julilili42/papers huggingface dataset:
N-Glycoside of Indolo[2,3-a]pyrrolo[3,4-c]carbazole LCS1269 Exerts Anti-Glioblastoma Effects by G2 Cell Cycle Arrest and CDK1 Activity Modulation: Molecular Docking Studies, Biological Investigations, and ADMET Prediction
2024-12-06

Background/Objectives: Indolo[2,3-a]pyrrolo[3,4-c]carbazole scaffold is successfully used as an efficient structural motif for the design and development of different antitumor agents. In this study, we investigated the anti-glioblastoma therapeutic potential of glycosylated indolocarbazole analog LCS1269 utilizing in vitro, in vivo, and in silico approaches. Methods: Cell viability was estimated by an MTT assay. The distribution of cell cycle phases was monitored using flow cytometry. Mitotic figures were visualized by fluorescence microscopy. Quantitative RT-PCR was used to evaluate the gene expression. The protein expression was assessed by Western blotting. Molecular docking and computational ADMET were approved for the probable protein target simulations and predicted pharmacological assessments, respectively. Results: Our findings clearly suggest that LCS1269 displayed a significant cytotoxic effect against diverse glioblastoma cell lines and patient-derived glioblastoma cultures as well as strongly suppressed xenograft growth in nude mice. LCS1269 exhibited more potent anti-proliferative activity toward glioblastoma cell lines and patient-derived glioblastoma cultures compared to conventional drug temozolomide. We further demonstrated that LCS1269 treatment caused the severe G2 phase arrest of cell cycle in a dose-dependent manner. Mechanistically, we proposed that LCS1269 could affect the CDK1 activity both by targeting active site of this enzyme and indirectly, in particular through the modulation of the Wee1/Myt1 and FOXM1/Plk1 signaling pathways, and via p21 up-regulation. LCS1269 also showed favorable pharmacological characteristics in in silico ADME prediction in comparison with staurosporine, rebeccamycin, and becatecarin as reference drugs. Conclusions: Further investigations of LCS1269 as an anti-glioblastoma medicinal agent could be very promising.
Hospital-Acquired Pressure Ulcers and Long-Term Motor Score Recovery in Patients With Acute Cervical Spinal Cord Injury
2024-12-06

Importance Pressure ulcers (PUs) are (1) prevalent secondary complications after spinal cord injury (SCI), (2) present with elevated systemic inflammatory tone, and (3) may interfere with healing processes underlying neurological recovery (disrepair). Objective To investigate whether PUs acquired during initial hospitalization are associated with neurological and functional long-term outcome and survival after SCI. Design, Setting, and Participants Multicenter cohort study at 20 centers of the prospective SCI Model Systems (SCIMS) Database (Birmingham, AL). Patients with acute traumatic cervical SCI with relevant motor impairment (ie, American Spinal Injury Association [ASIA] impairment scale [AIS] A, B, and C) were enrolled from January 1996 to September 2006 and followed up until June 2016. Data were analyzed from April 2021 to September 2024. Exposures PUs acquired during surgical or first rehabilitative SCI care. Main outcomes and measures The change in the ASIA motor score at 1 year after SCI was the primary end point. Secondary end points included the recovery of functional independence measure (FIM) motor score at 1 year after SCI and mortality up to 10 years. ASIA and FIM motor score were analyzed applying linear mixed models with random intercept adjusted for baseline neurological level, AIS, and sociodemographic factors. Mortality was analyzed using Cox regression. Results The study included 1282 patients with a mean (SD) age of 38.0 (15.7) years and consisted of 1028 (80.2%) male patients. Regarding race and ethnicity, 349 of 1249 (27.9%) were African American patients, 1139 of 1273 (89.5%) were non-Hispanic patients, and 834 of 1249 (66.8%) were White patients. During initial hospitalization, 594 patients (45.7%) acquired PUs. Exposure to PUs was associated with impaired motor recovery 1 year after SCI compared with unexposed patients (−9.1 ASIA motor score points; 95% CI, −12.3 to −6.0; P &amp;amp;lt; .001). In addition, PUs were associated with lower recovery of physical independence 1 year after SCI (−8.3 FIM motor score points; 95% CI: −11.1 to −5.5; P &amp;amp;lt; .001). Cox regression confirmed PUs as a risk marker for death up to 10 years after SCI (hazard ratio, 1.41; 95% CI, 1.09 to 1.82; P = .01). Conclusions and Relevance In this cohort study, PUs acquired during initial hospitalization after SCI were independently associated with poor long-term neurofunctional outcome. PUs constitute a modifiable factor associated with risk for worse long-term disability (recovery confounder) and elevated mortality.
A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations
2024-12-06

