involves karyotyping, whereas in the Netherlands, patients who undergo amniocentesis have a more limited assessment only for trisomies 13, 18, and 21 and the sex chromosomes; thus, the tradeoff is a bit different.In addition, cfDNA is provided as a screening test for trisomies 13, 18, and 21, not just for Down syndrome. However, the performance characteristics of cfDNA for trisomies 13 and 18 are not as favorable as for T21, with a higher rate of falsenegative and false-positive results. In addition, a percentage of patients-somewhere between 1.5% and 8%-fail to obtain a result, usually because of insufficient fetal DNA. Such "low fetal fraction" is associated with obesity, which is a significant problem affecting a high percentage of reproductive-aged women in the United States. It is estimated that 20% to 50% of cfDNA tests fail to provide adequate fetal DNA in obese women. In addition, low fetal fraction is also associated with aneuploidy; therefore, women with cfDNA test failure should be considered high risk and offered follow-up with diagnostic testing (as well as a second attempt at cfDNA). When these potential outcomes are all considered, the performance characteristics of cfDNA versus traditional screening are not as clearly superior.Like the authors of this abstracted paper, several other authors and experts (Prenat Diagn 2013;33 (7):636-642) have suggested a contingent approach, using multiple marker screening as an initial screening tool, and then offering NIPT to intermediate-risk patients and either cfDNA or invasive testing to the highest-risk patients. Before completely changing the current standard of care, we need to understand this tradeoff. These authors consider comparative costs, but do not really provide incremental cost-effectiveness ratios, which are the best way to compare these strategies. While cfDNA is a better test if we are looking at a very precise test for a single disorder, only in patients in whom the test is successful at providing a result current screening may be preferable if we are looking to screen the entire population for a broad range of birth defects. Cost utility analyses, conducted by independent investigators and considering all important outcomes, are clearly needed before our approach completely changes. -MEN)

No abstract

The emergence and dissemination of antibiotic-resistant bacterial pathogens have spurred the urgent need to develop novel antimicrobial agents with different mode of action. In this respect, we turned several fusogenic peptides (FPs) derived from the hemagglutinin glycoproteins (HAs) of IAV into potent antibacterials by replacing the negatively or neutrally charged residues of FPs with positively charged lysines. Their antibacterial activities were evaluated by testing the MICs against a panel of bacterial strains including S. aureus, S. mutans, P. aeruginosa, and E. coli. The results showed that peptides HA-FP-1, HA-FP-2-1, and HA-FP-3-1 were effective against both Gram-positive and Gram-negative bacteria with MICs ranging from 1.9 to 16.0 μm, while the toxicities toward mammalian cells were low. In addition, the mode of action and the secondary structure of these peptides were also discussed. These data not only provide several potent peptides displaying promising potential in development as broad antimicrobial agents, but also present a useful strategy in designing new antimicrobial agents.

Supplementary data are available at Bioinformatics online.

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.Proteolysis by the ubiquitin-proteasome system (UPS) is a tightly regulated biological process in eukaryotic cells and is crucial for their homeostasis, signaling, and fate determination. 1-3 Proteins subjected to degradation are typically marked by polyubiquitin chains to be hydrolyzed in a precise, rapid, timely, and ATP-dependent manner by the 19S regulatory subunit of the 26S proteasome. 3-6 UPS-dependent degradation essentially contributes to proteostasis and plays a key role in neuronal development and function 7,8 by regulating synaptic plasticity, 9,10

Genomic imprinting is an important epigenetic phenomenon in studying complex traits and has generally been examined by detecting parent-of-origin effects of alleles. The parental-asymmetry test (PAT) based on nuclear families with both parents and its extensions to deal with missing parental genotypes is simple and powerful for such a task. However, these methods only use case (affected) children in nuclear families and thus do not make full use of information on control (unaffected) children, if available, in these families. In this article, we propose a novel parent-of-origin effects test C-PATu (the combined test of PATu and 1-PATu) by using both the control and case children in nuclear families with one or both parents. C-PATu is essentially a weighted framework, in which the test based on all the control children and their parents and that based on all the case children and their parents are weighted according to the population disease prevalence. Simulation results demonstrate that the proposed tests control the size well under no parent-of-origin effects and using additional information from control children improves the power of the tests under the imprinting alternative. Application of C-PATu to a Framingham Heart Study data set further shows the feasibility in practical application of the test.

Previous work by Cho and Choi describing the development of a cyanoacrylamide-based fluorescence sensor for reversible detection of thiols in homogenous solutions was inadvertently omitted from the reference list of this Article. This work should have been cited in the first paragraph of the discussion, following the rationale behind the development of the Michael acceptor, as follows: 'A fluorescent sensor based on the cyanoacrylamide Michael acceptor has previously been shown to reversibly react with thiols in homogenous solutions but without any cellular applications, possibly due to the low quantum yield and poor aqueous solubility

Genomic imprinting is an important epigenetic factor in complex traits study, and there has recently been considerable interest in association study for quantitative traits by incorporating imprinting. However, these methods need the assumptions of Hardy-Weinberg equilibrium or only use information from families with one child. In this paper, by taking imprinting into account and making no assumption about the distribution of the quantitative traits, we propose two novel classes of Q-C-TDTI(c) and Q-C-MAX(c) family-based association tests for quantitative traits. The tests flexibly accommodate family data with missing parental genotype and with multiple siblings. Q-C-TDTI(c) is derived from a two-stage analysis, where in the first stage Q-C-PAT(c) is applied to test for imprinting effects and in the second stage we select the most appropriate statistic among three transmission disequilibrium tests for association according to the finding from Q-C-PAT(c). Another proposed Q-C-MAX(c) approach takes the maximum of the three statistics. Compared with the existing alternative methods, the simulation results demonstrate that the two proposed tests are robust to population stratification and have better performance for testing association under various scenarios. Further, the powerful and versatile Q-C-TDTI(c) test is applied to analyze Framingham Heart Study data.