julilili42/papers huggingface dataset:
Protocol for 3D Virtual Histology of Unstained Human Brain Tissue using Synchrotron Radiation Phase-Contrast Microtomography
2023-11-11

Abstract X-ray phase-contrast micro computed tomography using synchrotron radiation (SR PhC-μCT) offers unique 3D imaging capabilities for visualizing microstructure of the human brain. Its applicability for unstained soft tissue is an area of active research. Acquiring images from a tissue block without needing to section it into thin slices, as required in routine histology, allows for investigating the microstructure in its natural 3D space. This paper presents a detailed step-by-step guideline for imaging unstained human brain tissue at resolutions of a few micrometers with SR PhC-μCT implemented at SYRMEP, the hard X-ray imaging beamline of Elettra, the Italian synchrotron facility. We present examples of how blood vessels and neurons appear in the images acquired with isotropic 5 μm and 1 μm voxel sizes. Furthermore, the proposed protocol can be used to investigate important biological substrates such as neuromelanin or corpora amylacea. Their spatial distribution can be studied using specifically tailored segmentation tools that are validated by classical histology methods. In conclusion, SR PhC-μCT using the proposed protocols, including data acquisition and image processing, offers viable means of obtaining information about the anatomy of the human brain at the cellular level in 3D.
‘A great star falls’—cometology in Syriac language and literature
2023-11-11

Abstract The Syriac language has, among all the Aramaic varieties, by far the largest number of terms for ‘comet’ or ‘meteor’. Is there a simple explanation for this fact? The systematic investigation of Syriac technical terminology in the field of astral sciences addresses this question. Such a study also impacts three issues relevant to Semitic studies: (1) The question of the sources and languages the Syriac writers were able to access; (2) the linguistic strategies for the creation of neologisms; (3) the existence of a common Aramaic technical koiné (standard literary Aramaic). This article sets forth the terms for comets and meteors in Syriac as a representative selection of astral terminology, and investigates their value for the questions mentioned above. The two pillars of this investigation are the comparison of the literary genres in which this terminology surfaces with those of other Near Eastern literatures in which this terminology surfaces, and the linguistic analysis of these terms in Syriac.
Ethical, legal and social aspects of human cerebral organoids and their governance in Germany, the United Kingdom and the United States
2023-11-13

Human cerebral organoids (HCOs) are model systems that enable researchers to investigate the human brain in ways that had previously been impossible. The emergence of HCOs was accompanied by both expert and layperson discussions concerning the possibility of these novel entities developing sentience or consciousness. Such concerns are reflected in deliberations about how to handle and regulate their use. This perspective article resulted from an international and interdisciplinary research retreat “Ethical, Legal and Social Aspects of Human Cerebral Organoids and their Governance in Germany, the United Kingdom and the United States”, which took place in Tübingen, Germany, in August 2022. The retreat focused on whether HCO research requires new ethical and regulatory approaches. It addressed epistemic issues around the detection and theorisation of consciousness, ethical concerns around moral status and research conduct, difficulties for legislation and guidelines managing these entities, and public engagement.
Urinary phenotyping of SARS-CoV-2 infection connects clinical diagnostics with metabolomics and uncovers impaired NAD+ pathway and SIRT1 activation
2023-11-13

Abstract Objectives The stratification of individuals suffering from acute and post-acute SARS-CoV-2 infection remains a critical challenge. Notably, biomarkers able to specifically monitor viral progression, providing details about patient clinical status, are still not available. Herein, quantitative metabolomics is progressively recognized as a useful tool to describe the consequences of virus-host interactions considering also clinical metadata. Methods The present study characterized the urinary metabolic profile of 243 infected individuals by quantitative nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography mass spectrometry (LC–MS). Results were compared with a historical cohort of noninfected subjects. Moreover, we assessed the concentration of recently identified antiviral nucleosides and their association with other metabolites and clinical data. Results Urinary metabolomics can stratify patients into classes of disease severity, with a discrimination ability comparable to that of clinical biomarkers. Kynurenines showed the highest fold change in clinically-deteriorated patients and higher-risk subjects. Unique metabolite clusters were also generated based on age, sex, and body mass index (BMI). Changes in the concentration of antiviral nucleosides were associated with either other metabolites or clinical variables. Increased kynurenines and reduced trigonelline excretion indicated a disrupted nicotinamide adenine nucleotide (NAD + ) and sirtuin 1 (SIRT1) pathway. Conclusions Our results confirm the potential of urinary metabolomics for noninvasive diagnostic/prognostic screening and show that the antiviral nucleosides could represent novel biomarkers linking viral load, immune response, and metabolism. Moreover, we established for the first time a casual link between kynurenine accumulation and deranged NAD + /SIRT1, offering a novel mechanism through which SARS-CoV-2 manipulates host physiology.
Psychological, Social, and Behavioral Conditions of Anti-VEGF Patients: Results from the ALBATROS Data Collection
2023-11-13

