julilili42/papers huggingface dataset:
Nitric oxide modulates contrast suppression in a subset of mouse retinal ganglion cells
2024-06-10

Neuromodulators have major influences on the regulation of neural circuit activity across the nervous system. Nitric oxide (NO) has been shown to be a prominent neuromodulator in many circuits and has been extensively studied in the retina. Here, it has been associated with the regulation of light adaptation, gain control, and gap junctional coupling, but its effect on the retinal output, specifically on the different types of retinal ganglion cells (RGCs), is still poorly understood. In this study, we used two-photon Ca2+ imaging and multi-electrode array (MEA) recordings to measure light-evoked activity of RGCs in the ganglion cell layer in the ex vivo mouse retina. This approach allowed us to investigate the neuromodulatory effects of NO on a cell type-level. Our findings reveal that NO selectively modulates the suppression of temporal responses in a distinct subset of contrast-suppressed RGC types, increasing their activity without altering the spatial properties of their receptive fields. Given that NO release is triggered by quick changes in light levels under photopic conditions, we propose that these RGC types signal fast contrast changes to higher visual regions. Remarkably, we found that about one-third of the RGC types, recorded using two-photon Ca2+ imaging, exhibited consistent, cell type-specific adaptational response changes throughout an experiment, independent of NO. By employing a paired-recording paradigm, we could disentangle those additional adaptational response changes from drug-induced modulations. Taken together, our research highlights the selective neuromodulatory effects of NO on RGCs and emphasizes the need of considering non-pharmacological activity changes, like adaptation, in such study designs.
Astronaut omics and the impact of space on the human body at scale
2024-06-11

Abstract Future multi-year crewed planetary missions will motivate advances in aerospace nutrition and telehealth. On Earth, the Human Cell Atlas project aims to spatially map all cell types in the human body. Here, we propose that a parallel Human Cell Space Atlas could serve as an openly available, global resource for space life science research. As humanity becomes increasingly spacefaring, high-resolution omics on orbit could permit an advent of precision spaceflight healthcare. Alongside the scientific potential, we consider the complex ethical, cultural, and legal challenges intrinsic to the human space omics discipline, and how philosophical frameworks may benefit from international perspectives.
Chemical Predictive Modelling and Natural Product‐based Divergent Synthesis – Design of Type B PPAPs with Nanomolar Activities against MRSA
2024-06-11

Abstract In response to the pressing global challenge of antibiotic resistance, time efficient design and synthesis of novel antibiotics are of immense need. Polycyclic polyprenylated acylphloroglucinols (PPAP) were previously reported to effectively combat a range of gram‐positive bacteria. Although the exact mode of action is still not clear, we conceptualized a late‐stage divergent synthesis approach to expand our natural product‐based PPAP library by 30 additional entities to perform SAR studies against methicillin‐resistant Staphylococcus aureus (MRSA). Although at this point only data from cellular assays are available and understanding of molecular drug‐target interactions are lacking, the experimental data were used to generate 3D‐QSAR models via an artificial intelligence training and to identify a common pharmacophore model. The experimentally validated QSAR model enabled the estimation of anti‐MRSA activities of a virtual compound library consisting of more than 100,000 in‐silico generated B PPAPs, out of which the 20 most promising candidates were synthesized. These novel PPAPs revealed significantly improved cellular activities against MRSA with growth inhibition down to concentrations less than 1 μm.
Tumor microenvironment of Burkitt lymphoma: different immune signatures with different clinical behavior
2024-06-11

