Stringency of antisense regulation varies based on volatility of mRNA target region

Bacteria can regulate gene expression by transcribing antisense RNA to interfere with protein translation. Antisense has been shown to control a wide variety of prokaryotic proteins, including membrane proteins, protein toxins, and proteins involved in transport and metabolism. This type of regulation can be used in the production of biologics to optimize the health of the culture and maximize production of the desired product. We examined naturally occurring antisense to enhance design principles for product optimization. We found that the level of secondary structure fluctuation of the antisense binding site varied depending on the function of the target. We hypothesized that stringency of regulation by naturally evolved antisense was driven by the impact of the target molecule on cellular survival. Specifically, high stringency was important for toxin-antitoxin systems where survival depended on high levels of control. Toxin-antitoxin systems rely on effective antisense to prevent the translation of self-damaging proteins. Antisense-based systems regulating transport and metabolism potentially benefited from less stringent antisense control. Basal levels of antisense-regulated proteins involved in metabolic processes could allow for quick adaptation to changing nutrient conditions. More than fifty naturally occurring sense/antisense pairs were analyzed to demonstrate that antisense binding sites correlate to the level of stringency needed in regulating the target protein. Please click Additional Files below to see the full abstract

Genetic Diversity of Four Filipino Negrito Populations from Luzon: Comparison of Male and Female Effective Population Sizes and Differential Integration of Immigrants into Aeta and Agta Communities

Genetic data corresponding to four negrito populations (two Aeta and two Agta; n = 120) from the Luzon region of the Philippines have been analyzed. These data comprise mitochondrial DNA (mtDNA) hypervariable segment 1 haplotypes and haplogroups, Y-chromosome haplogroups and short tandem repeats (STRs), autosomal STRs, and X-chromosome STRs. The genetic diversity and structure of the populations were investigated at a local, regional, and interregional level. We found a high level of autosomal differentiation, combined with no significant reduction in diversity, consistent with long-term settlement of the Luzon region by the ancestors of the Agta and Aeta followed by reduced gene flow between these two ethnolinguistic groups. Collectively, the Aeta have a much higher ratio of female:male effective population size than do the Agta, a finding that supports phylogenetic analysis of their mtDNA and Y-chromosome haplogroups, which suggests different genetic sex-biased contributions from putative Austronesian source populations. We propose that factors of social organization that led to the reduction in Agta female effective population size may also be linked to the limited incorporation of female lineages associated with the settlement of the Philippines by Austronesian speakers; conversely, the reduction in Aeta male effective population size, relative to females, could be indicative of a limited incorporation of male lineages associated with this demographic process

A Guide to Text Analysis with Latent Semantic Analysis in R with Annotated Code: Studying Online Reviews and the Stack Exchange Community

In this guide, we introduce researchers in the behavioral sciences in general and MIS in particular to text analysis as done with latent semantic analysis (LSA). The guide contains hands-on annotated code samples in R that walk the reader through a typical process of acquiring relevant texts, creating a semantic space out of them, and then projecting words, phrase, or documents onto that semantic space to calculate their lexical similarities. R is an open source, popular programming language with extensive statistical libraries. We introduce LSA as a concept, discuss the process of preparing the data, and note its potential and limitations. We demonstrate this process through a sequence of annotated code examples: we start with a study of online reviews that extracts lexical insight about trust. That R code applies singular value decomposition (SVD). The guide next demonstrates a realistically large data analysis of Stack Exchange, a popular Q&A site for programmers. That R code applies an alternative sparse SVD method. All the code and data are available on github.com

A CMOS TDI image sensor for Earth observation

Time Delay and Integration (TDI) is used to increase the Signal to Noise Ratio (SNR) in image sensors when imaging fast moving objects. One important TDI application is in Earth observation from space. In order to operate in the space radiation environment, the effect that radiation damage has on the performance of the image sensors must be understood. This work looks at prototype TDI sensor pixel designs, produced by e2v technologies. The sensor is a CCD-like charge transfer device, allowing in-pixel charge summation, produced on a CMOS process. The use of a CMOS process allows potential advantages such as lower power consumption, smaller pixels, higher line rate and extra on-chip functionality which can simplify system design. CMOS also allows a dedicated output amplifier per column allowing fewer charge transfers and helping to facilitate higher line rates than CCDs. In this work the effect on the pixels of radiation damage from high energy protons, at doses relevant to a low Earth orbit mission, is presented. This includes the resulting changes in Charge Transfer inefficiency (CTI) and dark signal

Short text messages to encourage adherence to medication and follow-up for people with psychosis (Mobile.Net): randomized controlled trial in Finland

Background: A text messaging service (short message service [SMS]) has the potential to target large groups of people with long-term illnesses such as serious mental disorders, who may have difficulty with treatment adherence. Robust research on the impact of mobile technology interventions for these patients remains scarce. Objective: The main objective of our study was to investigate the impact of individually tailored short text messages on the rate of psychiatric hospital readmissions, health care service use, and clinical outcomes. In addition, we analyzed treatment costs. Methods: Between September 2011 and November 2012, we randomly assigned 1139 people to a tailored text message intervention (n=569) or usual care (n=570). Participants received semiautomated text messages for up to 12 months or usual care. The primary outcome, based on routinely collected health register data, was patient readmission into a psychiatric hospital during a 12-month follow-up period. Secondary outcomes were related to other service use, coercion, medication, adverse events, satisfaction, social functioning, quality of life, and economic factors (cost analysis). Results: There was 98.24% (1119/1139) follow-up at 12 months. Tailored mobile telephone text messages did not reduce the rate of hospital admissions (242/563, 43.0% of the SMS group vs 216/556, 38.8% of the control group; relative risk 1.11; 95% CI 0.92-1.33; P=.28), time between hospitalizations (mean difference 7.0 days 95% CI –8.0 to 24.0; P=.37), time spent in a psychiatric hospital during the year (mean difference 2.0 days 95% CI –2.0 to 7.0; P=.35), or other service outcomes. People who received text messages were less disabled, based on Global Assessment Scale scores at the time of their readmission, than those who did not receive text messages (odds ratio 0.68; 95% CI 0.47-0.97; P=.04). The costs of treatment were higher for people in the SMS group than in the control group (mean €10,103 vs €9210, respectively, P<.001). Conclusions: High-grade routinely collected data can provide clear outcomes for pragmatic randomized trials. SMS messaging tailored with the input of each individual patient did not decrease the rate of psychiatric hospital visits after the 12 months of follow-up. Although there may have been other, more subtle effects, the results of these were not evident in outcomes of agreed importance to clinicians, policymakers, and patients and their families

The cDNA and deduced amino acid sequence of the γ subunit of the L-type calcium channel from rabbit skeletal muscle

Complementary DNAs for the γ subunit of the calcium channel of rabbit skeletal muscle were isolated on the basis of peptide sequences derived from the purified protein. The deduced primary structure is without homology to other known protein sequences and is consistent with the γ subunit being an integral membrane protein

Identification and characterization of an irreversible inhibitor of CDK2

Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)- 9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds

Factors associated with dropout during recruitment and follow-up periods of a mHealth-based randomized controlled trial for Mobile.Net to encourage treatment adherence for people with serious mental health problems

Background: Clinical trials are the gold standard of evidence-based practice. Still many papers inadequately report methodology in randomized controlled trials (RCTs), particularly for mHealth interventions for people with serious mental health problems. To ensure robust enough evidence, it is important to understand which study phases are the most vulnerable in the field of mental health care. Objective: We mapped the recruitment and the trial follow-up periods of participants to provide a picture of the dropout predictors from a mHealth-based trial. As an example, we used a mHealth-based multicenter RCT, titled “Mobile.Net,” targeted at people with serious mental health problems. Methods: Recruitment and follow-up processes of the Mobile.Net trial were monitored and analyzed. Recruitment outcomes were recorded as screened, eligible, consent not asked, refused, and enrolled. Patient engagement was recorded as follow-up outcomes: (1) attrition during short message service (SMS) text message intervention and (2) attrition during the 12-month follow-up period. Multiple regression analysis was used to identify which demographic factors were related to recruitment and retention. Results: We recruited 1139 patients during a 15-month period. Of 11,530 people screened, 36.31% (n=4186) were eligible. This eligible group tended to be significantly younger (mean 39.2, SD 13.2 years, P<.001) and more often women (2103/4181, 50.30%) than those who were not eligible (age: mean 43.7, SD 14.6 years; women: 3633/6514, 55.78%). At the point when potential participants were asked to give consent, a further 2278 refused. Those who refused were a little older (mean 40.2, SD 13.9 years) than those who agreed to participate (mean 38.3, SD 12.5 years; t1842=3.2, P<.001). We measured the outcomes after 12 months of the SMS text message intervention. Attrition from the SMS text message intervention was 4.8% (27/563). The patient dropout rate after 12 months was 0.36% (4/1123), as discovered from the register data. In all, 3.12% (35/1123) of the participants withdrew from the trial. However, dropout rates from the patient survey (either by paper or telephone interview) were 52.45% (589/1123) and 27.8% (155/558), respectively. Almost all participants (536/563, 95.2%) tolerated the intervention, but those who discontinued were more often women (21/27, 78%; P=.009). Finally, participants’ age (P<.001), gender (P<.001), vocational education (P=.04), and employment status (P<.001) seemed to predict their risk of dropping out from the postal survey. Conclusions: Patient recruitment and engagement in the 12-month follow-up conducted with a postal survey were the most vulnerable phases in the SMS text message-based trial. People with serious mental health problems may need extra support during the recruitment process and in engaging them in SMS text message-based trials to ensure robust enough evidence for mental health care