Background: Retinal diseases such as neovascular age related macular degeneration (nAMD), diabetic macular edema (DME) or branch-/central retinal vein occlusion (B/CRVO) have significant implications for patients&amp;#039; social and psychological well-being. To gain a comprehensive understanding of patients&amp;#039; backgrounds and attitudes, we developed an exploratory questionnaire, the Basic Care and Patient Satisfaction Questionnaire (BPZ-9).&#x0D; Methods: The ALBATROS study aimed to assess the care situation of treatment-naïve patients diagnosed with either nAMD, DME or B/CRVO. The data collection took place at the beginning of treatment and after twelve months of anti-VEGF (vascular endothelial growth factor) therapy. The BPZ-9 instrument comprises nine questions to evaluate patients’ psychological and social situation and their satisfaction with treatment.&#x0D; Results: Data were collected from 1.478 nAMD (mean 78 years), 445 DME (67 years), 233 BRVO (70 years) and 144 CRVO (71 years) patients at 102 study centers throughout Germany. Approximately one third of the patients was living alone and six percent were in organized care. One in four patients had difficulties to walk and one in five needed accompany for treatment. Anxiety to lose vision was present in three out of four patients at the beginning and slightly decreased to two out of three over the 12-month treatment preriod. The distress of having a retinal disease was generally higher than the distress related to treatment. Most patients reported high treatment satisfaction (73%) and felt well informed (81%).&#x0D; Conclusion: Patients receiving anti-VEGF therapy commonly experience impaired mobility, dependency on others, distress and the fear of vision loss.
Distinct oxygenation modes of the Gulf of Oman during the past 43,000 years – a multi-proxy approach
2023-11-13

Abstract. Climatic conditions and its change shape the strength and extent of the oxygen minimum zone (OMZ). The presence and variability of the OMZ in the Arabian Sea is of importance for their ecosystem. The state of oxygenation has, for instance, an impact on the pelagic and benthic faunal community or the nitrogen and carbon cycles. The understanding of the dynamics of the OMZ, its marine environmental is of importance due to its climate feedbacks. In this study, we combined three independent proxies to reconstruct the oxygenation state of the water column and bottom water in the Gulf of Oman for the past about 43 ka for the first time. We used nitrogen isotopes (δ15N) as well as the alkane ratio (lycopane + n-C35)/n-C31 and benthic foraminiferal faunal analysis to reconstruct the strength of the OMZ in the water column and bottom water oxygenation, respectively. Our results show that the Gulf of Oman experienced strong pronounced OMZ and bottom water deoxygenation during the Holocene. Contrary, during the Last Glacial Maximum (LGM)/ Marine Isotope Stage (MIS) 2 the Gulf of Oman was very well ventilated with a highly diverse benthic foraminiferal community. This may have been caused by stronger wind-induced mixing and better ventilation by oxygen-rich water masses. Our results also show moderate oxygenation during MIS 3 with deoxygenation events during most of the warmer Dansgaard-Oeschger (D/O) events. We propose two distinct oxygenation modes for the Gulf of Oman: 1) a stable period of either strongly pronounced water column OMZ and bottom water deoxygenation or well-oxygenated water column and bottom water conditions and 2) an unstable period of oscillating oxygenation states between moderately oxygenated (stadials) and deoxygenated (interstadial, D/O events) conditions.
Nuclear dualism without extensive DNA elimination in the ciliateLoxodes magnus
2023-11-13

Abstract Ciliates are unicellular eukaryotes with two distinct kinds of nuclei in each cell: transcriptionally active somatic macronuclei (MAC) and silent germline micronuclei (MIC). In the best-studied model species, both nuclei can divide asexually, but only germline MICs participate in meiosis, karyogamy, and development into new MACs. During MIC-to-MAC development, thousands of mobile element relics in the germline, called internally eliminated sequences (IESs), are excised. This genome editing enables IESs to persist by shielding them from somatic natural selection. Editing itself is a costly, time-consuming process, hypothetically maintained by evolutionary addiction. Loxodes magnus and its relatives (class Karyorelictea) are cytologically unusual because their MACs do not divide asexually, but must develop anew from mitotically generated MIC copies every cell division. Here, we report that Loxodes genome development is also unconventional. We found no canonical germline-limited IESs in Loxodes despite careful purification and long-read sequencing of MICs and MACs. The k-mer content of these nuclei overlapped, and indels found by read mapping were consistent with allele variants rather than IESs. Two other hallmarks of genome editing—domesticated DDE-family transposases and editing-associated small RNAs—were also absent. Nonetheless, histone marks, nucleosome and DNA N6-methyladenosine distributions in vegetative Loxodes cells are consistent with actively transcribed MACs and inactive MICs, like other ciliates. Both genomes, not only the MIC, were large and replete with retrotransposon sequences. Given the costs associated with genome editing, we hypothesize that karyorelicteans like Loxodes have lost or streamlined editing during MIC-to-MAC development, and have found a way out of the addictive cycle.
Structural insights in the GTP-driven monomerization and activation of a bacterial LRRK2 homologue using allosteric nanobodies
2023-11-13