Abstract Burkitt lymphoma (BL) is characterized by a tumor microenvironment (TME) in which macrophages represent the main component, determining a distinct histological appearance known as “starry sky” pattern. However, in some instances, BL may exhibit a granulomatous reaction that has been previously linked to favorable prognosis and spontaneous regression. The aim of our study was to deeply characterize the immune landscape of 7 cases of Epstein-Barr virus–positive (EBV+) BL with granulomatous reaction compared with 8 cases of EBV+ BL and 8 EBV-negative (EBV–) BL, both with typical starry sky pattern, by Gene expression profiling performed on the NanoString nCounter platform. Subsequently, the data were validated using multiplex and combined immunostaining. Based on unsupervised clustering of differentially expressed genes, BL samples formed 3 distinct clusters differentially enriched in BL with a diffuse granulomatous reaction (cluster 1), EBV+ BL with typical starry sky pattern (cluster 2), EBV– BL with typical “starry sky” (cluster 3). We observed variations in the immune response signature among BL with granulomatous reaction and BL with typical “starry sky,” both EBV+ and EBV–. The TME signature in BL with diffuse granulomatous reaction showed a proinflammatory response, whereas BLs with “starry sky” were characterized by upregulation of M2 polarization and protumor response. Moreover, the analysis of additional signatures revealed an upregulation of the dark zone signature and epigenetic signature in BL with a typical starry sky. Tumor-associated macrophages and epigenetic regulators may be promising targets for additional therapies for BL lymphoma, opening novel immunotherapeutic strategies.
Comment on egusphere-2024-820
2024-06-11

<strong class="journal-contentHeaderColor">Abstract.</strong> Western disturbances (WDs) are synoptic-scale weather systems embedded within the subtropical westerly jet. Manifesting as upper-level troughs often associated with a lower-tropospheric low over Western India, they share some dynamical features with extratropical cyclones. WDs are most common during the boreal winter (December to March), during which they bring the majority of precipitation &ndash; both rain and snow &ndash; to the Western Himalaya, as well as to surrounding areas of north India, Pakistan and the Tibetan Plateau. WDs are also associated with weather hazards such as heavy snowfall, hailstorms, fog, cloudbursts, avalanches, frost, and coldwaves. In this paper, we review the recent understanding and development on WDs. Recent studies have collectively made use of novel data, novel analysis techniques, and the increasing availability of high-resolution weather and climate models. This review is separated into six main sections &ndash; structure and thermodynamics, precipitation and impacts, teleconnections, modelling experiments, forecasting at a range of scales, and paleoclimate and climate change &ndash; each motivated with a brief discussion of the accomplishments and limitations of previous research. A number of step changes in understanding are synthesised. Use of new modelling frameworks and tracking algorithms has significantly improved knowledge of WD structure and variability, and a more frequentist approach can now be taken. Improved observation systems have helped quantification of water security over the Western Himalaya. Convection-permitting models have improved our understanding of how WDs interact with the Himalayas to trigger natural hazards. Improvements in paleoclimate and future climate modelling experiments have helped to explain how WDs and their impacts over the Himalaya respond to large-scale natural and anthropogenic forcings. We end by summarising unresolved questions and outlining key future WD research topics.
Multiple regulators control the biosynthesis of brasilicardin inNocardia terpenica
2024-06-11

Abstract Brasilicardin A, BraA, is a secondary metabolite produced by the bacterium Nocardia terpenica , and a promising drug due to its potent immunosuppressive activity and low cytotoxicity. Currently, a semisynthetic approach confers production of a complete compound but suffers from insufficient heterologous biosynthesis of BraA intermediates used in the chemical semi-synthesis steps leading to only lab scale quantities of the compound. A better understanding of the involved gene expression regulatory pathways within the brasilicardin biosynthetic gene cluster, Bra-BGC, is a prerequisite to further improve production titers. However, the transcriptional regulation of the Bra-BGC has only been superficially analyzed, till now. In this study, we comprehensively analyze the functions of several unstudied transcriptional regulators, KstR, SdpR and OmpR, encoded within the close vicinity of the Bra-BGC, and delve into the role of the previously described cluster-situated activator Bra12. We present, that Bra12 and the novel regulator SdpR, bind several DNA sequences located in the promoter regions of the genes essential for BraA biosynthesis. Subsequently, we demonstrate the complex regulatory network through which both regulators are capable of controlling activity of those gene promoters and thus gene expression in Bra-BGC. Furthermore, using the heterologous producer strain Amycolatopsis japonicum , we present, that Bra12 and SdpR regulators play opposite roles in brasilicardin congener biosynthesis. Finally, we propose a comprehensive model of multilevel gene expression regulation in Bra-BGC and propose the roles of locally encoded transcriptional regulators.
Erste Erfahrungen mit der neuen KULAP-Maßnahme K61 – Verspätete Aussaat zum Schutz von Feldvögeln
2024-06-11