Abstract We have identified a new inherited bone marrow failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense (MS) mutation were found in 3 patients from 2 unrelated families. Although 2 affected siblings with a stop-codon COPZ1 mutation suffered from CN that involves other hematologic lineages and nonhematologic tissues, the patient with a MS COPZ1 mutation had isolated neutropenia. Both COPZ1 mutations were localized to a highly evolutionarily conserved region. The resulting truncated (TR) COPZ1 protein was predicted to display diminished interaction with its COPI complex partner, COPG1. These findings were consistent with the observed block in retrograde protein transport from the Golgi apparatus to the endoplasmic reticulum (ER) in human fibroblasts carrying TR COPZ1. Human CD34+ cells with TR or MS COPZ1 had significantly impaired granulocytic differentiation, and in zebrafish embryos, TR Copz1 also resulted in defective myelopoiesis. Intracellularly, TR COPZ1 downregulated JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways, while inducing STING, interferon-stimulated genes, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species levels in hematopoietic cells. MS COPZ1 deregulated interferon and JAK/STAT signaling but less than the TR protein. Finally, treatment with the small molecule HIF1α stabilizer IOX2 or transduction of cells with COPZ2 restored defective granulopoiesis in COPZ1-mutated human CD34+ cells, offering potential therapeutic options.
Structural basis of the allosteric regulation of cyanobacterial glucose-6-phosphate dehydrogenase by the redox sensor OpcA
2024-12-06

The oxidative pentose phosphate (OPP) pathway is a fundamental carbon catabolic route for generating reducing power and metabolic intermediates for biosynthetic processes. In addition, its first two reactions form the OPP shunt, which replenishes the Calvin-Benson cycle under certain conditions. Glucose-6-phosphate dehydrogenase (G6PDH) catalyzes the first and rate-limiting reaction of this metabolic route. In photosynthetic organisms, G6PDH is redox-regulated to allow fine-tuning and to prevent futile cycles while carbon is being fixed. In cyanobacteria, regulation of G6PDH requires the redox protein OpcA, but the underlying molecular mechanisms behind this allosteric activation remain elusive. Here, we used enzymatic assays and in vivo interaction analyses to show that OpcA binds G6PDH under different environmental conditions. However, complex formation enhances G6PDH activity when OpcA is oxidized and inhibits it when OpcA is reduced. To understand the molecular basis of this regulation, we used cryogenic electron microscopy to determine the structure of Synechocystis G6PDH and the G6PDH–OpcA complex. OpcA binds the G6PDH tetramer and induces conformational changes in the active site of G6PDH. The redox sensitivity of OpcA is achieved by intramolecular disulfide bridge formation, which influences the allosteric regulation of G6PDH. In vitro assays reveal that the level of G6PDH activation depends on the number of bound OpcA molecules, which implies that this mechanism allows delicate fine-tuning. Our findings unveil a unique molecular mechanism governing the regulation of the OPP in Synechocystis .
Supervised Automated Kinetic Perimetry (SAKP) Using Simulated Visual Field Data – Presentation of a New Examination Technique
2024-12-06

Abstract Purpose The aim of this study was to develop, optimise, train, and evaluate an algorithm for performing Supervised Automated Kinetic Perimetry (SAKP) using digitalised perimetric simulation data. Methods The original SAKP algorithm was based on findings from a multicentre study to establish reference values by semi-automated kinetic perimetry (SKP) combined with an automated examination method with moving stimuli (“Program K”, developed in Japan). The algorithm evaluated the outer angles of isopter segments and responded to deviations from expected values by placing examination vectors to measure the outer boundaries of the visual field (VF). Specialised interpolation methods were also used to create individual 3D hills of vision and local “probing vectors” to optimise the eccentricity of the vector origins. This algorithm was trained iteratively on seven representative digitalised 3D VF results from five typical classes and optimised in each step: (1) Normal VF, (2) Central scotoma, (3) Concentric VF constriction, (4) Retinal nerve fibre layer defects in the visual field (VFDs), (5) VFDs with respect to the vertical meridian. The optimised SAKP algorithm was then applied to a new set of twenty 3D VF results of varying origin and severity. The primary targets were measured in agreement between actual calculated VF expressed as accuracy (A), that is, the ratio between the area containing correct predictions and total area of predictions measured between 0 = worst and 1 = best, and examination duration (T). The results are given as median (and interquartile range). We also verified the testʼs robustness by varying individual error rates (ERs) and error magnitudes (EMs). Results The median and interquartile range (IQR, in brackets) for the total of representative VFs were 0.93 (0.02) for A and 7.0 min (5.2 min) for T, respectively. A gave the best result for altitudinal VFDs and VFDs with hemianopic character and macular sparing (0.98 each) and worst in superior wedge-shaped VFDs (0.78); T was shortest in blind spot displacement (3.9 min) and longest in hemianopic VFDs with hemianopic character and macular sparing with preserved temporal crescent (12.1 min). Error rate and magnitude (up to 30% each) only showed a comparatively low influence on A and T. Conclusion The SAKP algorithm presented here achieves a comparatively high degree of accuracy and robustness for actual, simulated visual field data within acceptable examination times. This algorithm is currently being prepared for application in real patient examinations under clinical conditions.
A Method for the Combined Functional Assessment of Photoreceptors and Ganglion Cells in Acute Retinal Explants
2024-12-06