Abstract The Roco proteins are a family of GTPases, characterized by the conserved presence of a Roc-COR tandem domain. These proteins entered the limelight after mutations in human LRRK2 were identified as a major cause of familial Parkinson’s disease. LRRK2 is a large and complex protein combining a GTPase and protein kinase activity, and disease mutations increase the kinase activity, while presumably decreasing the GTPase activity. Although a cross-communication between both catalytic activities has been suggested, the underlying mechanisms and the regulatory role of the GTPase domain remain unknown. Recently, several structures of LRRK2 have been reported, but so far structures of Roco proteins in their activated GTP-bound state are lacking. Here, we use single particle cryo-EM to solve the structure of a simpler bacterial Roco protein (CtRoco) in its GTP-bound state, aided by the use of two conformation-specific nanobodies: Nb Roco1 and Nb Roco2 . This structure presents CtRoco in an active monomeric state, featuring very significant conformational changes compared to the previously solved nucleotide-free dimer structure. In particular, the structure shows a very large GTP-induced conformational change of the LRR domain, unleashing it from the Roc-COR domains, using the LRR-Roc linker as a hinge. Furthermore, this structure shows how Nb Roco1 and Nb Roco2 collaborate to activate CtRoco in an allosteric way. Altogether, our data provide important new insights in the activation mechanism of Roco proteins, with relevance to LRRK2 regulation, and suggest new routes for the allosteric modulation of their GTPase activity.
Developing, Validating, and Implementing a Mental Model Test for Primary School Students (Doctoral Consortium)
2023-11-13

This doctoral research aims to address the lack of empirical studies on identifying mental models in primary school students, particularly in relation to programming concepts such as loops and conditionals. The objective is to develop and validate a mental model test and explore its potential in enhancing programming competence. The research will employ a mixed methods approach, utilizing an online questionnaire and interviews with primary school students attending computational thinking courses. The test will be validated by subject matter experts, and its correlation with other instruments will be assessed for criterion validation. Subsequently, the validated test will be implemented within a conceptual change teaching approach to evaluate its applicability and impact through a randomized controlled field trial.
Calorie restriction reduces biomarkers of cellular senescence in humans
2023-11-14

Abstract Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young‐to‐middle‐aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging‐related conditions. Using plasma specimens from the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIETM) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA‐IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA‐sequencing data from a subset of participants, we observed a significant reduction in a senescence‐focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.
Impact of climate change-induced warming on groundwater temperatures and quality
2023-11-14

Abstract The impacts of climate change-induced warming on our ecosystems can no longer be neglected, but our understanding of consequences for groundwater ecosystems in general and groundwater quality in particular is alarmingly incomplete. In this review, we therefore provide an overview of the current state of knowledge related to the impact of global warming on our precious groundwater resources. Groundwater warming in shallow aquifers is closely associated with increasing average land surface temperatures and has already reached + 1 K compared to pe-industrial times. Until the end of the twenty-first century, temperature increases in local groundwater of up to + 10 K are possible. Monitoring data, laboratory and field experiments all provide evidence that such temperature increases are sufficient to substantially modify groundwater quality through numerous and interlinked biogeochemical processes, which we have summarized in a conceptual overview. Warming impacts on groundwater are highly site-specific and spatially heterogeneous, which complicates their assessment and prediction. Locally, shallow unconfined and nutrient-rich floodplain aquifers are most susceptible to warming-induced changes. Importantly, processes affecting water quality are not only modified by a long-term rise in groundwater temperatures, but also in the short-term during weather extremes, which is of great relevance for riverbank filtration. At the regional scale, aquifers in cold regions impacted by permafrost thawing are especially vulnerable to warming. As the majority of temperature-sensitive processes affecting groundwater quality are not or only very slowly reversable, we pressingly require comprehensive mechanistic understanding before it is too late to develop suitable countermeasures and management strategies.
Radiochemistry: A Hot Field with Opportunities for Cool Chemistry
2023-11-14

Recent Food and Drug Administration (FDA) approval of diagnostic and therapeutic radiopharmaceuticals and concurrent miniaturization of particle accelerators leading to improved access has fueled interest in the development of chemical transformations suitable for short-lived radioactive isotopes on the tracer scale. This recent renaissance of radiochemistry is paired with new opportunities to study fundamental chemical behavior and reactivity of elements to improve their production, separation, and incorporation into bioactive molecules to generate new radiopharmaceuticals. This outlook outlines pertinent challenges in the field of radiochemistry and indicates areas of opportunity for chemical discovery and development, including those of clinically established (C-11, F-18) and experimental radionuclides in preclinical development across the periodic table.
Symptoms of mental disorders and oral contraception use: A systematic review and meta-analysis
2023-11-14