First experiences with the new KULAP measure K61 (delayed sowing to protect field birds) in the lower Isar Valley // Since 2023, the Bavarian Cultural Landscape Program (KULAP) has included the measure K61 (delayed sowing for the protection of field birds), primarily to promote lapwing (Vanellus vanellus) protection. In the district of Dingolfing-Landau, the suitability of the first K61 fields for lapwing protection was analysed. They were compared with fields without delayed sowing and fields with a non-disturbance agreement on specifically selected LPV lapwing areas. The mean breeding success (hatching success in brackets) per lapwing breeding pair was 0 (0.67) on fields without an agreement on non-disturbance, 1.0 (1.2) on K61 plots and 1.93 (1.95) on lapwing plots of the local landcare organisation (LPV). These initial results show that the KULAP measure K61 improves lapwing protection per breeding pair compared to fields without delayed sowing. However, the breeding and hatching success on K61 plots is lower than on LPV lapwing plots. This is because LPV lapwing protection is agreed specifically for fields that are particularly suitable for lapwing breeding or where lapwings are already breeding. In addition, the LPV lapwing fields are supervised and their farmers advised by nature managers of the landcare organisation.
Elevated fecal calprotectin is associated with gut microbial dysbiosis, altered serum markers and clinical outcomes in older individuals
2024-06-12

Abstract Fecal calprotectin is an established marker of gut inflammation in inflammatory bowel disease (IBD). Elevated levels of fecal calprotectin as well as gut microbial dysbiosis have also been observed in other clinical conditions. However, systemic and multi-omics alterations linked to elevated fecal calprotectin in older individuals remain unclear. This study comprehensively investigated the relationship between fecal calprotectin levels, gut microbiome composition, serum inflammation and targeted metabolomics markers, and relevant lifestyle and medical data in a large sample of older individuals (n = 735; mean age ± SD: 68.7 ± 6.3) from the TREND cohort study. Low (0–50 μg/g; n = 602), moderate (&gt; 50–100 μg/g; n = 64) and high (&gt; 100 μg/g; n = 62) fecal calprotectin groups were stratified. Several pro-inflammatory gut microbial genera were significantly increased and short-chain fatty acid producing genera were decreased in high vs. low calprotectin groups. In serum, IL-17C, CCL19 and the toxic metabolite indoxyl sulfate were increased in high vs. low fecal calprotectin groups. These changes were partially mediated by the gut microbiota. Moreover, the high fecal calprotectin group showed increased BMI and a higher disease prevalence of heart attack and obesity. Our findings contribute to the understanding of fecal calprotectin as a marker of gut dysbiosis and its broader systemic and clinical implications in older individuals.
Bacterial histone HBb from Bdellovibrio bacteriovorus compacts DNA by bending
2024-06-12

