Fieldscormier6128

Most of the technical information was accurate or corrected within the conversation. For most users this enquiry was part of a broader decision-making process and there was no evidence that users planned to make decisions based on forum discussions alone.

Our analysis has implications for healthcare organisations that offer or signpost to online information on contraception. It suggests that improvements in the online 'wrap around' information are needed to help decide when to consult, prepare for the consultation, understand the information given and manage post-consultation questions.

Our analysis has implications for healthcare organisations that offer or signpost to online information on contraception. Selleck WP1130 It suggests that improvements in the online 'wrap around' information are needed to help decide when to consult, prepare for the consultation, understand the information given and manage post-consultation questions.The predictive capabilities of deep neural networks (DNNs) continue to evolve to increasingly impressive levels. However, it is still unclear how training procedures for DNNs succeed in finding parameters that produce good results for such high-dimensional and nonconvex loss functions. In particular, we wish to understand why simple optimization schemes, such as stochastic gradient descent, do not end up trapped in local minima with high loss values that would not yield useful predictions. We explain the optimizability of DNNs by characterizing the local minima and transition states of the loss-function landscape (LFL) along with their connectivity. We show that the LFL of a DNN in the shallow network or data-abundant limit is funneled, and thus easy to optimize. Crucially, in the opposite low-data/deep limit, although the number of minima increases, the landscape is characterized by many minima with similar loss values separated by low barriers. This organization is different from the hierarchical landscapes of structural glass formers and explains why minimization procedures commonly employed by the machine-learning community can navigate the LFL successfully and reach low-lying solutions.CRISPR-Cas genome engineering has revolutionized biomedical research by enabling targeted genome modification with unprecedented ease. In the popular model organism Drosophila melanogaster, gene editing has so far relied exclusively on the prototypical CRISPR nuclease Cas9. Additional CRISPR systems could expand the genomic target space, offer additional modes of regulation, and enable the independent manipulation of genes in different cells of the same animal. Here we describe a platform for efficient Cas12a gene editing in Drosophila We show that Cas12a from Lachnospiraceae bacterium, but not Acidaminococcus spec., can mediate robust gene editing in vivo. In combination with most CRISPR RNAs (crRNAs), LbCas12a activity is high at 29 °C, but low at 18 °C, enabling modulation of gene editing by temperature. LbCas12a can directly utilize compact crRNA arrays that are substantially easier to construct than Cas9 single-guide RNA arrays, facilitating multiplex genome engineering. Furthermore, we show that conditional expression of LbCas12a is sufficient to mediate tightly controlled gene editing in a variety of tissues, allowing detailed analysis of gene function in a multicellular organism. We also test a variant of LbCas12a with a D156R point mutation and show that it has substantially higher activity and outperforms a state-of-the-art Cas9 system in identifying essential genes. Cas12a gene editing expands the genome-engineering toolbox in Drosophila and will be a powerful method for the functional annotation of the genome. This work also presents a fully genetically encoded Cas12a system in an animal, laying out principles for the development of similar systems in other genetically tractable organisms for multiplexed conditional genome engineering.Cholesterol is an integral component of eukaryotic cell membranes and a key molecule in controlling membrane fluidity, organization, and other physicochemical parameters. It also plays a regulatory function in antibiotic drug resistance and the immune response of cells against viruses, by stabilizing the membrane against structural damage. While it is well understood that, structurally, cholesterol exhibits a densification effect on fluid lipid membranes, its effects on membrane bending rigidity are assumed to be nonuniversal; i.e., cholesterol stiffens saturated lipid membranes, but has no stiffening effect on membranes populated by unsaturated lipids, such as 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). This observation presents a clear challenge to structure-property relationships and to our understanding of cholesterol-mediated biological functions. Here, using a comprehensive approach-combining neutron spin-echo (NSE) spectroscopy, solid-state deuterium NMR (2H NMR) spectroscopy, and molecular dynamics (MD) simulations-we report that cholesterol locally