Worldwide, over 150 million adolescent and adult women use oral contraceptives (OC). An association between OC-use and the emergence of symptoms of mental disorders has been suggested. This systematic review and meta-analysis provide an overview of published research regarding symptoms of mental disorders in association with OC-use, factoring the influence of OC types, age of first-use, duration of OC-intake, and previous diagnoses of mental disorders. A systematic literature search was conducted between June-July 2022. 22 studies were included. While most found no significant OC-use effects on mental symptoms, some hinted at OCs as a potential risk. The existing evidence regarding the potential link between progestin-only OC-use and an elevated risk of mental symptoms in comparison to combined OC-use remains inconclusive. However, due to emerging indications suggesting that the formulation of OC might play a role in mental health outcomes, this topic warrants further investigation. Moreover, indications of an increased risk for depressive symptoms in adolescent OC-users should be noted. Hence, while general population effects seem unlikely, they cannot be completely disregarded. The decision on OC-use should depend on the patient's medical history and should be re-evaluated regularly.
Stage‐Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3
2023-11-14

Spinocerebellar ataxia type 3/Machado–Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross‐sectional data of 292 spinocerebellar ataxia type 3/Machado–Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado–Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400–406
Structural and molecular characterization of lopinavir and ivermectin as breast cancer resistance protein (BCRP/ABCG2) inhibitors
2023-11-14

A current clinical challenge in cancer is multidrug resistance (MDR) mediated by ABC transporters. Breast cancer resistance protein (BCRP) or ABCG2 transporter is one of the most important ABC transporters implicated in MDR and the use of inhibitors is a promising approach to overcome the resistance in cancer. This study aimed to characterize the molecular mechanism of ABCG2 inhibitors identified by a repurposing drug strategy using antiviral, anti-inflammatory and antiparasitic agents. Lopinavir and ivermectin can be considered as pan-inhibitors of ABC transporters, since both compounds inhibited ABCG2, P-glycoprotein and MRP1. They inhibited ABCG2 activity showing IC50 values of 25.5 and 23.4 μM, respectively. These drugs were highly cytotoxic and not transported by ABCG2. Additionally, these drugs increased the 5D3 antibody binding and did not affect the mRNA and protein expression levels. Cell-based analysis of the type of inhibition suggested a non-competitive inhibition, which was further corroborated by in silico approaches of molecular docking and molecular dynamics simulations. These results showed an overlap of the lopinavir and ivermectin binding sites on ABCG2, mainly interacting with E446 residue. However, the substrate mitoxantrone occupies a different site, binding to the F436 region, closer to the L554/L555 plug. In conclusion, these results revealed the mechanistic basis of lopinavir and ivermectin interaction with ABCG2.
On- vs. Off-Pump CABG in Heart Failure Patients with Reduced Ejection Fraction (HFrEF): A Multicenter Analysis
2023-11-14

Objective: This study aimed to compare postoperative outcomes and 30-day mortality in patients with reduced ejection fraction (&lt;40%) who underwent isolated coronary artery bypass grafting (CABG) with (ONCAB) and without (OPCAB) the use of cardiopulmonary bypass. Methods: data from four university hospitals in Germany, spanning from January 2017 to December 2021, were retrospectively analyzed. A total of 551 patients were included in the study, and various demographic, intraoperative, and postoperative data were compared. Results: demographic parameters did not exhibit any differences. However, the OPCAB group displayed notably higher rates of preoperative renal insufficiency, urgent surgeries, and elevated EuroScore II and STS score. During surgery, the ONCAB group showed a significantly higher rate of complete revascularization, whereas the OPCAB group required fewer intraoperative transfusions. No disparities were observed in 30-day/in-hospital mortality for the entire cohort and the matched population between the two groups. Subsequent to surgery, the OPCAB group demonstrated significantly shorter mechanical ventilation times, reduced stays in the intensive care unit, and lower occurrences of ECLS therapy, acute kidney injury, delirium, and sepsis. Conclusions: the study’s findings indicate that OPCAB surgery presents a safe and viable alternative, yielding improved postoperative outcomes in this specific patient population compared to ONCAB surgery. Despite comparable 30-day/in-hospital mortality rates, OPCAB patients enjoyed advantages such as decreased mechanical ventilation durations, shorter ICU stays, and reduced incidences of ECLS therapy, acute kidney injury, delirium, and sepsis. These results underscore the potential benefits of employing OPCAB as a treatment approach for patients with coronary heart disease and reduced ejection fraction.