Abstract Significant progress has been made in studying the individual steps of retinal signaling, yet a comprehensive understanding of the functional interplay between photoreceptors, as input cells, and retinal ganglion cells (RGCs), as output cells, remains elusive. This connection is crucial to fully unravel the retina’s computational capabilities and its role in visual processing. To address this gap, this study introduces a novel technique that combines two-photon (2P) autofluorescence microscopy with multi-electrode array (MEA) recordings, enabling simultaneous testing of photoreceptor and RGC function. Unlike traditional methods that target isolated cell classes or structural analysis, this integrated technique provides the basis to investigate input-output relationships within the retinal neural network, offering a deeper understanding of its dynamic activity and adaptability to cellular dropout.
Standardized Response Assessment in Patients with Advanced Cholangiocarcinoma Treated with Personalized Therapy
2024-12-06

Background/Objectives: Current guidelines recommend Cisplatin/Gemcitabine/Durvalumab as first-line treatment for inoperable or recurrent cholangiocarcinoma (CCA). Molecular tumor boards (MTB) have the expertise to support organ-specific tumor boards with evidence-based treatment recommendations for subsequent lines of treatment, based on genomic tumor data and scientific evidence. This study evaluates the adoption of an MTB at a comprehensive cancer center in Germany and whether actionable genetic alterations are associated with specific imaging phenotypes. Methods: Patients with CCA referred to MTB were enrolled from May 2019 to September 2021. For comparison, a cohort of patients from a second center was included. Data on treatment recommendations, regimens, and survival were collected from prospective registries. Baseline and follow-up contrast-enhanced CT were analyzed according to RECIST 1.1. The chi-square test and t-test were used to compare categorical and continuous variables. Results: 583 patients were referred to the MTB, and 92 patients (47 female/51%) with a mean age of 60.3 ± 11.2 were referred for CCA treatment. 65/92 patients harbored 1–3 targetable mutations. Liver metastases were more frequently observed in patients with targetable mutations (84% vs. 62%). Metastasis to the liver and lung was associated with increased sums of diameters (93 mm and 111 mm vs. 40/73 mm in patients with no liver/lung metastasis). The number of metastases in individual organs was unrelated to treatment targets. Follow-up was available for 25 patients with a median time until imaging progression of 23 weeks. Progression occurred as target progression in 63%, nontarget progression in 13%, and appearance of new lesions in 63%. Conclusions: Most patients with CCA harbored targetable mutations, some were related to disease patterns on imaging. The pattern of treatment response and progression was as diverse as the metastatic spread.
No One Home? New Evidence for MIS 3 Occupations in the Western Cape (South Africa) from Mertenhof Rock Shelter
2024-12-07

Abstract Southern Africa features an intensively studied Stone Age sequence, though one with geographical and temporal gaps. The archaeology of Marine Isotope Stage (MIS) 3 remains understudied, particularly between ~ 50 and 25 ka. This period encompasses important ecological, demographic and cultural changes, most notably the transition from Middle Stone Age (MSA) to Later Stone Age (LSA) technologies. In western South Africa, previous research postulated a demographic hiatus during the second half of MIS 3, potentially due to hyperarid climatic conditions. Here, we provide evidence of occupation during this period at Mertenhof Rock Shelter (MRS) in the form of new chronometric and technological data. OSL estimates suggest two pulses of low-intensity occupations at ~ 50 ka and 41–37 ka, allowing for a diachronic assessment of technological changes. These sporadic MSA occupations complement the more widespread occurrence of open-air settlements along the Doring River during ~ 50–35 ka. At MRS, knappers procured local rock types and produced small flakes and some laminar elements via platform, bipolar and Levallois reduction. The retouched elements feature splintered pieces and denticulates but mostly lack points. Differences to contemporaneous sites in eastern southern Africa underscore ongoing technological regionalisation and demographic partitioning during MIS 3. The temporal changes in the sequence show some antecedents of Early LSA technological systems, which appear in the region around 25 ka, but not in a unidirectional manner. Lithic and chronometric evidence from MRS supports scenarios of a long MSA persistence within MIS 3 in southern Africa and a late emergence of the LSA sometime after 35 ka.
Short‐Term Dynamics of Low Molecular Weight Organic Substances and Biochar in Arable Soils
2024-12-08

