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Millicharged particles, proposed by various extensions of the standard model, can be created in pairs by high-energy photons within nuclear reactors and can interact electromagnetically with electrons in matter. Recently, the existence of a plasmon peak in the interaction cross-section with silicon in the eV range was highlighted as a promising approach to enhance low-energy sensitivities. The CONNIE and Atucha-II reactor neutrino experiments utilize Skipper-CCD sensors, which enable the detection of interactions in the eV range. We present world-leading limits on the charge of millicharged particles within a mass range spanning six orders of magnitude, derived through a comprehensive analysis and the combination of data from both experiments.

The Coherent Neutrino-Nucleus Interaction Experiment (CONNIE) aims to detect the coherent scattering (CE\\(\\nu\\)NS) of reactor antineutrinos off silicon nuclei using thick fully-depleted high-resistivity silicon CCDs. Two Skipper-CCD sensors with sub-electron readout noise capability were installed at the experiment next to the Angra-2 reactor in 2021, making CONNIE the first experiment to employ Skipper-CCDs for reactor neutrino detection. We report on the performance of the Skipper-CCDs, the new data processing and data quality selection techniques and the event selection for CE\\(\\nu\\)NS interactions, which enable CONNIE to reach a record low detection threshold of 15 eV. The data were collected over 300 days in 2021-2022 and correspond to exposures of 14.9 g-days with the reactor-on and 3.5 g-days with the reactor-off. The difference between the reactor-on and off event rates shows no excess and yields upper limits at 95% confidence level for the neutrino interaction rates comparable with previous CONNIE limits from standard CCDs and higher exposures. Searches for new neutrino interactions beyond the Standard Model were performed, yielding an improvement on the previous CONNIE limit on a simplified model with light vector mediators. A first dark matter (DM) search by diurnal modulation was performed by CONNIE and the results represent the best limits on the DM-electron scattering cross-section, obtained by a surface-level experiment. These promising results, obtained using a very small-mass sensor, illustrate the potential of Skipper-CCDs to probe rare neutrino interactions and motivate the plans to increase the detector mass in the near future.

Vertically stacked multiple microstrip resonators have been used to increase bandwidth of inherently narrowband microstrip antennas. Realization of such multi-layer antennas has been accomplished mostly by experimental iteration or full-wave analyses. Experimental iterations are expensive and time consuming, while full wave analyses are computationally intensive. To overcome these deficiencies, a multiport network model (MNM) is proposed for a two-layered microstrip antenna. The MNM uses separate network models to represent the internal and external fields associated with the stacked patches. The internal fields consist of uniform two-dimensional fields in two regions--those underneath the lower patch, and those between the stacked patches. The external fields are considered in two parts: (i) fringing fields between the patches and the ground plane as well as those fields coupling between the two patches, and (ii) radiation fields in the far zone. Network models are developed for modeling all these components. To obtain the internal field networks, the Z-matrix is computed using the two dimensional Green's function for rectangular segments. The two internal field networks are interconnected by enforcing continuity at the edges. To obtain the external fringing and coupling networks, multi-conductor coupled line analysis is used to calculate fringing capacitances and inductances. The radiated fields are represented by a generalized radiation conductance network. Network methods are used to match the internal and external fields at their interface. The network analysis yields the input impedance which determines the resonance frequency and antenna bandwidth. The analysis also yields the edge voltages for a given input excitation, which are used for evaluating the radiation field. The modeling approach is verified by comparing a MNM for a broadside coupled transmission line to a $\\pi$,c-mode coupled line analysis. The results indicate that the MNM is accurate for electrically thin substrates (less than one twentieth of a wavelength). The model is also verified for varying width to height ratios, W/h, and indicates that the model was suitable for application to stacked microstrip patch antennas. An analysis for a two-layer coaxially-fed microstrip patch is performed and compared to published results.

