julilili42/papers huggingface dataset:
Differential effects of HDAC inhibitors in the Rho I255d mouse model for autosomal dominant retinitis pigmentosa
2025-07-31

Abstract Retinitis Pigmentosa (RP) is an inherited neurodegenerative disease which leads to loss of retinal photoreceptors and blindness. Histone deacetylases (HDAC) were previously found to be involved in photoreceptor cell death, and HDAC inhibitors have shown protective effects in animal models for autosomal recessive RP. However, whether HDAC inhibitors can protect photoreceptors in autosomal dominant RP (ADRP) remains unclear. Here, we utilized the recently generated human homologous Rho I255d/+ ADRP mouse model to investigate degenerative mechanisms and the therapeutic potential of HDAC inhibitors. To visualize photoreceptor HDAC activity, we applied an in situ HDAC activity assay on post-natal (P) day 20 wild type (WT) and Rho I255d/+ retina. Treatment with the HDAC class I/II inhibitor Trichostatin A and the HDAC class III inhibitor nicotinamide (NAM) suggested that most HDAC activity detected in Rho I255d/+ photoreceptors was related to class I/II isoforms. The therapeutic potential of different HDAC inhibitors, targeting different HDAC isoforms, was evaluated on organotypic retinal explants cultured under completely controlled conditions. HDAC inhibitors tested included SAHA (Vorinostat), MPT0G211, ACY-957, and NAM. Readouts comprised the TUNEL assay, immunostaining for activated calpain-2 and caspase-3, cone arrestin-3, and bromodeoxyuridine (BrdU)-labeling. Among the compounds tested, MPT0G211, targeting predominantly cytoplasmic HDAC-6, exhibited the strongest protective effect on both rod and cone photoreceptors. Remarkably, ACY-957, inhibiting nuclear HDAC-1/-2, at higher concentration induced both photoreceptor cell death and cell proliferation. High levels of NAM, blocking mitochondrial and nuclear HDACs, caused selective rod cell death, without affecting cones. All HDAC inhibitors tested had no or only minor effects on neurons of the inner retina. Our study highlights the complexity of HDAC activity during photoreceptor neurodegeneration and cautions against the use of unspecific inhibitors. At the same time, it showcases important differences between rod and cone photoreceptors and suggests especially HDAC-6 as a potential target for future therapy development. Graphical abstract
Student-performed periodontal therapy: retrospective cohort study on outcomes and related recommendations for enhancing undergraduate periodontal education
2025-07-31

Abstract Background The aim of the study was to evaluate periodontal treatment success in patients treated by undergraduates. The findings shall be used to gain implications for future curriculum frameworks. Methods In this retrospective cohort study, the medical records of 107 patients (median age 58 years, 48% female) diagnosed with stage III periodontitis who were treated by students were analyzed. Anamnestic and periodontal clinical parameters (bleeding on probing (BOP%), periodontal pocket depths (PD), plaque control record (PCR) were extracted at baseline (T0), re-evaluation (T1, median 3mth), and last SPC visit (T2, median 47mth after T0). The primary outcome was assessing the relative proportion of patients achieving specific treatment endpoints at T1 (EP1 = BOP &lt; 20% and EP2 = ≤ 4site with PD ≥ 5 mm), secondary outcomes included identification of factors influencing these specific endpoints at T1 and T2. Results All parameters (BOP, PD, PCR) improved statistically significantly during step 1, 2 and 4 of periodontal therapy. In contrast, a worsening of PCR between T1 and T2 ( p = 0.049) was observed. Achieving EP1 at T1 was achieved by 49% of al patients. It was positively affected by being female and negatively by T0 BOP (OR3.90, p = 0.008, OR0.95, p &lt; 0.001), EP2 at T1 was achieved by 29% of all patients and influenced by the number of PD ≥ 6 mm at T0 (OR0.98, p &lt; 0.001). At T2 the relative proportion of patients dropped to 37%(EP1) and 26%(EP2), with EP1 significantly affected by plaque control at T2 (OR0.96, p = 0.003) and EP2 significantly affected by PD ≥ 6 mm at T1 (OR0.69, p &lt; 0.001). Conclusions Non-surgical therapy performed by students significantly improves periodontal outcomes in Stage III periodontitis. Particularly residual pockets and plaque seemed to affect unmet treatment targets.
Comprehensive data aleatory uncertainty propagation in regression random forest using a Monte Carlo approach: a struggle with incomplete data provision using a case study on probabilistic soil moisture regionalization
2025-07-31