Abstract Histones are essential for genome compaction and transcription regulation in eukaryotes, where they assemble into octamers to form the nucleosome core. In contrast, archaeal histones assemble into dimers that form hypernucleosomes upon DNA binding. Although histone homologs have been identified in bacteria recently, their DNA-binding characteristics remain largely unexplored. Our study reveals that the bacterial histone HBb (Bd0055) is indispensable for the survival of Bdellovibrio bacteriovorus, suggesting critical roles in DNA organization and gene regulation. By determining crystal structures of free and DNA-bound HBb, we unveil its distinctive dimeric assembly, diverging from those of eukaryotic and archaeal histones, while also elucidating how it binds and bends DNA through interaction interfaces reminiscent of eukaryotic and archaeal histones. Building on this, by employing various biophysical and biochemical approaches, we further substantiated the ability of HBb to bind and compact DNA by bending in a sequence-independent manner. Finally, using DNA affinity purification and sequencing, we reveal that HBb binds along the entire genomic DNA of B. bacteriovorus without sequence specificity. These distinct DNA-binding properties of bacterial histones, showcasing remarkable similarities yet significant differences from their archaeal and eukaryotic counterparts, highlight the diverse roles histones play in DNA organization across all domains of life.
Myeloid cell-derived interleukin-6 induces vascular dysfunction and vascular and systemic inflammation
2024-06-12

Abstract Aims The cytokine interleukin-6 (IL-6) plays a central role in the inflammation cascade as well as cardiovascular disease progression. Since myeloid cells are a primary source of IL-6 formation, we aimed to generate a mouse model to study the role of myeloid cell-derived IL-6 in vascular disease. Methods and results Interleukin-6-overexpressing (IL-6OE) mice were generated and crossed with LysM-Cre mice, to generate mice (LysM-IL-6OE mice) overexpressing the cytokine in myeloid cells. Eight- to 12-week-old LysM-IL-6OE mice spontaneously developed inflammatory colitis and significantly impaired endothelium-dependent aortic relaxation, increased aortic reactive oxygen species (ROS) formation, and vascular dysfunction in resistance vessels. The latter phenotype was associated with decreased survival. Vascular dysfunction was accompanied by a significant accumulation of neutrophils, monocytes, and macrophages in the aorta, increased myeloid cell reactivity (elevated ROS production), and vascular fibrosis associated with phenotypic changes in vascular smooth muscle cells. In addition to elevated Mcp1 and Cxcl1 mRNA levels, aortae from LysM-IL-6OE mice expressed higher levels of inducible NO synthase and endothelin-1, thus partially accounting for vascular dysfunction, whereas systemic blood pressure alterations were not observed. Bone marrow (BM) transplantation experiments revealed that vascular dysfunction and ROS formation were driven by BM cell-derived IL-6 in a dose-dependent manner. Conclusion Mice with conditional overexpression of IL-6 in myeloid cells show systemic and vascular inflammation as well as endothelial dysfunction. A decrease in circulating IL-6 levels by replacing IL-6-producing myeloid cells in the BM improved vascular dysfunction in this model, underpinning the relevant role of IL-6 in vascular disease.
The Late Pliocene–Middle Pleistocene Large Mammal Faunal Units of Greece
2024-06-12

Located at the eastern corner of Mediterranean Europe, Greece occupies a critical position for mammal dispersals to/from Europe, Asia, and Africa and constitutes a potential passageway towards Western Europe. During recent decades, numerous fieldwork campaigns in several Pliocene–Pleistocene sites have greatly enriched the fossil record and provided valuable taxonomic and biostratigraphic data. However, a fully developed reference biochronological unit scheme for the Greek record that could contribute to correlations at a continental scale is still pending. In this article, we provide the updated Late Pliocene to Middle Pleistocene large mammal succession, and we introduce the Faunal Units (FUs) of Greece. We define eight FUs, the Milia, Dafnero, Gerakarou, Tsiotra Vryssi, Krimni, Apollonia, Marathousa, and Apidima FUs (from the oldest to the youngest), which are determined by a set of first and last local occurrences. The results form the basis for discussion of already set turnovers, dispersals, and extinction/immigration events and showcase the importance of the local record for the investigation of the European terrestrial ecosystems. By developing the first detailed biochronological scheme for the Pliocene–Pleistocene of Southeastern Europe, this study comprises the basis for an expanded Balkan faunal unit scale and a reference framework for future investigations.
Two-dimensional sequential selective comprehensive chiral×reversed-phase liquid chromatography of synthetic phosphorothioate oligonucleotide diastereomers
2024-06-12