Acne vulgaris, a high-prevalence skin condition afflicting people, persists as a significant challenge in the absence of effective treatments and emerging antibiotic resistance. To address this pressing concern, exploration of innovative approaches is of the utmost importance. Asparagopsis armata, an invasive red seaweed renowned for its diverse array of bioactive compounds, emerges as a promising candidate. This study seeks to elucidate the potential utility of A. armata biomass in the treatment of acne vulgaris. Crude extracts were obtained through solid–liquid extraction, and fractions were obtained using liquid–liquid extraction. The analyzed bioactivities included antioxidant, antimicrobial, and anti-inflammatory. Also, chemical characterization was performed to identify free fatty acids and compounds through LC-MS and elements. The present findings unveil compelling attributes, including anti-Cutibacterium acnes activity, cytotoxic and non-cytotoxic effects, antioxidant properties, and its ability to reduce nitric oxide production with consequent anti-inflammatory potential. Additionally, chemical characterization provides insights into its mineral elements, free fatty acids, and diverse compounds. The observed antimicrobial efficacy may be linked to halogenated compounds and fatty acids. Cytoprotection appears to be associated with the presence of glycerolipids and glycosylated metabolites. Furthermore, its antioxidant activity, coupled with anti-inflammatory properties, can be attributed to phenolic compounds, such as flavonoids. This study underscores the potential of A. armata as a natural ingredient in skincare formulations, offering an important contribution to the ongoing battle against acne vulgaris.

Coffea arabica , an allotetraploid hybrid of Coffea eugenioides and Coffea canephora , is the source of approximately 60% of coffee products worldwide, and its cultivated accessions have undergone several population bottlenecks. We present chromosome-level assemblies of a di-haploid C. arabica accession and modern representatives of its diploid progenitors, C. eugenioides and C. canephora . The three species exhibit largely conserved genome structures between diploid parents and descendant subgenomes, with no obvious global subgenome dominance. We find evidence for a founding polyploidy event 350,000–610,000 years ago, followed by several pre-domestication bottlenecks, resulting in narrow genetic variation. A split between wild accessions and cultivar progenitors occurred ~30.5 thousand years ago, followed by a period of migration between the two populations. Analysis of modern varieties, including lines historically introgressed with C. canephora , highlights their breeding histories and loci that may contribute to pathogen resistance, laying the groundwork for future genomics-based breeding of C. arabica . Chromosome-level genome assemblies of allotetraploid Coffea arabica and representatives of its diploid progenitors, Coffea eugenioides and Coffea canephora , provide insights into Arabica’s diversification history.

For 20 years, dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and a platelet P2Y12 receptor inhibitor, has been the gold standard of antithrombotic pharmacology after percutaneous coronary intervention (PCI). In the past 5 years, several investigations have challenged this paradigm by testing the efficacy and safety of P2Y12 inhibitor monotherapy (that is, without aspirin) following a short course of DAPT. Collectively, these studies suggested a reduction in the risk of major bleeding and no significant increase in thrombotic or ischaemic events compared with guideline-recommended DAPT. Current recommendations are evolving to inform clinical practice on the ideal candidates for P2Y12 inhibitor monotherapy after PCI. Generalizing the results of studies of P2Y12 inhibitor monotherapy requires a thorough understanding of their design, populations, interventions, comparators and results. In this Review, we provide an up-to-date overview on the use of P2Y12 inhibitor monotherapy after PCI, including supporting pharmacodynamic and clinical evidence, practical recommendations and future directions.The evolution of stent design has reduced the incidence of stent thrombosis, meaning that the duration of dual antiplatelet therapy after percutaneous coronary intervention (PCI) might be shortened. In this Review, the authors describe the current evidence base and ongoing clinical trials into the use of P2Y12 inhibitor monotherapy after PCI.

New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear. We did an individual patient data meta-analysis of randomised clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520. We obtained individual data for 26 616 patients in 20 randomised trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78–0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71–0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78–1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88–1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50–0·80, p<0·001) and target-vessel revascularisation (0·55, 0·50–0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year. The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year. Bern University Hospital.