Data uncertainty never decreases along processing chains and should always be reported alongside processing results. In this study, we attempt to propagate aleatory data uncertainty through a multiple regression analysis to generate regionalized probabilistic soil moisture maps. We employ a non-parametric solution for multiple regression by means of random forests within a Monte Carlo framework. Our input data comprise sparse soil moisture data and spatially dense auxiliary soil and topographic maps, which serve as response and predictor variables in our regression model, respectively. While the methodology is technically straightforward, challenges arise due to incomplete communication of data uncertainty by data providers. This results in knowledge gaps that must be filled by subjective assumptions rather than data-driven insights. We highlight the issues that hinder straightforward uncertainty propagation, ultimately making our final uncertainty quantification of regionalized soil maps an optimistic estimate. Additionally, we sketch how existing uncertainty classification schemes could help data providers deliver quantified uncertainties with their data, enabling users to more accurately assess and report uncertainties in their derived data products.
Fc-optimized CD276 antibody enhances NK cell activation against non-small cell lung cancer
2025-07-31

Non-small cell lung cancer (NSCLC) is one of the most common and lethal cancers worldwide, with a poor prognosis for many patients, especially in advanced stages. The development of immune checkpoint inhibitors (ICIs) has transformed treatment strategies for NSCLC. ICIs targeting PD-1/PD-L1 have shown substantial bene!t, but these therapies are not effective in all patients and are also associated with significant side effects. One promising target for NSCLC immunotherapy is CD276 (B7-H3), an immune checkpoint molecule that is highly overexpressed in many tumors, but minimally expressed in healthy tissues. CD276 is involved in immune escape mechanisms, tumor growth, and metastasis, making it an attractive target for patients unresponsive to PD-1/PD- L1-directed therapies. To address the limitations of T cell-based ICIs, natural killer (NK) cells are being explored as a complementary strategy, as they directly lyse tumor cells through antibody-dependent cellular cytotoxicity (ADCC). Here, we present an Fc-optimized CD276 antibody, 8H8_SDIE, which enhances NK cell reactivity by improving its binding affinity to CD16. In our preclinical studies 8H8_SDIE specifically binds to CD276 on NSCLC cell lines, resulting in significant NK cell activation, characterized by increased expression of CD69 and CD107a, and the secretion of cytotoxic mediators such as IFNγ, perforin, and granzyme B. These findings suggest that 8H8_SDIE may provide a novel therapeutic option for patients with CD276-positive NSCLC, particularly those who have failed to respond to conventional T cell-activating ICIs. By engaging NK cells, this approach could overcome the limitations of PD-1/PD-L1-directed therapies, offering a new way to combat ICI-resistant tumors.
FBXO7 Pathogenic Variants in Early‐Onset Parkinsonism: Insights from a Neuroimaging Perspective and Review of the Literature
2025-07-31

ABSTRACT Background Early onset parkinsonism caused by F‐box only protein7 ( FBXO7 ) pathogenic variants is a rare autosomal recessive disorder presenting with a combination of parkinsonism, pyramidal signs, dystonia, cognitive impairment, and psychiatric features. Although previous case reports have mentioned neuroimaging findings, there is no comprehensive study characterizing the radiological spectrum of FBXO7 pathogenic variants. Cases Ten patients from seven families followed at two tertiary centers in Turkey were included. The cohort included six males and four females with a mean onset age of 21.1 years. Frontal atrophy was the most common MRI finding, followed by global cortical and cerebellar atrophy. One patient showed iron accumulation in the pallidum, and two exhibited severe dopaminergic deficit on DaTSCAN. Literature Review Pathogenic variants in the FBXO7 gene have been identified in diverse populations over the past 15 years, contributing to a broader understanding of clinical and radiological spectrum. Global cortical atrophy has emerged as the most frequently reported neuroimaging finding in FBXO7‐related parkinsonism. Conclusions FBXO7 pathogenic variants are associated with heterogeneous neuroimaging findings. Frontal and global cortical atrophy are common, while iron deposition and DaTSCAN abnormalities offer additional diagnostic clues. Larger, longitudinal studies are necessary to establish specific imaging biomarkers for FBXO7 ‐related neurodegeneration.
Ion-exchange chromatography, capillary isoelectric focusing, and capillary zone electrophoresis coupled to mass spectrometry for charge variant analysis of monoclonal antibodies
2025-07-31

