julilili42/papers huggingface dataset:
Characterization of Monoclonal Antibody Charge Variants under Near-Native Separation Conditions using Nanoflow Sheath Liquid Capillary Electrophoresis-Mass Spectrometry
2024-05-03

Monoclonal antibodies (mAbs) undergo multiple post-translational modifications (PTMs), e.g., charge variants, oxidation, etc., during production and storage, necessitating evaluation of the resulting PTMs as critical quality attributes (CQA) for protein quality and safety. Charge variants PTMs can be separated using capillary zone electrophoresis (CZE). The CZE EACA method developed by He et al. (2011) with UV detection is applied routinely in the pharmaceutical industry for analyzing charge variants. However, the method cannot be directly hyphenated with mass spectrometry (MS), preventing direct identification of separated charge variants due to the non-volatile background electrolyte (BGE), which hinders reliable charge variant identification. This study presents a CZE-UV/MS method using a neutral static capillary coating of hydroxypropyl methylcellulose combined with a volatile BGE at pH 5.0 to allow MS-compatible mAb charge variant separations. The effect of several parameters, including pH and concentration of BGE, voltage, and injected mAb concentrations in terms of separation performance on a panel of mAbs was investigated. The final method was tested with mAbs of IgG subclasses (IgG1 and IgG4) with different pI (7.4-9.2), and degrees of heterogeneity. Basic and acidic variants were separated from the parent mAb using a BGE of 50 mM acetic acid adjusted at pH 5.0. A linear correlation in relative charge variant abundance was obtained between our method and the EACA method. CZE-MS coupling was done using the nanoCEasy, a low-flow sheath liquid interface, and allowed the identification and quantitation of various low-abundance variants (&lt;10% relative abundance with respect to the main compound). This method uses volatile buffers and operates at pH closer to non-denaturing conditions (pH 5.0), allowing for flexibility in hyphenation with MS. This method can be a useful tool for in-depth charge variants characterization of mAbs.
Health, home and hearth: how war nurses negotiated their place at the table during the dawn of Francoist Spain
2024-05-03

During the Spanish Civil War, around 15,000 women were deployed as nurses or auxiliaries in the military health service of the Francoist army. Many of them worked behind the firing lines and came close to the combat and destruction. When the war drew to an end, these frontline nurses were demobilized and sent home to hearth and family. For some of them, returning home was a relief; for others, it meant the end to a professional career and meaningful vocation outside family control. Some of them used the tumultuous 'post-war' months to raise their voices, demanding the same treatment as male veterans. They wanted the same privileges these men enjoyed, such as free university access or ex-combatant status. Rallying together in support of such interests, they transcended several social borders, like Francoist ideas of complementary gender roles, concepts of nurses being acquiescent angels at sickbeds, and values of unconditional subordination and obedience. By pushing marriage into the future, they further violated Francoist expectations of a woman's 'proper' biographical trajectory. In all these endeavours to gain a place at the table of Francoist Spain, they found support from their male colleagues and superiors. Drawing from sources of the Francoist military health service, this paper argues that their petitions echoed the elitist and gendered views concerning the making of the victor's society. These perspectives reflected the intricate integration processes within the heterogeneous support base from which the Spanish dictator Francisco Franco drew his legitimacy and backing both during and after the war.
Integrative Analysis of miRNA Expression Profiles Reveals Distinct and Common Molecular Mechanisms Underlying Broad Diagnostic Groups of Severe Mental Disorders
2024-05-03