ABSTRACT Background Main transformation pathways of low molecular weight organic substances (LMWOS) are understood, but only limited knowledge exists on their transformations in different soils and on their interactions with biochar. Aim Objectives were to study short‐term pathways of 13 C‐labelled LMWOS with different functional groups in the presence and absence of biochar in arable loess soils. Methods Soils from three sites were incubated with or without artificially aged biochar and 13 C‐labelled acetate, alanine or glucose at different rates (10 or 50 μmol C g −1 soil) at 60% water holding capacity and 15°C for 5 days, and total and substrate‐derived CO 2 ‐C and microbial biomass C (MBC) were determined and analyses of variance were calculated. Results Cumulative CO 2 ‐C (ΣCO 2 ‐C) emission was significantly ( p ≤ 0.05) affected by substrate rate and type and their interaction. Biochar significantly stimulated total, but not substrate‐derived ΣCO 2 ‐C (ΣCO 2 ‐C SD ) emission. Box‐Cox transformed MBC was significantly affected by site, substrate rate and type, whereas biochar had no significant effect. Substrate‐derived MBC (MBC SD ) and carbon use efficiency (CUE) were significantly affected by site, substrate rate and type and their interaction. Conclusions MBC SD and CUE results at low addition rate confirmed the greater importance of glucose for the build‐up of MBC compared to acetate and alanine, whereas the latter were mineralized to a greater extent. Biochar, once it is aged, which is the typical biochar form in soil, did not significantly affect build‐up of MBC SD and CUE and only slightly increased total, but not ΣCO 2 ‐C SD emission.
Flavopiridol restores granulopoiesis in experimental models of severe congenital neutropenia
2024-12-08

Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways causing maturation arrest of granulocytic progenitors. We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of CN associated with ELANE mutations (ELANE-CN) and performed an in silico drug repurposing analysis of the transcriptomics of iPSC-generated hematopoietic stem and progenitor cells. We identified flavopiridol, a Food and Drug Administration (FDA)-approved pan-cyclin-dependent kinase inhibitor, as a potential therapeutic. Treatment with low-dose flavopiridol rescued defective granulopoiesis in primary CD34<sup>+</sup> cells of CN patients with different inherited gene mutations in vitro and in two zebrafish CN models in vivo without any toxic effects and leading to functional granulocytes. Flavopiridol also restored granulopoiesis caused by diminished CEBPA expression, a known defective signaling molecule in CN. Thus, we described for the first time a potential therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia.
Does sleep help children to generalise features like adults?
2024-12-08

Summary Children and adults have been shown to benefit from sleep with regard to the consolidation of declarative memories. Especially during childhood, the generalisation of information from social and non‐social contexts is important for adaptable behaviour in new situations and might show specific features in children. Here, we investigated whether adults ( n = 18) and children ( n = 19) differ in their generalisation of features assessed in wake and sleep conditions. In a social paradigm, certain face features were associated with different types of offers (fair, unfair, friendly). While children tended to better recognise these faces, adults were better than children at associating the type of offer to unknown faces sharing these features with the previously encoded faces in the sleep condition. To assess generalisation of features in a non‐social context, a probabilistic evaluative conditioning paradigm was used, where stimuli were associated with positive or negative values. We found no difference between children and adults or between the sleep and wake condition in the change in evaluation of the conditioned stimuli when paired congruently with a predefined value (positive/negative). Together, our results suggest a differential feature generalisation from mainly social contexts in children compared with adults.
MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration
2024-12-09

Abstract Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Since its conception, MIBiG has been regularly updated to expand data coverage and remain up to date with innovations in natural product research. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard. In a massive community annotation effort, 267 contributors performed 8304 edits, creating 557 new entries and modifying 590 existing entries, resulting in a new total of 3059 curated entries in MIBiG. Particular attention was paid to ensuring high data quality, with automated data validation using a newly developed custom submission portal prototype, paired with a novel peer-reviewing model. MIBiG 4.0 also takes steps towards a rolling release model and a broader involvement of the scientific community. MIBiG 4.0 is accessible online at https://mibig.secondarymetabolites.org/.
Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept
2024-12-09

The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable <i>in vitro</i> and <i>in vivo</i> models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy. The IMI2/EU project imSAVAR (immune safety avatar: non-clinical mimicking of the immune system effects of immunomodulatory therapies) aims at creating a platform for novel tools and models for enhanced non-clinical prediction of possible adverse events associated with immunomodulatory therapies. This platform shall in the future guide early non-clinical safety assessment of novel immune therapeutics thereby also reducing the costs of their development. Therefore, we review current opportunities and challenges associated with non-clinical <i>in vitro</i> and <i>in vivo</i> models for the safety assessment of CAR T cell therapy ranging from organ-on-chip models up to advanced biomarker screening.