Monoclonal antibody (mAb) charge variant analysis, which ensures the quality of biopharmaceuticals, is primarily performed by either cation exchange chromatography (CEX), capillary isoelectric focusing (CIEF), or capillary zone electrophoresis (CZE). Though selectivity is different for all methods, mAb proteoforms can be quantified on the intact level with a low risk of artifacts. Identification and characterization can be performed by mass spectrometry (MS), but coupling is hampered by the use of nonvolatile constituents. Here, we present comparative data and a thorough review of CEX-MS, CIEF-MS, and CZE-MS for the analysis of charge variants on the intact level. The separation of the proteoforms is confirmed by online UV detection with subsequent online MS coupling. Each method was tested for generic use by measuring 10 mAbs with an isoelectric point (pI) of 7.3 to 8.7 without individually adjusting the method parameters for each mAb. The methods and the identified proteoforms are compared among each other as well as to a previously published CZE-MS method on the subunit level. The lysine variant was used to compare the resolution of the different separation methods and showed a high resolving power for all separation methods tested. The different method selectivities were revealed by the monoglycosylation, which was found in the peak of the main variant with CEX and CIEF, while it was separated from the main peak with CZE. In combination with a comprehensive literature review, our results provide a complete overview of the current state of the methods with information on the advantages and limitations of each methodology.
Expression of Bovine Meat and Milk Factor in Hepatocellular Carcinoma and Colorectal Liver Metastasis Patients
2025-07-31

ABSTRACT Bovine meat and milk factors (BMMFs) are plasmid‐like DNA molecules isolated from cow's milk, meat, and human cancer tissues proposed to contribute to the development of specific types of cancer including colorectal cancer (CRC) and breast cancer based on chronic inflammation‐associated indirect carcinogenesis. Chronic necro‐inflammation of the liver poses a strong risk factor for the induction of hepatocellular carcinoma (HCC), which is associated with high intake of meat. Whether BMMFs contribute to HCC carcinogenesis or the development of colorectal liver metastasis (CRLM) remains unknown. Therefore, in this study, the presence of BMMFs was assessed in the liver of patients with viral and nonviral hepatitis‐related HCC ( n = 25), CRLM (14) and in healthy liver tissue from autopsy specimens (18) using monoclonal antibodies against the conserved BMMF Rep protein for immunohistochemistry, immunofluorescence detection, and immunoblotting. Rep was expressed in all tumor‐distant and peritumor tissue specimens of HCC and CRLM patients and associated with CD68 + macrophages around portal triads. The number of Rep + CD68 + cells was increased in HCC and CRLM patients compared to healthy liver tissue, which may indicate a link between BMMFs and tumor‐associated chronic inflammation in the liver. Exclusively in viral hepatitis‐linked HCC, Rep expression was also detected in the tumor. In addition, specifically in the liver of healthy individuals, we observed a well‐defined gradient Rep expression in hepatocytes around the central veins. Altogether, these observations may indicate that the presence of BMMFs in the liver is associated with chronic inflammation and may represent a novel risk factor or surrogate marker for liver cancer.
INTEGRAL/ISGRI Post 2024-Periastron View of PSR B1259-63
2025-07-31

