Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy.

BackgroundMultiple system atrophy (MSA) is a neurodegenerative disease characterized by parkinsonism, ataxia and dysautonomia. Histopathologically, the hallmark of MSA is the abnormal accumulation of alpha-synuclein (α-syn) within oligodendroglial cells, leading to neuroinflammation, demyelination and neuronal death. Currently, there is no disease-modifying treatment for MSA. In this sense, we have previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation.ResultsIn this manuscript, we used the most effective AFFITOPE® (AFF 1) for immunizing MBP-α-syn transgenic mice, a model of MSA that expresses α-syn in oligodendrocytes. Vaccination with AFF 1 resulted in the production of specific anti-α-syn antibodies that crossed into the central nervous system and recognized α-syn aggregates within glial cells. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn, reduced demyelination in neocortex, striatum and corpus callosum, and reduced neurodegeneration. Clearance of α-syn involved activation of microglia and reduced spreading of α-syn to astroglial cells.ConclusionsThis study further validates the efficacy of vaccination with AFFITOPEs® for ameliorating the neurodegenerative pathology in synucleinopathies

Assessment of a novel biomechanical fracture model for distal radius fractures

Background: Distal radius fractures (DRF) are one of the most common fractures and often need surgical treatment, which has been validated through biomechanical tests. Currently a number of different fracture models are used, none of which resemble the in vivo fracture location. The aim of the study was to develop a new standardized fracture model for DRF (AO-23.A3) and compare its biomechanical behavior to the current gold standard. Methods: Variable angle locking volar plates (ADAPTIVE, Medartis) were mounted on 10 pairs of fresh-frozen radii. The osteotomy location was alternated within each pair (New: 10 mm wedge 8 mm / 12 mm proximal to the dorsal / volar apex of the articular surface; Gold standard: 10 mm wedge 20 mm proximal to the articular surface). Each specimen was tested in cyclic axial compression (increasing load by 100 N per cycle) until failure or -3 mm displacement. Parameters assessed were stiffness, displacement and dissipated work calculated for each cycle and ultimate load. Significance was tested using a linear mixed model and Wald test as well as t-tests. Results: 7 female and 3 male pairs of radii aged 74 +/- 9 years were tested. In most cases (7/10), the two groups showed similar mechanical behavior at low loads with increasing differences at increasing loads. Overall the novel fracture model showed a significant different biomechanical behavior than the gold standard model (p < 0,001). The average final loads resisted were significantly lower in the novel model (860 N +/- 232 N vs. 1250 N +/- 341 N; p = 0.001). Conclusion: The novel biomechanical fracture model for DRF more closely mimics the in vivo fracture site and shows a significantly different biomechanical behavior with increasing loads when compared to the current gold standard

Single-Cell Approach to Monitor the Unfolded Protein Response During Biotechnological Processes With Pichia pastoris

Pichia pastoris (Komagataella sp.) is broadly used for the production of secreted recombinant proteins. Due to the high rate of protein production, incorrectly folded proteins may accumulate in the endoplasmic reticulum (ER). To restore their proper folding, the cell triggers the unfolded protein response (UPR); however, if the proteins cannot be repaired, they are degraded, which impairs process productivity. Moreover, a non-producing/non-secreting subpopulation of cells might occur, which also decreases overall productivity. Therefore, an in depth understanding of intracellular protein fluxes and population heterogeneity is needed to improve productivity. Under industrially relevant cultivation conditions in bioreactors, we cultured P. pastoris strains producing three different recombinant proteins: penicillin G acylase from Escherichia coli (EcPGA), lipase B from Candida antarctica (CaLB) and xylanase A from Thermomyces lanuginosus (TlXynA). Extracellular and intracellular product concentrations were determined, along with flow cytometry-based single-cell measurements of cell viability and the up-regulation of UPR. The cell population was distributed into four clusters, two of which were viable cells with no UPR up-regulation, differing in cell size and complexity. The other two clusters were cells with impaired viability, and cells with up-regulated UPR. Over the time course of cultivation, the distribution of the population into these four clusters changed. After 30 h of production, 60% of the cells producing EcPGA, which accumulated in the cells (50–70% of the product), had up-regulated UPR, but only 13% of the cells had impaired viability. A higher proportion of cells with decreased viability was observed in strains producing CaLB (20%) and TlXynA (27%). The proportion of cells with up-regulated UPR in CaLB-producing (35%) and TlXynA-producing (30%) strains was lower in comparison to the EcPGA-producing strain, and a smaller proportion of CaLB and TlXynA (&lt;10%) accumulated in the cells. These data provide an insight into the development of heterogeneity in a recombinant P. pastoris population during a biotechnological process. A deeper understanding of the relationship between protein production/secretion and the regulation of the UPR might be utilized in bioprocess control and optimization with respect to secretion and population heterogeneity