Present demographic trends suggest a rise in the contributions of human pharmaceuticals into coastal ecosystems, underpinning an increasing demand to evaluate the ecotoxicological effects and implications of drug residues in marine risk assessments. Propranolol, a non-selective B-adrenoceptor blocker, is used worldwide to treat high blood pressure conditions and other related cardiovascular conditions. Although diatoms lack B-adrenoceptors, this microalgal group presents receptor-like kinases and proteins with a functional analogy to the animal receptors and that can be targeted by propranolol. In the present work, the authors evaluated the effect of this non-selective B-adrenoceptor blocker in diatom cells using P. tricornutum as a model organism, to evaluate the potential effect of this compound in cell physiology (growth, lipids and energy metabolism and oxidative stress) and its potential relevance for marine ecosystems. Propranolol exposure leads to a significant reduction in diatom cell growth, more evident in the highest concentrations tested. This is likely due to the observed impairment of the main primary photochemistry processes and the enhancement of the mitochondrial respiratory activity. More specifically, propranolol decreased the energy transduction from photosystem II (PSII) to the electron transport chain, leading to an increase in oxidative stress levels. Cells exposed to propranolol also exhibited high-dissipated energy flux, indicating that this excessive energy is effciently diverted, to some extent, from the photosystems, acting to prevent irreversible photoinhibition. As energy production is impaired at the PSII donor side, preventing energy production through the electron transport chain, diatoms appear to be consuming storage lipids as an energy backup system, to maintain essential cellular functions. This consumption will be attained by an increase in respiratory activity. Considering the primary oxygen production and consumption pathways, propranolol showed a significant reduction of the autotrophic O2 production and an increase in the heterotrophic mitochondrial respiration. Both mechanisms can have negative effects on marine trophic webs, due to a decrease in the energetic input from marine primary producers and a simultaneous oxygen production decrease for heterotrophic species. In ecotoxicological terms, bio-optical and fatty acid data appear as highly effcient tools for ecotoxicity assessment, with an overall high degree of classification when these traits are used to build a toxicological profile, instead of individually assessed.

As both a commensal and a major cause of healthcare-associated infections in humans, Enterococcus faecalis is a remarkably adaptable organism. We investigated how E. faecalis adapts in a mammalian host as a pathogen by characterizing changes in the transcriptome during infection in a rabbit model of subdermal abscess formation using transcriptional microarrays. The microarray experiments detected 222 and 291 differentially regulated genes in E. faecalis OG1RF at two and eight hours after subdermal chamber inoculation, respectively. The profile of significantly regulated genes at two hours post-inoculation included genes involved in stress response, metabolism, nutrient acquisition, and cell surface components, suggesting genome-wide adaptation to growth in an altered environment. At eight hours post-inoculation, 88% of the differentially expressed genes were down-regulated and matched a transcriptional profile consistent with a (p)ppGpp-mediated stringent response. Subsequent subdermal abscess infections with E. faecalis mutants lacking the (p)ppGpp synthetase/hydrolase RSH, the small synthetase RelQ, or both enzymes, suggest that intracellular (p)ppGpp levels, but not stringent response activation, influence persistence in the model. The ability of cells to synthesize (p)ppGpp was also found to be important for growth in human serum and whole blood. The data presented in this report provide the first genome-wide insights on E. faecalis in vivo gene expression and regulation measured by transcriptional profiling during infection in a mammalian host and show that (p)ppGpp levels affect viability of E. faecalis in multiple conditions relevant to mammalian infection. The subdermal abscess model can serve as a novel experimental system for studying the E. faecalis stringent response in the context of the mammalian immune system.

Quadruplex ligands are often considered as telomerase inhibitors. Given the fact that some of these molecules are present in the clinical setting, it is important to establish the validity of this assertion. To analyze the effects of these compounds, we used a direct assay with telomerase-enriched extracts. The comparison of potent ligands from various chemical families revealed important differences in terms of effects on telomerase initiation and processivity. Although most quadruplex ligands may lock a quadruplex-prone sequence into a quadruplex structure that inhibits the initiation of elongation by telomerase, the analysis of telomerase-elongation steps revealed that only a few molecules interfered with the processivity of telomerase (i.e., inhibit elongation once one or more repeats have been incorporated). The demonstration that these molecules are actually more effective inhibitors of telomeric DNA amplification than extension by telomerase contributes to the already growing suspicion that quadruplex ligands are not simple telomerase inhibitors but, rather, constitute a different class of biologically active molecules. We also demonstrate that the popular telomeric repeat amplification protocol is completely inappropriate for the determination of telomerase inhibition by quadruplex ligands, even when PCR controls are included. As a consequence, the inhibitory effect of many quadruplex ligands has been overestimated.