PSR B1259-63/LS 2883 is a well-studied gamma-ray binary hosting a pulsar in a 3.4-year eccentric orbit around a Be-type star. Its non-thermal emission spans from radio to TeV energies, exhibiting a significant increase near the periastron passage. This paper is dedicated to the analysis of INTEGRAL observations of the system following its last periastron passage in June 2024. We aim to study the spectral evolution of this gamma-ray binary in the soft (0.3–10 keV) and hard (30–300 keV) X-ray energy bands. We performed a joint analysis of the data taken by INTEGRAL/ISGRI in July–August 2024 and quasi-simultaneous Swift/XRT observations. The spectrum of the system in the 0.3–300 keV band is well described by an absorbed power law with a photon index of Γ=1.42±0.03. We place constraints on potential spectral curvature, limiting the break energy Eb&gt;30 keV for ΔΓ&gt;0.3 and cutoff energy Ecutoff&gt;150 keV at a 95% confidence level. For one-zone leptonic emission models, these values correspond to electron distribution spectral parameters of Eb,e&gt;0.8 TeV and Ecutoff,e&gt;1.7 TeV, consistent with previous constraints derived by H.E.S.S.
Identification of the negamycin split biosynthetic gene cluster in Kitasatospora purpeofusca ATCC21470
2025-07-31

SUMMARY Negamycin is a ribosome-targeting antibiotic with activity against Gram-positive and Gram-negative bacteria including ESKAPE pathogens. Furthermore, it promotes premature stop codon readthrough. Its therapeutic potential is limited by low natural production and synthetic complexity. To enable scalable biosynthesis, we identified and characterized its genetic basis in Kitasatospora purpeofusca ATCC 21470. Two distant chromosomal regions, neg1 and neg2 , were found to be essential. Deletion of neg1 , involved in nitrite provision for N-N bond formation, reduced production to ∼10%, while deletion of neg2 , which directs β-lysine generation and scaffold assembly, abolished it completely. Isotope-labeling experiments confirmed nitrite incorporation. Transcriptomic and proteomic analyses further supported the involvement of both regions. The heterologous expression of neg1 along with the neg2 region in Streptomyces albidoflavus reconstituted negamycin biosynthesis, confirming the unusual involvement of two distant gene clusters in the biosynthesis, and provides a foundation for biotechnological production and further development of this promising antibiotic. SIGNIFICANCE The rapid rise of antimicrobial resistance (AMR), particularly among Gram-negative ESKAPE pathogens, represents one of the most urgent global health threats. Despite this, the discovery and development of new antibiotics have stagnated. Addressing this challenge requires the exploration of natural products with novel mechanisms of action, alongside the development of scalable production strategies. Negamycin has emerged as a compelling candidate in this regard, characterized by an unusual mechanism of action and therapeutic potential extending beyond traditional antibacterial use. However, its development has been constrained by low production yields in the native producer. In this study, we identify and characterize the biosynthetic genes responsible for negamycin production, providing a foundation for pathway engineering, yield optimization, and the rational design of new analogs.
Toward a model of uORF-mediated translational control: An integrated bioinformatic and experimental approach
2025-07-31

Abstract Upstream open reading frames (uORFs) are short translated regions that occur in the 5□ untranslated regions (5□ UTRs) of mRNA transcripts where they primarily serve to repress expression translation of the downstream primary open reading frame (pORF). Their widespread presence across mammalian transcriptomes suggests an important role in shaping the proteome, although the mechanistic basis of their regulatory effects remain incompletely understood. Here we present an integrated experimental and computational investigation into the features that govern uORF-mediated translation control. Using high-resolution proteomics data from 29 healthy human tissues and machine learning-based simulations, we have systematically dissected how features including uORF length, amino acid composition, start codon position, stop codon position, and Kozak context influence repressive activity, and performed experimental validation using reporter gene constructs. We also investigated how multiple uORFs within a single 5□ UTR can interact in synergistic or antagonistic ways, with the potential to produce counterintuitive effects on pORF translation. From these studies, we present a model of uORF function, suggesting a hierarchy of uORF feature importance, and proposing that a combination of uORF translation initiation probability, ribosome recycling rate, intercistronic ternary complex recharging requirements, and ribosome stalling mechanisms underlie uORF repressive activity. Together, these studies provide a comprehensive view of the molecular logic underlying uORF activity, offering new insights into their endogenous and highlighting their potential as targets for drug development.
Pangenomic context reveals the extent of intraspecific plant NLR evolution
2025-08-01

