PETAL LOSS, a trihelix transcription factor gene, regulates perianth architecture in the Arabidopsis flower

Perianth development is specifically disrupted in mutants of the PETAL LOSS (PTL) gene, particularly petal initiation and orientation. We have cloned PTL and show that it encodes a plant-specific trihelix transcription factor, one of a family previously known only as regulators of light-controlled genes. PTL transcripts were detected in the early-developing flower, in four zones between the initiating sepals and in their developing margins. Strong misexpression of PTL in a range of tissues universally results in inhibition of growth, indicating that its normal role is to suppress growth between initiating sepals, ensuring that they remain separate. Consistent with this, sepals are sometimes fused in ptl single mutants, but much more frequently in double mutants with either of the organ boundary genes cup-shaped cotyledon1 or 2. Expression of PTL within the newly arising sepals is apparently prevented by the PINOID auxin-response gene. Surprisingly, PTL expression could not be detected in petals during the early stages of their development, so petal defects associated with PTL loss of function may be indirect, perhaps involving disruption to signalling processes caused by overgrowth in the region. PTL-driven reporter gene expression was also detected at later stages in the margins of expanding sepals, petals and stamens, and in the leaf margins; thus, PTL may redundantly dampen lateral outgrowth of these organs, helping define their final shape

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue

The techno-ecological practice as the politics of ontological coalitions

The paper focuses on the art projects aimed at visualizing (grasping) the physical or biological phenomena through interfaces and / or installations designed specifically for such purpose. Such works often mirror the post-­digital condition of our time where the digital technologies constitute the common background for everyday activities, no longer having the allure of "new" and "exciting" (Berry, Dieter et al., 2015). In this process, both the networked technologies of wireless communication and the act of crossing the boundaries between the digital and the physical play the crucial role as the post-­digital networked imagery increasingly becomes directly connected to the physical environment. I would like to ponder on the questions of processuality and relationality involved in such instances where the complexity of the hybrid works of art clearly transgresses the paradigm of representationalism (Thrift, 2008;; Anderson and Harrison, 2010;; Kember and Zylinska, 2012). The particular attention is given to the fact that such artworks bond different ontological realms (discursive, physical, digital) and different agents (human and non-­human, carbon-­based and software-­based) forging “ontological coalitions” (Malafouris, 2013). Throughout the article the mutlirealist and relational perspective is offered, inspired by the propositions of Gilbert Simondon and Etienne Souriau. Based on the research project supported by National Science Centre Poland ("The aesthetics of post-­digital imagery: between new materialism and object-­oriented philosophy", 2016/21/B/HS2/00746)

Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data

To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of β cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery

Approaches to improve the diagnosis and management of infertility

Recent advances in our understanding of the causes of infertility and of assisted reproductive technology (ART) have led to the development of complex diagnostic tools, prognostic models and treatment options. The Third Evian Annual Reproduction (EVAR) Workshop Meeting was held on 26-27 April 2008 to evaluate evidence supporting current approaches to the diagnosis and management of infertility and to identify areas for future research efforts. Specialist reproductive medicine clinicians and scientists delivered presentations based on published literature and ongoing research on patient work-up, ovarian stimulation and embryo quality assessment during ART. This report is based on the expert presentations and subsequent group discussions and was supplemented with publications from literature searches and the authors' knowledge. It was agreed that single embryo transfer (SET) should be used with increasing frequency in cycles of ART. Continued improvements in cryopreservation techniques, which improve pregnancy rates using supernumerary frozen embryos, are expected to augment the global uptake of SET. Adaptation and personalization of fertility therapy may help to optimize efficacy and safety outcomes for individual patients. Prognostic modelling and personalized management strategies based on individual patient characteristics may prove to represent real progress towards improved treatment. However, at present, there is limited good-quality evidence to support the use of these individualized approaches. Greater quality control and standardization of clinical and laboratory evaluations are required to optimize ART practices and improve individual patient outcomes. Well-designed, good-quality studies are required to drive improvements to the diagnosis and management of ART processes

Buried Versus Exposed Kirschner Wires Following Fixation of Hand Fractures: l Clinician and Patient Surveys

Background: Fractures of the metacarpals and phalanges are common. Placement of Kirschner wires (K-wires) is the most common form of surgical fixation. After placement, a key decision is whether to bury the end of a K-wire or leave it protruding from the skin (exposed). A recent systematic review found no evidence to support either approach. The aim of study was to investigate current clinical practice, understand the key factors influencing clinician decision-making, and explore patient preferences to inform the design of a randomized clinical trial. Methods: The steering group developed surveys for hand surgeons, hand therapists, and patients. Following piloting, they were distributed across the United Kingdom hand surgery units using the Reconstructive Surgery Trials Network. Results: A total of 423 hand surgeons, 187 hand therapists, and 187 patients completed the surveys. Plastic surgeons and junior surgical trainees preferred to leave K-wires not buried. Ease of removal correlated with a decision to leave wires exposed, whereas perceived risk of infection correlated with burying wires. Cost did not affect the decision. Hand therapists were primarily concerned about infection and patient-related outcomes. Patients were most concerned about wire-related problems and pain. Conclusion: This national survey provides a new understanding of the use of K-wires to manage hand fractures in the United Kingdom. A number of nonevidence-based factors seem to influence the decision to bury or leave K-wires exposed. The choice has important clinical and health economic implications that justify a randomized controlled trial

Biological versus chronological ovarian age:implications for assisted reproductive technology

<p>Abstract</p> <p>Background</p> <p>Women have been able to delay childbearing since effective contraception became available in the 1960s. However, fertility decreases with increasing maternal age. A slow but steady decrease in fertility is observed in women aged between 30 and 35 years, which is followed by an accelerated decline among women aged over 35 years. A combination of delayed childbearing and reduced fecundity with increasing age has resulted in an increased number and proportion of women of greater than or equal to 35 years of age seeking assisted reproductive technology (ART) treatment.</p> <p>Methods</p> <p>Literature searches supplemented with the authors' knowledge.</p> <p>Results</p> <p>Despite major advances in medical technology, there is currently no ART treatment strategy that can fully compensate for the natural decline in fertility with increasing female age. Although chronological age is the most important predictor of ovarian response to follicle-stimulating hormone, the rate of reproductive ageing and ovarian sensitivity to gonadotrophins varies considerably among individuals. Both environmental and genetic factors contribute to depletion of the ovarian oocyte pool and reduction in oocyte quality. Thus, biological and chronological ovarian age are not always equivalent. Furthermore, biological age is more important than chronological age in predicting the outcome of ART. As older patients present increasingly for ART treatment, it will become more important to critically assess prognosis, counsel appropriately and optimize treatment strategies. Several genetic markers and biomarkers (such as anti-Müllerian hormone and the antral follicle count) are emerging that can identify women with accelerated biological ovarian ageing. Potential strategies for improving ovarian response include the use of luteinizing hormone (LH) and growth hormone (GH). When endogenous LH levels are heavily suppressed by gonadotrophin-releasing hormone analogues, LH supplementation may help to optimize treatment outcomes for women with biologically older ovaries. Exogenous GH may improve oocyte development and counteract the age-related decline of oocyte quality. The effects of GH may be mediated by insulin-like growth factor-I, which works synergistically with follicle-stimulating hormone on granulosa and theca cells.</p> <p>Conclusion</p> <p>Patients with biologically older ovaries may benefit from a tailored approach based on individual patient characteristics. Among the most promising adjuvant therapies for improving ART outcomes in women of advanced reproductive age are the administration of exogenous LH or GH.</p