Nucleic acid and non-nucleic acid-based reprogramming of adult limbal progenitors to pluripotency

Reprogramming somatic cells to a pluripotent state by nucleic acid based (NAB) approaches, involving the ectopic expression of transcription factors, has emerged as a standard method. We recently demonstrated that limbal progenitors that regenerate cornea are reprogrammable to pluripotency by a non-NAB approach through simple manipulation of microenvironment thus extending the possible therapeutic use of these readily accessible cells beyond the proven treatment of corneal diseases and injury. Therefore, to determine the validity and robustness of non-cell autonomous reprogramming of limbal progenitors for a wider clinical use, here, we have compared their reprogramming by non-NAB and NAB approaches. We observed that both approaches led to (1) the emergence of colonies displaying pluripotency markers, accompanied by a temporal reciprocal changes in limbal-specific and pluripotency gene expression, and (2) epigenetic alterations of Oct4 and Nanog, associated with the de-novo activation of their expression. While the efficiency of reprogramming and passaging of re-programmed cells were significantly better with the NAB approach, the non-NAB approach, in contrast, led to a regulated reprogramming of gene expression, and a significant decrease in the expression of Hormad1, a gene associated with immunogenic responses. The reprogramming efficiency by non-NAB approach was influenced by exosomes present in conditioned medium. Cells reprogrammed by both approaches were capable of differentiating along the three germ lineages and generating chimeras. The analysis suggests that both approaches are effective in reprogramming limbal progenitors but the non-NAB approach may be more suitable for potential clinical applications by averting the risk of insertional mutagenesis and immune responses associated with the NAB approach

The Sloan Digital Sky Survey Reverberation Mapping Project: Investigation of Continuum Lag Dependence on Broad-Line Contamination and Quasar Properties

This work studies the relationship between accretion-disk size and quasar properties, using a sample of 95 quasars from the SDSS-RM project with measured lags between the $g$ and $i$ photometric bands. Our sample includes disk lags that are both longer and shorter than predicted by the \citet{SS73} model, requiring explanations which satisfy both cases. Although our quasars each have one lag measurement, we explore the wavelength-dependent effects of diffuse broad line region (BLR) contamination through our sample's broad redshift range, $0.1<z<1.2$. We do not find significant evidence of variable diffuse \FeII\ and Balmer nebular emission in the root-mean-square (RMS) spectra, nor from Anderson-Darling tests of quasars in redshift ranges with and without diffuse nebular emission falling in the observed-frame filters. Contrary to previous work, we do not detect a significant correlation between measured continuum and BLR lags in our luminous quasar sample, similarly suggesting that our continuum lags are not dominated by diffuse nebular emission. Similar to other studies, we find that quasars with larger-than-expected continuum lags have lower 3000~\AA\ luminosity, and we additionally find longer continuum lags with lower X-ray luminosity and black hole mass. Our lack of evidence for diffuse BLR contribution to the lags indicates that the anti-correlation between continuum lag and luminosity is not likely to be due to the Baldwin effect. Instead, these anti-correlations favor models in which the continuum lag increases in lower-luminosity AGN, including scenarios featuring magnetic coupling between the accretion disk and X-ray corona, and/or ripples or rims in the disk.Comment: 15 pages, 10 figure

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

The SDSS-V Black Hole Mapper Reverberation Mapping Project: Unusual Broad-Line Variability in a Luminous Quasar

We present a high-cadence multi-epoch analysis of dramatic variability of three broad emission lines (MgII, H$\beta$, and H$\alpha$) in the spectra of the luminous quasar ($\lambda L_{\lambda}$(5100\r{A}) = $4.7 \times 10^{44}$ erg s$^{-1}$) SDSS J141041.25+531849.0 at $z = 0.359$ with 127 spectroscopic epochs over 9 years of monitoring (2013-2022). We observe anti-correlations between the broad emission-line widths and flux in all three emission lines, indicating that all three broad emission lines "breathe" in response to stochastic continuum variations. We also observe dramatic radial velocity shifts in all three broad emission lines, ranging from $\Delta{v}$ $\sim$400 km s$^{-1}$ to $\sim$800 km s$^{-1}$, that vary over the course of the monitoring period. Our preferred explanation for the broad-line variability is complex kinematics in the broad-line region gas. We suggest a model for the broad-line variability that includes a combination of gas inflow with a radial gradient, an azimuthal asymmetry (e.g., a hot spot), superimposed on the stochastic flux-driven changes to the optimal emission region ("line breathing"). Similar instances of line-profile variability due to complex gas kinematics around quasars are likely to represent an important source of false positives in radial velocity searches for binary black holes, which typically lack the kind of high-cadence data we analyze here. The long-duration, wide-field, and many-epoch spectroscopic monitoring of SDSS-V BHM-RM provides an excellent opportunity for identifying and characterizing broad emission-line variability, and the inferred nature of the inner gas environment, of luminous quasars

HIV-1 recombinants with multiple parental strains in low-prevalence, remote regions of Cameroon: Evolutionary relics?

