations at ...~1.8 billion years ago was traditionally taken as evidence for the demise of ferruginous oceans, but recent geochemical studies show that ferruginous conditions persisted throughout the later Precambrian, and were even a feature of Phanerozoic ocean anoxic events. Here, to reconcile these observations, we track the evolution of oceanic Fe-concentrations by considering the temporal record of banded iron formations and marine red beds. We find that marine red beds are a prominent feature of the sedimentary record since the middle Ediacaran (~580 million years ago). Geochemical analyses and thermodynamic modelling reveal that marine red beds formed when deep-ocean Fe-concentrations were > 4 nM. By contrast, banded iron formations formed when Fe-concentrations were much higher (> 50 μM). Thus, the first widespread development of marine red beds constrains the timing of deep-ocean oxygenation.The evolution of oceanic redox state in the past is poorly known. Here, the authors present a temporal record of banded iron formations and marine red beds, which indicate deep-ocean oxygenation occurred in the middle Ediacaran, coinciding with the onset of widespread marine red beds.
Motivation: Phylogenetic and evolutionary inference can be severely misled if recombination is not accounted for, hence screening for it should be an essential component of nearly every comparative ...study. The evolution of recombinant sequences can not be properly explained by a single phylogenetic tree, but several phylogenies may be used to correctly model the evolution of non-recombinant fragments. Results: We developed a likelihood-based model selection procedure that uses a genetic algorithm to search multiple sequence alignments for evidence of recombination breakpoints and identify putative recombinant sequences. GARD is an extensible and intuitive method that can be run efficiently in parallel. Extensive simulation studies show that the method nearly always outperforms other available tools, both in terms of power and accuracy and that the use of GARD to screen sequences for recombination ensures good statistical properties for methods aimed at detecting positive selection. Availability: Freely available Contact:spond@ucsd.edu
PDF
