Passive, broadband and low-frequency suppression of laser amplitude noise to the shot-noise limit using hollow-core fibre

We use hollow-core fibre to preserve the spectrum and temporal profile of picosecond laser pulses in CBD to suppress 2.6 dB of amplitude noise at MHz noise frequencies, to within 0.01 dB of the shot-noise limit. We provide an enhanced version of the CBD scheme that concatenates circuits to suppress over multiple frequencies and over broad frequency ranges --- we perform a first demonstration that reduces total excess amplitude noise, between 2 - 6 MHz, by 85%. These demonstrations enable passive, broad-band, all-guided fibre laser technology operating at the shot-noise limit.Comment: 8 pages, 8 figure

Accessing the purity of a single photon by the width of the Hong-Ou-Mandel interference

We demonstrate a method to determine the spectral purity of single photons. The technique is based on the Hong-Ou-Mandel (HOM) interference between a single photon state and a suitably prepared coherent field. We show that the temporal width of the HOM dip is not only related to reciprocal of the spectral width but also to the underlying quantum coherence. Therefore, by measuring the width of both the HOM dip and the spectrum one can directly quantify the degree of spectral purity. The distinct advantage of our proposal is that it obviates the need for perfect mode matching, since it does not rely on the visibility of the interference. Our method is particularly useful for characterizing the purity of heralded single photon states.Comment: Extended version, 16 pages, 9 figure

A two-way photonic interface for linking Sr+ transition at 422 nm to the telecommunications C-band

We report a single-stage bi-directional interface capable of linking Sr+ trapped ion qubits in a long-distance quantum network. Our interface converts photons between the Sr+ emission wavelength at 422 nm and the telecoms C-band to enable low-loss transmission over optical fiber. We have achieved both up- and down-conversion at the single photon level with efficiencies of 9.4% and 1.1% respectively. Furthermore we demonstrate noise levels that are low enough to allow for genuine quantum operation in the future.Comment: 5 pages, 4 figure

The Exosome Component Rrp6 Is Required for RNA Polymerase II Termination at Specific Targets of the Nrd1-Nab3 Pathway

Publisher’s version made available under a Creative Commons license.The exosome and its nuclear specific subunit Rrp6 form a 3'-5' exonuclease complex that regulates diverse aspects of RNA biology including 3' end processing and degradation of a variety of noncoding RNAs (ncRNAs) and unstable transcripts. Known targets of the nuclear exosome include short (<1000 bp) RNAPII transcripts such as small noncoding RNAs (snRNAs), cryptic unstable transcripts (CUTs), and some stable unannotated transcripts (SUTs) that are terminated by an Nrd1, Nab3, and Sen1 (NNS) dependent mechanism. NNS-dependent termination is coupled to RNA 3' end processing and/or degradation by the Rrp6/exosome in yeast. Recent work suggests Nrd1 is necessary for transcriptome surveillance, regulating promoter directionality and suppressing antisense transcription independently of, or prior to, Rrp6 activity. It remains unclear whether Rrp6 is directly involved in termination; however, Rrp6 has been implicated in the 3' end processing and degradation of ncRNA transcripts including CUTs. To determine the role of Rrp6 in NNS termination globally, we performed RNA sequencing (RNA-Seq) on total RNA and perform ChIP-exo analysis of RNA Polymerase II (RNAPII) localization. Deletion of RRP6 promotes hyper-elongation of multiple NNS-dependent transcripts resulting from both improperly processed 3' RNA ends and faulty transcript termination at specific target genes. The defects in RNAPII termination cause transcriptome-wide changes in mRNA expression through transcription interference and/or antisense repression, similar to previously reported effects of depleting Nrd1 from the nucleus. Elongated transcripts were identified within all classes of known NNS targets with the largest changes in transcription termination occurring at CUTs. Interestingly, the extended transcripts that we have detected in our studies show remarkable similarity to Nrd1-unterminated transcripts at many locations, suggesting that Rrp6 acts with the NNS complex globally to promote transcription termination in addition to 3' end RNA processing and/or degradation at specific targets

A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy.