increases the bending rigidity of DOPC membranes, similar to saturated membranes, by increasing the bilayer's packing density. All three techniques, inherently sensitive to mesoscale bending fluctuations, show up to a threefold increase in effective bending rigidity with increasing cholesterol content approaching a mole fraction of 50%. Our observations are in good agreement with the known effects of cholesterol on the area-compressibility modulus and membrane structure, reaffirming membrane structure-property relationships. The current findings point to a scale-dependent manifestation of membrane properties, highlighting the need to reassess cholesterol's role in controlling membrane bending rigidity over mesoscopic length and time scales of important biological functions, such as viral budding and lipid-protein interactions.RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. link2 Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. link3 However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown. A lipidomic analysis of primary human keratinocytes revealed accumulation of numerous lipid species during suspension-induced differentiation. A small interfering RNA screen of 258 lipid-modifying enzymes identified two genes that on knockdown induced epidermal differentiation ELOVL1, encoding elongation of very long-chain fatty acids protein 1, and SLC27A1, encoding fatty acid transport protein 1. By intersecting lipidomic datasets from suspension-induced differentiation and knockdown keratinocytes, we pinpointed candidate bioactive lipid subspecies as differentiation regulators. Several of these-ceramides and glucosylceramides-induced differentiation when added to primary keratinocytes in culture. Our results reveal the potential of lipid subspecies to regulate exit from the epidermal stem cell compartment.In decision making under risk (DMR) participants' choices are based on probability values systematically different from those that are objectively correct. Similar systematic distortions are found in tasks involving relative frequency judgments (JRF). These distortions limit performance in a wide variety of tasks and an evident question is, Why do we systematically fail in our use of probability and relative frequency information? We propose a bounded log-odds model (BLO) of probability and relative frequency distortion based on three assumptions 1) log-odds probability and relative frequency are mapped to an internal log-odds scale, 2) boundedness the range of representations of probability and relative frequency are bounded and the bounds change dynamically with task, and 3) variance compensation the mapping compensates in part for uncertainty in probability and relative frequency values. We compared human performance in both DMR and JRF tasks to the predictions of the BLO model as well as 11 alternative models, each missing one or more of the underlying BLO assumptions (factorial model comparison). The BLO model and its assumptions proved to be superior to any of the alternatives. In a separate analysis, we found that BLO accounts for individual participants' data better than any previous model in the DMR literature. We also found that, subject to the boundedness limitation, participants' choice of distortion approximately maximized the mutual information between objective task-relevant values and internal values, a form of bounded rationality.The Arctic is experiencing a rapid shift toward warmer regimes, calling for a need to understand levels of biodiversity and ecosystem responses to climate cycles. This study presents genetic data for 109 Arctic marine forest species (seaweeds), which revealed contiguous populations extending from the Bering Sea to the northwest Atlantic, with high levels of genetic diversity in the east Canadian Arctic. One-fifth of the species sampled appeared restricted to Arctic waters. Further supported by hindcasted species distributions during the Last Glacial Maximum, we hypothesize that Arctic coastal systems were recolonized from many geographically disparate refugia leading to enriched diversity levels in the east Canadian Arctic, with important contributions stemming from northerly refugia likely centered along southern Greenland. Our results suggest Arctic marine biomes persisted through cycles of glaciation, leading to unique assemblages in polar waters, rather than being entirely derived from southerly (temperate) areas following glaciation. As such, Arctic marine species are potentially born from selective pressures during Cenozoic global cooling and eventual ice conditions beginning in the Pleistocene. Arctic endemic diversity was likely additionally driven by repeated isolations into globally disparate refugia during glaciation. This study highlights the need to take stock of unique Arctic marine biodiversity. Amplification of warming and loss of perennial ice cover are set to dramatically alter available Arctic coastal habitat, with the potential loss of diversity and decline in ecosystem resilience.