In recent years, many nucleic acid-based pharmaceuticals have been approved and entered the market, and even a larger number are in late stage clinical trials. Conventional oligonucleotides are facing issues in vivo like fast renal clearance and nuclease degradation. Therefore, to increase their stability, phosphorothioation is a frequent modification of therapeutic oligonucleotides (ONs) which also leads to improved binding affinity facilitating cell internalization and intracellular distribution. At the same time, by replacing a phosphodiester linkage with a phosphorothioate group, a phosphorous stereogenic center is generated which causes the formation of R<sub>p</sub>- and S<sub>p</sub>-diastereomers. It increases the structural diversity. For example, with 15 of those phosphorothioate (PS) linkages, 32,768 different diastereomers are expected. Since the phosphorothioate is introduced non-stereoselectively, the molecular complexity of the resultant phosphorothioate ON products is tremendously increased impeding the chromatographic separation in the course of quality control. Since distinct phosphorothioate diastereomers have different bioactivities and pharmacological properties, there is increasing interest in implications of stereoisomerism of phosphorothiate oligonucleotides. From a quality and regulatory viewpoint, batch-to-batch reproducibility of the diastereomer profile may be of significant concern. In order to address this issue, this study investigates the stereoselectivity of LC methods for two phosphorothioate oligonucleotide (PSO) compounds differing in their molecular size and numbers of PS linkages. Diastereoselectivity of ion-pairing reversed-phase liquid chromatography (IP-RPLC), RPLC without ion-pairing agents and LC with chiral polysaccharide-based column were evaluated for model PSOs and an active pharmaceutical ingredient (API) of PSO with trivalent N-acetylgalactosamine (GalNAc) conjugate. Due to the structural complexity of PSOs, the separation power for the diastereomer mixture was increased by using sequential selective comprehensive two-dimensional chromatography with an amylose tris(α-methylbenzylcarbamate)-immobilized chiral stationary phase (CSP) in the first dimension and ion-pair RPLC with ethylammonium acetate in the second dimension. Improved diastereomer selectivity was obtained and a larger number of peaks could be separated.
Assessing sorption of fluoroquinolone antibiotics in soils from a Kd compilation based on pure organic and mineral components
2024-06-12

The presence of fluoroquinolone (FQ) antibiotics in soils may cause a threat to human health due to overexposure and the generation of antibiotic resistance genes. Understanding their sorption behavior in soils is important to predict subsequent FQ (bio) availability. Here, FQ sorption in pure soil organic (i.e., humic substances) and mineral (i.e., metal oxides; phyllosilicates) components is evaluated through a solid-liquid distribution coefficient (K<sub>d</sub> (FQ)) dataset consisting of 243 entries originated from 80 different studies, to elucidate their respective contribution to the overall K<sub>d</sub> (FQ) in bulk soils. First, different factors affecting FQ sorption and desorption in each of these soil phases are critically discussed. The strong role of pH in K<sub>d</sub> (FQ), due to the simultaneous effect on both FQ speciation and surface charge changes, encouraged the derivation of normalized sorption coefficients for the cationic, zwitterionic and anionic FQ species in humic substances and in different phyllosilicates. K<sub>d</sub> (FQ) in metal oxides revealed a key role of metal nature and material specific surface area due to complexation sorption mechanisms at neutral pH. Cumulative distribution functions (CDF) were applied to each dataset to establish a sorption affinity range for each phase and to derive best estimate K<sub>d</sub> (FQ) values for those materials where normalized sorption coefficients to FQ species were unavailable. The data analysis conducted in the different soil phases set the basis for a K<sub>d</sub> (FQ) prediction model, which combined the respective sorption affinity of each phase for FQ and phase abundance in soil to estimate K<sub>d</sub> (FQ) in bulk soils. The model was subsequently validated with sorption data in well characterized soils compiled from the literature.