<title>Abstract</title> Micro RNAs (miRNAs) play a crucial role as regulators of various biological processes and have been implicated in the pathogenesis of mental disorders such as schizophrenia and bipolar disorders. In this study, we investigate the expression patterns of miRNAs in the PsyCourse Study (n=1,786), contrasting three broad diagnostic groups: Psychotic (Schizophrenia-spectrum disorders), Affective (Bipolar Disorder I, II and recurrent Depression), and neurotypic healthy individuals. Through comprehensive analyses, including differential miRNA expression, miRNA transcriptome-wide association study (TWAS), and predictive modelling, we identified multiple miRNAs unique to Psychotic and Affective groups as well as shared by both. Furthermore, we performed integrative analysis to identify the target genes of the dysregulated miRNAs and elucidate their potential roles in psychosis. Our findings reveal significant alterations of multiple miRNAs such as miR-584-3p and miR-99b-5p across the studied diagnostic groups, highlighting their role as molecular correlates. Additionally, the miRNA TWAS analysis discovered previously known and novel genetically dysregulated miRNAs confirming the relevance in the etiology of the diagnostic groups. Importantly, novel factors and putative molecular mechanisms underlying these groups were uncovered through the integration of miRNA-target gene interactions. This comprehensive investigation provides valuable insights into the molecular underpinnings of severe mental disorders, shedding light on the complex regulatory networks involving miRNAs.
Cholangiocyte RAGE drives the ductular reaction which provides biliary drainage but fuels liver injury
2024-05-03

<title>Abstract</title> Ductular reactions inevitably co-occur with liver tissue injury along with inflammation, cholestasis, and fibrosis. However, it remains unknown whether they represent an adaptive response facilitating bile drainage, or if they exacerbate dysfunction. By using a reporter mouse with cholangiocyte-specific deletion of the pattern recognition receptor RAGE, specific effects of the DR could be differentiated from the consequences of the cytotoxicity of the CDE-diet. While CDE-diet induced hepatoxicity triggers the DR via RAGE-dependent DAMP-sensing on cholangiocytes, it does not itself lead to loss of liver function. Instead, the presence of DR causes downregulation of basolateral bile acid transporters. Thus, although the DR forms a contiguous network capable of draining bile, it remains unutilized due to interrupted bile acid transport from blood to hepatocytes. The de-differentiating influence of the DR on hepatocytes thereby results in cholestasis and eventual fibrosis, that are more insidious to liver function than its initial cytotoxic trigger.
Mechanisms of emmetropization and what might go wrong in myopia
2024-05-04

Studies in animal models and humans have shown that refractive state is optimized during postnatal development by a closed-loop negative feedback system that uses retinal image defocus as an error signal, a mechanism called emmetropization. The sensor to detect defocus and its sign resides in the retina itself. The retina and/or the retinal pigment epithelium (RPE) presumably releases biochemical messengers to change choroidal thickness and modulate the growth rates of the underlying sclera. A central question arises: if emmetropization operates as a closed-loop system, why does it not stop myopia development? Recent experiments in young human subjects have shown that (1) the emmetropic retina can perfectly distinguish between real positive defocus and simulated defocus, and trigger transient axial eye shortening or elongation, respectively. (2) Strikingly, the myopic retina has reduced ability to inhibit eye growth when positive defocus is imposed. (3) The bi-directional response of the emmetropic retina is elicited with low spatial frequency information below 8 cyc/deg, which makes it unlikely that optical higher-order aberrations play a role. (4) The retinal mechanism for the detection of the sign of defocus involves a comparison of defocus blur in the blue (S-cone) and red end of the spectrum (L + M-cones) but, again, the myopic retina is not responsive, at least not in short-term experiments. This suggests that it cannot fully trigger the inhibitory arm of the emmetropization feedback loop. As a result, with an open feedback loop, myopia development becomes "open-loop".
Unravelling undiagnosed rare disease cases by HiFi long-read genome sequencing
2024-05-04