BACKGROUND: Despite improved clinical outcomes seen following antiretroviral therapy (ART), resting CD4+ T cells continue to harbor latent human immunodeficiency virus type one (HIV-1). However, such cells are not likely the solitary viral reservoir and as such defining where and how others harbor virus is imperative for eradication measures. To such ends, we used HIV-1ADA-infected NOD.Cg-Prkdc (scid) Il2rg (tm1Wjl) /SzJ mice reconstituted with a human immune system to explore two long-acting ART regimens investigating their abilities to affect viral cell infection and latency. At 6 weeks of infection animals were divided into four groups. One received long-acting (LA) cabotegravir (CAB) and rilpivirine (RVP) (2ART), a second received LA CAB, lamivudine, abacavir and RVP (4ART), a third were left untreated and a fourth served as an uninfected control. After 4 weeks of LA ART treatment, blood, spleen and bone marrow (BM) cells were collected then phenotypically characterized. CD4+ T cell subsets, macrophages and hematopoietic progenitor cells were analyzed for HIV-1 nucleic acids by droplet digital PCR. RESULTS: Plasma viral loads were reduced by two log10 or to undetectable levels in the 2 and 4ART regimens, respectively. Numbers and distributions of CD4+ memory and regulatory T cells, macrophages and hematopoietic progenitor cells were significantly altered by HIV-1 infection and by both ART regimens. ART reduced viral DNA and RNA in all cell and tissue compartments. While memory cells were the dominant T cell reservoir, integrated HIV-1 DNA was also detected in the BM and spleen macrophages in both regimen-treated mice. CONCLUSION: Despite vigorous ART regimens, HIV-1 DNA and RNA were easily detected in mature macrophages supporting their potential role as an infectious viral reservoir

Phosphatase Rtr1 Regulates Global Levels of Serine 5 RNA Polymerase II C-Terminal Domain Phosphorylation and Cotranscriptional Histone Methylation

In eukaryotes, the C-terminal domain (CTD) of Rpb1 contains a heptapeptide repeat sequence of (Y1S2P3T4S5P6S7)n that undergoes reversible phosphorylation through the opposing action of kinases and phosphatases. Rtr1 is a conserved protein that colocalizes with RNA polymerase II (RNAPII) and has been shown to be important for the transition from elongation to termination during transcription by removing RNAPII CTD serine 5 phosphorylation (Ser5-P) at a selection of target genes. In this study, we show that Rtr1 is a global regulator of the CTD code with deletion of RTR1 causing genome-wide changes in Ser5-P CTD phosphorylation and cotranscriptional histone H3 lysine 36 trimethylation (H3K36me3). Using chromatin immunoprecipitation and high-resolution microarrays, we show that RTR1 deletion results in global changes in RNAPII Ser5-P levels on genes with different lengths and transcription rates consistent with its role as a CTD phosphatase. Although Ser5-P levels increase, the overall occupancy of RNAPII either decreases or stays the same in the absence of RTR1 Additionally, the loss of Rtr1 in vivo leads to increases in H3K36me3 levels genome-wide, while total histone H3 levels remain relatively constant within coding regions. Overall, these findings suggest that Rtr1 regulates H3K36me3 levels through changes in the number of binding sites for the histone methyltransferase Set2, thereby influencing both the CTD and histone codes

Comparison of a User-Centered Design, Self-Management App to Existing mHealth Apps for Persons Living With HIV