Nucleotide-binding leucine-rich repeat (NLR) proteins are major components of the plant immune system, recognizing pathogen effectors and triggering defense responses. Because of the diversity of pathogen effector repertoires, NLRs have extraordinary sequence, structural, and regulatory variability. Although processes contributing to NLR diversity have been identified, the precise evolution of NLRs in their genomic context and along the multiple axes of diversity has been difficult to trace. We integrate genome-specific full-length transcript, homology, and transposable element information to annotate 3,789 NLRs in 17 diverse Arabidopsis thaliana accessions. We define 121 pangenomic NLR neighborhoods, which vary greatly in size, content, and complexity. NLRs are diverse across many axes, and multiple metrics are required to fully capture NLR variation. Based on these findings, we propose that diversity in diversity generation is fundamental to maintaining a functionally "adaptive" immune system in plants and that mechanistic studies should consider multiple axes of immune system diversity.
Coexistence, Extinction and Survival—The Evolutionary History of Bison Species in Western Eurasia
2025-08-01

ABSTRACT European bison ( Bison bonasus ) are one of the few European megafaunal species to survive the Late Pleistocene mass megafaunal extinction. Current conservation management efforts have proceeded in the absence of information about their evolutionary history, which has been obscured by recent severe population bottlenecks. We characterized mitochondrial genomes from 135 ancient bison samples spanning &gt; 50,000 years (&gt; 50 ka) across the Eurasian continent and detected three distinct phylogenetic groups: two distinct clades of European bison and the extinct steppe bison ( Bison priscus ). The geographical distributions and dietary/ecological signatures of the three groups overlapped during the Late Pleistocene climate cycles and tracked environmental changes including vegetation cover and human impacts. The abundance of European bison specimens responded negatively to the extent of forest cover, including Holocene cycles of abrupt atmospheric‐ocean circulation changes originating in the North Atlantic. European bison remain preferentially adapted to an open environment, but with today's anthropogenic landscapes, are now largely restricted to forest habitats with negative implications under scenarios of future environmental change.
Phenotypic spectrum of cardiac conduction disturbance and cardiomyopathy linked to titin canonical splice-site variants
2025-08-01

Abstract Aims Truncating variations in the titin gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) and have been implicated in various arrhythmic and heart failure phenotypes. Nonetheless, predicting the pathogenicity of a distinct subtype of TTNtv, canonical splice-site variations (TTNcsv), remains challenging. Furthermore, the precise transcriptional and phenotypic consequences associated with TTNcsv remain unclear. We evaluated the transcriptional profiles of TTN in vitro, focusing on TTNcsv found in patients with cardiac dysfunction, and compared them with their phenotypic manifestations. Methods and results Genome-wide linkage analysis, whole-exome sequencing, and whole-genome sequencing were performed on a five-generation family with cardiac conduction disturbance (CCD). In addition, whole-genome sequencing was performed on 402 Japanese biobank patients with cardiomyopathy (CM) or unidentified cardiac dysfunction. Transcriptional profiles of TTNcsv were evaluated by RNA-Seq of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and endomyocardial biopsy specimens, and by minigene assays. A rare segregating TTNcsv (c.49049-2A&amp;gt;C) was identified in the five-generation family with CCD. RNA-Seq and minigene assays revealed complex aberrant TTN splicing transcripts: predominantly non-truncating transcripts caused by an 18 bp in-frame deletion (83–90%) and minor truncating transcripts (10–17%). Two additional TTNcsv were identified in biobank participants by whole-genome sequencing. A minigene assay of TTNcsv c.67348+1G&amp;gt;A, identified in a CCD patient with mild cardiac dysfunction, revealed predominantly non-truncating transcripts (95%), caused by retention of a 90 bp in-frame intron, along with 5% truncating TTN transcripts, caused by a 50 bp frameshift deletion, mirroring the TTNcsv observed in the familial CCD. In contrast, the DCM-associated TTNcsv c.67637-2A&amp;gt;G generated 87% truncating TTN transcripts, attributed to frameshift intron retention and cryptic splicing. Conclusion The clinical data from this family suggest a close association between TTNcsv and CCD, which may involve an increase in non-truncating transcripts. Further studies are required to determine their precise relationship and the underlying mechanisms.