Abstract Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilised 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single nucleotide variants (SNVs), insertion-deletions (InDels), and short tandem repeat (STR) expansions in extensively studied RD families without clear molecular diagnoses. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Rare Disease Network (ERN) experts. Of these, 21 families were affected by so-called ‘unsolvable’ syndromes for which genetic causes remain unknown, and 93 families with at least one individual affected by a rare neurological, neuromuscular, or epilepsy disorder without genetic diagnosis despite extensive prior testing. Clinical interpretation and orthogonal validation of variants in known disease genes yielded thirteen novel genetic diagnoses due to de novo and rare inherited SNVs, InDels, SVs, and STR expansions. In an additional four families, we identified a candidate disease-causing SV affecting several genes including an MCF2 / FGF13 fusion and PSMA3 deletion. However, no common genetic cause was identified in any of the ‘unsolvable’ syndromes. Taken together, we found (likely) disease-causing genetic variants in 13.0% of previously unsolved families and additional candidate disease-causing SVs in another 4.3% of these families. In conclusion, our results demonstrate the added value of HiFi long-read genome sequencing in undiagnosed rare diseases.
Excessive endometrial PlGF- Rac1 signalling underlies endometrial cell stiffness linked to pre-eclampsia
2024-05-04

Abstract Cell stiffness is regulated by dynamic interaction between ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1) proteins, besides other biochemical and molecular regulators. In this study, we investigated how the Placental Growth Factor (PlGF) changes endometrial mechanics by modifying the actin cytoskeleton at the maternal interface. We explored the global effects of PlGF in endometrial stromal cells (EnSCs) using the concerted approach of proteomics, atomic force microscopy (AFM), and electrical impedance spectroscopy (EIS). Proteomic analysis shows PlGF upregulated RhoGTPases activating proteins and extracellular matrix organization-associated proteins in EnSCs. Rac1 and PAK1 transcript levels, activity, and actin polymerization were significantly increased with PlGF treatment. AFM further revealed an increase in cell stiffness with PlGF treatment. The additive effect of PlGF on actin polymerization was suppressed with siRNA-mediated inhibition of Rac1, PAK1, and WAVE2. Interestingly, the increase in cell stiffness by PlGF treatment was pharmacologically reversed with pravastatin, resulting in improved trophoblast cell invasion. Taken together, aberrant PlGF levels in the endometrium can contribute to an altered pre-pregnancy maternal microenvironment and offer a unifying explanation for the pathological changes observed in conditions such as pre-eclampsia (PE).
Penetration Profiles of Four Topical Antifungals in Mycotic Human Toenails Quantified by Matrix-Assisted Laser Desorption Ionization–Fourier Transform Ion Cyclotron Resonance Imaging
2024-05-04

In this study, MALDI-FTICR was successfully applied to the quantitative analysis of antifungal distribution in human mycotic nails. The findings suggest that amorolfine penetrates deeper layers of the nail and accumulates at concentrations far exceeding the MIC needed to exert antimycotic activity.
Synthetic, non-person related panoramic radiographs created by generative adversarial networks in research, clinical, and teaching applications
2024-05-05

Synthetic images can be used for university teaching and patient education without relying on patient-related data. They can also be utilized to upscale existing training datasets to improve the accuracy of AI-based diagnostic systems. The study thereby supports clinical teaching as well as diagnostic and therapeutic decision-making.
Reply on RC1
2024-05-05

<strong class="journal-contentHeaderColor">Abstract.</strong> For many ice core related scientific questions, like the analysis of fast changing climate signals, the depth resolution of conventional methods of analysis is not sufficient. In this study we present a setup of Laser Ablation Inductively Coupled Plasma &ndash; Mass Spectrometry (LA-ICP-MS) for high resolution glacier ice impurity analysis to the sub-millimetre scale. This setup enables chemical impurity ice core analysis to a depth resolution of ~ 80 &mu;m while consuming only minimal amounts of ice. The system was used for simultaneous analysis of sodium, magnesium and aluminium incorporated in the ice structure. In a first case study within the framework of the WACSWAIN (WArm Climate Stability of the West Antarctic ice sheet in the last INterglacial) project, the method was applied to a selection of samples from Skytrain ice core (West Antarctica), on a total length of 6.7 m consisting of about 130 single samples. The main goal of this study was to use the new LA-ICP-MS method to extract meaningful climate signals on a depth resolution level beyond the limits of Continuous Flow Analysis (CFA). A comparison between low resolution CFA data and the high resolution LA-ICP-MS data reveals generally good agreement on the decimetre scale. Stacking of parallel laser measurements together with frequency analysis is used to analyse the high resolution LA-ICP-MS data on the millimetre scale. Spectral analysis revealed that despite effects of impurity accumulation in ice crystal grain boundaries, periodic concentration changes in the Skytrain ice core on the millimetre scale can be identified in ice from 26 ka BP (kilo years before present; 1950 CE) and also from the Last Interglacial (LIG). These findings can open new possibilities for climate data interpretation with respect to fast changes in the last glacial and beyond.
Reply on RC2
2024-05-05

<strong class="journal-contentHeaderColor">Abstract.</strong> For many ice core related scientific questions, like the analysis of fast changing climate signals, the depth resolution of conventional methods of analysis is not sufficient. In this study we present a setup of Laser Ablation Inductively Coupled Plasma &ndash; Mass Spectrometry (LA-ICP-MS) for high resolution glacier ice impurity analysis to the sub-millimetre scale. This setup enables chemical impurity ice core analysis to a depth resolution of ~ 80 &mu;m while consuming only minimal amounts of ice. The system was used for simultaneous analysis of sodium, magnesium and aluminium incorporated in the ice structure. In a first case study within the framework of the WACSWAIN (WArm Climate Stability of the West Antarctic ice sheet in the last INterglacial) project, the method was applied to a selection of samples from Skytrain ice core (West Antarctica), on a total length of 6.7 m consisting of about 130 single samples. The main goal of this study was to use the new LA-ICP-MS method to extract meaningful climate signals on a depth resolution level beyond the limits of Continuous Flow Analysis (CFA). A comparison between low resolution CFA data and the high resolution LA-ICP-MS data reveals generally good agreement on the decimetre scale. Stacking of parallel laser measurements together with frequency analysis is used to analyse the high resolution LA-ICP-MS data on the millimetre scale. Spectral analysis revealed that despite effects of impurity accumulation in ice crystal grain boundaries, periodic concentration changes in the Skytrain ice core on the millimetre scale can be identified in ice from 26 ka BP (kilo years before present; 1950 CE) and also from the Last Interglacial (LIG). These findings can open new possibilities for climate data interpretation with respect to fast changes in the last glacial and beyond.
Proteolysis of the pericellular matrix: Pinpointing the role and involvement of matrix metalloproteinases in early osteoarthritic remodeling
2024-05-06

The pericellular matrix (PCM) serves a critical role in signal transduction and mechanoprotection in chondrocytes. Osteoarthritis (OA) leads to a gradual deterioration of the cartilage, marked by a shift in the spatial arrangement of chondrocytes from initially isolated strands to large cell clusters in end-stage degeneration. These changes coincide with progressive enzymatic breakdown of the PCM. This study aims to assess the role and involvement of specific matrix metalloproteinases (MMPs) in PCM degradation during OA. We selected cartilage samples from 148 OA patients based on the predominant spatial chondrocyte patterns. The presence of various MMPs (-1,-2,-3,-7,-8,-9,-10,-12,-13) was identified by multiplexed immunoassays. For each pattern and identified MMP, the levels and activation states (pro-form vs. active form) were measured by zymograms and western blots. The localization of these MMPs was determined using immunohistochemical labeling. To verify these results, healthy cartilage was exposed to purified MMPs, and the consecutive structural integrity of the PCM was analyzed through immunolabeling and proximity ligation assay. Screening showed elevated levels of MMP-1,-2,-3,-7, and -13, with their expression profile showing a clear dependency of the degeneration stage. MMP-2 and -7 were localized in the PCM, whereas MMP-1,-7, and -13 were predominantly intracellular. We found that MMP-2 and -3 directly disrupt collagen type VI, and MMP-3 and -7 destroy perlecan. MMP-2, -3, and -7 emerge as central players in early PCM degradation in OA. With the disease's initial stages already displaying elevated peaks in MMP expression, this insight may guide early targeted therapies to halt abnormal PCM remodeling. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) causes a gradual deterioration of the articular cartilage, accompanied by a progressive breakdown of the pericellular matrix (PCM). The PCM's crucial function in protecting and transmitting signals within chondrocytes is impaired in OA. By studying 148 OA-patient cartilage samples, the involvement of matrix metalloproteinases (MMPs) in PCM breakdown was explored. Findings highlighted elevated levels of certain MMPs linked to different stages of degeneration. Notably, MMP-2, -3, and -7 were identified as potent contributors to early PCM degradation, disrupting key components like collagen type VI and perlecan. Understanding these MMPs' roles in initiating OA progression, especially in its early stages, provides insights into potential targets for interventions to preserve PCM integrity and potentially impeding OA advancement.
Gene therapy in pediatrics – Clinical studies and approved drugs (as of 2023)
2024-05-06

Gene therapy in pediatrics represents a cutting-edge therapeutic strategy for treating a range of genetic disorders that manifest in childhood. Gene therapy involves the modification or correction of a mutated gene or the introduction of a functional gene into a patient's cells. In general, it is implemented through two main modalities namely ex vivo gene therapy and in vivo gene therapy. Currently, a noteworthy array of gene therapy products has received valid market authorization, with several others in various stages of the approval process. Additionally, a multitude of clinical trials are actively underway, underscoring the dynamic progress within this field. Pediatric genetic disorders in the fields of hematology, oncology, vision and hearing loss, immunodeficiencies, neurological, and metabolic disorders are areas for gene therapy interventions. This review provides a comprehensive overview of the evolution and current progress of gene therapy-based treatments in the clinic for pediatric patients. It navigates the historical milestones of gene therapies, currently approved gene therapy products by the U.S. Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for children, and the promising future for genetic disorders. By providing a thorough compilation of approved gene therapy drugs and published results of completed or ongoing clinical trials, this review serves as a guide for pediatric clinicians to get a quick overview of the situation of clinical studies and approved gene therapy products as of 2023.
You can count on your fingers: Finger-based intervention improves first-graders’ arithmetic learning
2024-05-06

The question of whether finger use should be encouraged or discouraged in early mathematics instruction remains a topic of debate. Scientific evidence on this matter is scarce due to the limited number of systematic intervention studies. Accordingly, we conducted an intervention study in which first-graders (M<sub>age</sub> = 6.48 years, SD = 0.35) completed a finger-based training (18 sessions of ∼ 30 min each) over the course of the first school year. The training was integrated into standard mathematics instruction in schools and compared with business-as-usual curriculum teaching. At the end of first grade and in a follow-up test 9 months later in second grade, children who received the finger training (n = 119) outperformed the control group (n = 123) in written addition and subtraction. No group differences were observed for number line estimation tasks. These results suggest that finger-based numerical strategies can enhance arithmetic learning, supporting the idea of an embodied representation of numbers, and challenge the prevailing skepticism about finger use in primary mathematics education.
The role of planetary health in urologic oncology
2024-05-06

We are used to making decisions based on the best outcome for patients without considering the impact that each decision can have on the environment. In the present article, we outline options and choices for a more climate-friendly approach in urologic oncology.
Wigner 6j symbols with gluon lines: completing the set of 6j symbols required for color decomposition
2024-05-06

A bstract We construct a set of Wigner 6j symbols with gluon lines (adjoint representations) in closed form, expressed in terms of similar 6j symbols with quark lines (fundamental representations). Together with these Wigner 6j symbols with quark lines, this gives a set of 6j symbols sufficient for treating QCD color structure for any number of external particles, in or beyond perturbation theory. This facilitates a complete treatment of QCD color structure in terms of orthogonal multiplet bases, without the need of ever explicitly constructing the corresponding bases. We thereby open up for a completely representation theory based treatment of SU(N) color structure, with the potential of significantly speeding up the color structure treatment.