Background: There is preliminary evidence that mobile health (mHealth) apps are feasible, attractive, and an effective platform for the creation of self-management tools for persons living with HIV (PLWH). As a foundation for the current study, we conducted formative research using focus groups, participatory design sessions, and usability evaluation methods to inform the development of a health management app for PLWH. The formative research resulted in identification of the following functional requirements of a mHealth app for self-management: (1) communication between providers and peers, (2) medication reminders, (3) medication log, (4) lab reports, (5) pharmacy information, (6) nutrition and fitness, (7) resources (eg, social services, substance use, video testimonials), (8) settings, and (9) search function. Objective: The purpose of this study was to conduct an ecological review of the existing apps for PLWH and to compare the functionality of existing apps with the app specifications identified in our formative work. Methods: We searched two mobile app stores (Google Play and iTunes) and found a total of 5606 apps. We reviewed the apps, narrowed our search terms, and found a total of 112 apps. Of these, we excluded 97 (86.6%) apps that were either not in English (10/112, 8.9%), not HIV focused (32/112, 28.9%), or focused only on HIV prevention (2/112, 7.8%); targeted health care providers (26/112, 23.2%); provided information only on conference schedules and events (7/112, 6.3%), fundraisers (7/112, 6.3%), specific clinics (7/112, 6.3%), international or narrow local resources (3/112, 2.7%); or were identified in the first search but were no longer on the market at the next review (4/112, 3.6%). The 15 apps meeting inclusion criteria were then evaluated for inclusion of the nine functionalities identified in our earlier work. Results: Of the 15 apps that we included in our final review, none had all of the functionalities that were identified in our formative work. The apps that we identified included the following functionalities: communication with providers and/or peers (4/15, 27%), medication reminders (6/15, 40%), medication logs (7/15, 47%), lab reports (5/15, 33%), pharmacy information (4/15, 27%), resources (7/15, 47%), settings (11/15, 73%), and search function (6/15, 40%). No apps included nutrition or fitness information. Conclusions: Currently, there are only a small number of apps that have been designed for PLWH to manage their health. Of the apps that are currently available, none have all of the desired functionalities identified by PLWH and experts in our formative research. Findings from this work elucidate the need to develop and evaluate mobile apps that meet PLWH’s desired functional specifications

Loss of Nmp4 optimizes osteogenic metabolism and secretion to enhance bone quality

A goal of osteoporosis therapy is to restore lost bone with structurally sound tissue. Mice lacking the transcription factor Nuclear Matrix Protein 4 (Nmp4, Zfp384, Ciz, ZNF384) respond to several classes of osteoporosis drugs with enhanced bone formation compared to wild type (WT) animals. Nmp4-/- mesenchymal stem/progenitor cells (MSPCs) exhibit an accelerated and enhanced mineralization during osteoblast differentiation. To address the mechanisms underlying this hyper-anabolic phenotype, we carried out RNA-sequencing and molecular and cellular analyses of WT and Nmp4-/- MSPCs during osteogenesis to define pathways and mechanisms associated with elevated matrix production. We determined that Nmp4 has a broad impact on the transcriptome during osteogenic differentiation, contributing to the expression of over 5,000 genes. Phenotypic anchoring of transcriptional data was performed for the hypothesis-testing arm through analysis of cell metabolism, protein synthesis and secretion, and bone material properties. Mechanistic studies confirmed that Nmp4-/- MSPCs exhibited an enhanced capacity for glycolytic conversion- a key step in bone anabolism. Nmp4-/- cells showed elevated collagen translation and secretion. Expression of matrix genes that contribute to bone material-level mechanical properties were elevated in Nmp4-/- cells, an observation that was supported by biomechanical testing of bone samples from Nmp4-/- and WT mice. We conclude that loss of Nmp4 increases the magnitude of glycolysis upon the metabolic switch, which fuels the conversion of the osteoblast into a super-secretor of matrix resulting in more bone with improvements in intrinsic quality

Gut thinking: the gut microbiome and mental health beyond the head

Background: In recent decades, dominant models of mental illness have become increasingly focused on the head, with mental disorders being figured as brain disorders. However, research into the active role that the microbiome-gut-brain axis plays in affecting mood and behaviour may lead to the conclusion that mental health is more than an internalised problem of individual brains. Objective: This article explores the implications of shifting understandings about mental health that have come about through research into links between the gut microbiome and mental health problems such as depression and anxiety. It aims to analyse the different ways that the lines between mind and body and mental and physical health are re-shaped by this research, which is starting to inform clinical and public understanding. Design: As mental health has become a pressing issue of political and public concern it has become increasingly constructed in socio-cultural and personal terms beyond clinical spaces, requiring a conceptual response that exceeds biomedical inquiry. This article argues that an interdisciplinary critical medical humanities approach is well positioned to analyse the impact of microbiome-gut-brain research on conceptions of mind. Results: The entanglement of mind and matter evinced by microbiome-gut-brain axis research potentially provides a different way to conceptualise the physical and social concomitants of mental distress. Conclusion: Mental health is not narrowly located in the head but is assimilated by the physical body and intermingled with the natural world, requiring different methods of research to unfold the meanings and implications of gut thinking for conceptions of human selfhood