<p>Abstract</p> <p>Background</p> <p>The HIV pandemic disseminated globally from Central West Africa, beginning in the second half of the twentieth century. To elucidate the virologic origins of the pandemic, a cross-sectional study was conducted of the genetic diversity of HIV-1 strains in villagers in 14 remote locations in Cameroon and in hospitalized and STI patients. DNA extracted from PBMC was PCR amplified from HIV(+) subjects. Partial <it>pol </it>amplicons (N = 164) and nearly full virus genomes (N = 78) were sequenced. Among the 3956 rural villagers studied, the prevalence of HIV infection was 4.9%; among the hospitalized and clinic patients, it was 8.6%.</p> <p>Results</p> <p>Virus genotypes fell into two distinctive groups. A majority of the genotyped strains (109/164) were the circulating recombinant form (CRF) known to be endemic in West Africa and Central West Africa, CRF02_AG. The second most common genetic form (9/164) was the recently described CRF22_01A1, and the rest were a collection of 4 different subtypes (A2, D, F2, G) and 6 different CRFs (-01, -11, -13, -18, -25, -37). Remarkably, 10.4% of HIV-1 genomes detected (17/164) were heretofore undescribed unique recombinant forms (URF) present in only a single person. Nearly full genome sequencing was completed for 78 of the viruses of interest. HIV genetic diversity was commonplace in rural villages: 12 villages each had at least one newly detected URF, and 9 villages had two or more.</p> <p>Conclusions</p> <p>These results show that while CRF02_AG dominated the HIV strains in the rural villages, the remainder of the viruses had tremendous genetic diversity. Between the trans-species transmission of SIV_cpzand the dispersal of pandemic HIV-1, there was a time when we hypothesize that nascent HIV-1 was spreading, but only to a limited extent, recombining with other local HIV-1, creating a large variety of recombinants. When one of those recombinants began to spread widely (i.e. became epidemic), it was recognized as a subtype. We hypothesize that the viruses in these remote Cameroon villages may represent that pre-epidemic stage of viral evolution.</p

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

A Randomized Placebo-Controlled Trial of Varenicline for Smoking Cessation Allowing Flexible Quit Dates

Introduction: Current smoking cessation guidelines recommend setting a quit date prior to starting pharmacotherapy. However, providing flexibility in the date of quitting may be more acceptable to some smokers. The objective of this study was to compare varenicline 1 mg twice daily (b.i.d.) with placebo in subjects using a flexible quit date paradigm after starting medication. Methods: In this double-blind, randomized, placebo-controlled international study, smokers of ≥10 cigarettes/day, aged 18-75 years, and who were motivated to quit were randomized (3:1) to receive varenicline 1 mg b.i.d. or placebo for 12 weeks. Subjects were followed up through Week 24. Subjects were instructed to quit between Days 8 and 35 after starting medication. The primary endpoint was carbon monoxide-confirmed continuous abstinence during Weeks 9-12, and a key secondary endpoint was continuous abstinence during Weeks 9-24. Results: Overall, 493 subjects were randomized to varenicline and 166 to placebo. Continuous abstinence was higher for varenicline than for placebo subjects at the end of treatment (Weeks 9-12: 53.1% vs. 19.3%; odds ratio [OR] 5.9; 95% CI, 3.7-9.4; p < .0001) and through 24 weeks follow-up (Weeks 9-24: 34.7% vs. 12.7%; OR 4.4; 95% CI, 2.6-7.5; p < .0001). Serious adverse events occurred in 1.2% varenicline (none were psychiatric) and 0.6% placebo subjects. Fewer varenicline than placebo subjects reported depression-related adverse events (2.3% vs. 6.7%, respectively). Conclusions: Varenicline 1 mg b.i.d. using a flexible quit date paradigm had similar efficacy and safety compared with previous fixed quit date studies. © The Author 2011. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Cognition based bTBI mechanistic criteria; a tool for preventive and therapeutic innovations

Blast-induced traumatic brain injury has been associated with neurodegenerative and neuropsychiatric disorders. To date, although damage due to oxidative stress appears to be important, the specific mechanistic causes of such disorders remain elusive. Here, to determine the mechanical variables governing the tissue damage eventually cascading into cognitive deficits, we performed a study on the mechanics of rat brain under blast conditions. To this end, experiments were carried out to analyse and correlate post-injury oxidative stress distribution with cognitive deficits on a live rat exposed to blast. A computational model of the rat head was developed from imaging data and validated against in vivo brain displacement measurements. The blast event was reconstructed in silico to provide mechanistic thresholds that best correlate with cognitive damage at the regional neuronal tissue level, irrespectively of the shape or size of the brain tissue types. This approach was leveraged on a human head model where the prediction of cognitive deficits was shown to correlate with literature findings. The mechanistic insights from this work were finally used to propose a novel helmet design roadmap and potential avenues for therapeutic innovations against blast traumatic brain injury

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine