Lateral Gene Expression in Drosophila Early Embryos Is Supported by Grainyhead-Mediated Activation and Tiers of Dorsally-Localized Repression

The general consensus in the field is that limiting amounts of the transcription factor Dorsal establish dorsal boundaries of genes expressed along the dorsal-ventral (DV) axis of early Drosophila embryos, while repressors establish ventral boundaries. Yet recent studies have provided evidence that repressors act to specify the dorsal boundary of intermediate neuroblasts defective (ind), a gene expressed in a stripe along the DV axis in lateral regions of the embryo. Here we show that a short 12 base pair sequence (“the A-box”) present twice within the ind CRM is both necessary and sufficient to support transcriptional repression in dorsal regions of embryos. To identify binding factors, we conducted affinity chromatography using the A-box element and found a number of DNA-binding proteins and chromatin-associated factors using mass spectroscopy. Only Grainyhead (Grh), a CP2 transcription factor with a unique DNA-binding domain, was found to bind the A-box sequence. Our results suggest that Grh acts as an activator to support expression of ind, which was surprising as we identified this factor using an element that mediates dorsally-localized repression. Grh and Dorsal both contribute to ind transcriptional activation. However, another recent study found that the repressor Capicua (Cic) also binds to the A-box sequence. While Cic was not identified through our A-box affinity chromatography, utilization of the same site, the A-box, by both factors Grh (activator) and Cic (repressor) may also support a “switch-like” response that helps to sharpen the ind dorsal boundary. Furthermore, our results also demonstrate that TGF-β signaling acts to refine ind CRM expression in an A-box independent manner in dorsal-most regions, suggesting that tiers of repression act in dorsal regions of the embryo

Knockdown of MBP-1 in Human Foreskin Fibroblasts Induces p53-p21 Dependent Senescence

MBP-1 acts as a general transcriptional repressor. Overexpression of MBP-1 induces cell death in a number of cancer cells and regresses tumor growth. However, the function of endogenous MBP-1 in normal cell growth regulation remains unknown. To unravel the role of endogenous MBP-1, we knocked down MBP-1 expression in primary human foreskin fibroblasts (HFF) by RNA interference. Knockdown of MBP-1 in HFF (HFF-MBPsi-4) resulted in an induction of premature senescence, displayed flattened cell morphology, and increased senescence-associated beta-galactosidase activity. FACS analysis of HFF-MBPsi-4 revealed accumulation of a high number of cells in the G1-phase. A significant upregulation of cyclin D1 and reduction of cyclin A was detected in HFF-MBPsi-4 as compared to control HFF. Senescent fibroblasts exhibited enhanced expression of phosphorylated and acetylated p53, and cyclin-dependent kinase inhibitor, p21. Further analysis suggested that promyolocytic leukemia protein (PML) bodies are dramatically increased in HFF-MBPsi-4. Together, these results demonstrated that knockdown of endogenous MBP-1 is involved in cellular senescence of HFF through p53-p21 pathway

Reduction and Return of Infectious Trachoma in Severely Affected Communities in Ethiopia

Trachoma is one of the leading causes of blindness in the developing world. The World Health Organization has a multi-pronged approach to controlling the ocular chlamydial infection that causes the disease, including distributing antibiotics to entire communities. Even a single community treatment dramatically reduces the prevalence of the infection. Unfortunately, infection returns back into communities after treatment, at least in severely affected areas such as rural Ethiopia. Here, we assess whether additional scheduled treatments in 16 communities in the Gurage area of Ethiopia further reduce infection, and whether the disease returns after distributions are stopped. In communities with the highest levels of trachoma ever studied, we find that repeated mass oral azithromycin distributions gradually reduce the prevalence of trachoma infection in a community, as long as these treatments are given frequently enough and to enough people in the community. Unfortunately, infection returns into the communities after the last treatment. Sustainable changes or complete local elimination of infection will be necessary to stop the return of ocular chlamydial in communities with very high prevalence of the disease

Addressing ethnic disparities in neurological research in the United Kingdom: An example from the prospective multicentre COVID-19 Clinical Neuroscience Study

\ua9 2024 The Author(s). Background: Minority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection. Methods: Participants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment. Results: 807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres’ catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-White ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups. Conclusions: Recruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here

MEG Can Map Short and Long-Term Changes in Brain Activity following Deep Brain Stimulation for Chronic Pain

Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON) and compared with pain experienced with no stimulation (DBS OFF). We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray) and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain

When Can Antibiotic Treatments for Trachoma Be Discontinued? Graduating Communities in Three African Countries

Trachoma, the major cause of infectious blindness in the world, occurs when repeated infections of the ocular strains of Chlamydia trachomatis lead to a cascade of conjunctival scarring, in-turned eyelids and eyelashes, and eventually blindness due to corneal opacity. To reduce the prevalence of infection, the World Health Organization (WHO) advocates at least three annual community-wide distributions of oral antibiotics in affected areas. This approach has proven effective, but there is room to explore other treatment strategies which reduce the use of antibiotics. Here, we used mathematical models and data from three trachoma-endemic countries (Tanzania, The Gambia, and Ethiopia) to analyze different treatment strategies. In the simulations, we show that a graduation strategy can reduce antibiotic distributions more than 2-fold in moderately affected areas. Both treatment strategies provide favorable results in reducing the prevalence of ocular chlamydia, but high costs and the potential for resistance are important issues to consider when administering mass doses of antibiotics

Importance of Coverage and Endemicity on the Return of Infectious Trachoma after a Single Mass Antibiotic Distribution

Trachoma, caused by ocular chlamydia infection, is the most common infectious cause of blindness in the world. The World Health Organization (WHO) recommends the SAFE strategy (eyelid surgery, antibiotics, facial hygiene, environmental improvements) for trachoma control. Oral antibiotics reduce the transmission of ocular chlamydia, but re-infection of treated individuals is common. Therefore, the WHO recommends annual mass antibiotic treatments to the entire village. The success of treatment is likely based on many factors, including the antibiotic coverage, or percentage of villagers who receive antibiotics. However, no studies have analyzed the importance of antibiotic coverage for the reduction of ocular chlamydia. Here, we performed multivariate regression analyses on data from a clinical trial of mass oral antibiotics for trachoma in a severely affected area of Ethiopia. At the relatively high levels of antibiotic coverage in our study, coverage was associated with post-treatment infection at two months, but not at six months. The amount of infection at baseline was strongly correlated with post-treatment infection at both two and six months. These results suggest that in areas with severe trachoma treated with relatively high antibiotic coverage, increasing coverage even further may have only a short-term benefit

Azimuthal anisotropy and correlations at large transverse momenta in p+pp+p and Au+Au collisions at sNN\sqrt{s_{_{NN}}}= 200 GeV

Results on high transverse momentum charged particle emission with respect to the reaction plane are presented for Au+Au collisions at $\sqrt{s_{_{NN}}}$= 200 GeV. Two- and four-particle correlations results are presented as well as a comparison of azimuthal correlations in Au+Au collisions to those in $p+p$ at the same energy. Elliptic anisotropy, $v_2$, is found to reach its maximum at $p_t \sim 3$ GeV/c, then decrease slowly and remain significant up to $p_t\approx 7$ -- 10 GeV/c. Stronger suppression is found in the back-to-back high-$p_t$ particle correlations for particles emitted out-of-plane compared to those emitted in-plane. The centrality dependence of $v_2$ at intermediate $p_t$ is compared to simple models based on jet quenching.Comment: 4 figures. Published version as PRL 93, 252301 (2004

Gravitational waves from single neutron stars: an advanced detector era survey

With the doors beginning to swing open on the new gravitational wave astronomy, this review provides an up-to-date survey of the most important physical mechanisms that could lead to emission of potentially detectable gravitational radiation from isolated and accreting neutron stars. In particular we discuss the gravitational wave-driven instability and asteroseismology formalism of the f- and r-modes, the different ways that a neutron star could form and sustain a non-axisymmetric quadrupolar "mountain" deformation, the excitation of oscillations during magnetar flares and the possible gravitational wave signature of pulsar glitches. We focus on progress made in the recent years in each topic, make a fresh assessment of the gravitational wave detectability of each mechanism and, finally, highlight key problems and desiderata for future work.Comment: 39 pages, 12 figures, 2 tables. Chapter of the book "Physics and Astrophysics of Neutron Stars", NewCompStar COST Action 1304. Minor corrections to match published versio

Azimuthal anisotropy in Au+Au collisions at sqrtsNN = 200 GeV

The results from the STAR Collaboration on directed flow (v_1), elliptic flow (v_2), and the fourth harmonic (v_4) in the anisotropic azimuthal distribution of particles from Au+Au collisions at sqrtsNN = 200 GeV are summarized and compared with results from other experiments and theoretical models. Results for identified particles are presented and fit with a Blast Wave model. Different anisotropic flow analysis methods are compared and nonflow effects are extracted from the data. For v_2, scaling with the number of constituent quarks and parton coalescence is discussed. For v_4, scaling with v_2^2 and quark coalescence is discussed.Comment: 26 pages. As accepted by Phys. Rev. C. Text rearranged, figures modified, but data the same. However, in Fig. 35 the hydro calculations are corrected in this version. The data tables are available at http://www.star.bnl.gov/central/publications/ by searching for "flow" and then this pape