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app

Distinct glutaminyl cyclase expression in Edinger–Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Aβ pathology in Alzheimer’s disease

Glutaminyl cyclase (QC) was discovered recently as the enzyme catalyzing the pyroglutamate (pGlu or pE) modification of N-terminally truncated Alzheimer’s disease (AD) Aβ peptides in vivo. This modification confers resistance to proteolysis, rapid aggregation and neurotoxicity and can be prevented by QC inhibitors in vitro and in vivo, as shown in transgenic animal models. However, in mouse brain QC is only expressed by a relatively low proportion of neurons in most neocortical and hippocampal subregions. Here, we demonstrate that QC is highly abundant in subcortical brain nuclei severely affected in AD. In particular, QC is expressed by virtually all urocortin-1-positive, but not by cholinergic neurons of the Edinger–Westphal nucleus, by noradrenergic locus coeruleus and by cholinergic nucleus basalis magnocellularis neurons in mouse brain. In human brain, QC is expressed by both, urocortin-1 and cholinergic Edinger–Westphal neurons and by locus coeruleus and nucleus basalis Meynert neurons. In brains from AD patients, these neuronal populations displayed intraneuronal pE-Aβ immunoreactivity and morphological signs of degeneration as well as extracellular pE-Aβ deposits. Adjacent AD brain structures lacking QC expression and brains from control subjects were devoid of such aggregates. This is the first demonstration of QC expression and pE-Aβ formation in subcortical brain regions affected in AD. Our results may explain the high vulnerability of defined subcortical neuronal populations and their central target areas in AD as a consequence of QC expression and pE-Aβ formation

The Liver Tumor Segmentation Benchmark (LiTS)

In this work, we report the set-up and results of the Liver Tumor Segmentation Benchmark (LITS) organized in conjunction with the IEEE International Symposium on Biomedical Imaging (ISBI) 2016 and International Conference On Medical Image Computing Computer Assisted Intervention (MICCAI) 2017. Twenty four valid state-of-the-art liver and liver tumor segmentation algorithms were applied to a set of 131 computed tomography (CT) volumes with different types of tumor contrast levels (hyper-/hypo-intense), abnormalities in tissues (metastasectomie) size and varying amount of lesions. The submitted algorithms have been tested on 70 undisclosed volumes. The dataset is created in collaboration with seven hospitals and research institutions and manually reviewed by independent three radiologists. We found that not a single algorithm performed best for liver and tumors. The best liver segmentation algorithm achieved a Dice score of 0.96(MICCAI) whereas for tumor segmentation the best algorithm evaluated at 0.67(ISBI) and 0.70(MICCAI). The LITS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource.Comment: conferenc

Interactional Construction of Social Authenticity: “Real” Identities and Intergroup relations in a Transylvania Internet Forum.

Authenticity has become an increasingly salient topic within various interactional traditions, including conversational and discourse analysis, discursive psychology, interactional sociolinguistics, pragmatics, and symbolic interactionism. However, there has been remarkably little cross‐fertilization of ideas and concepts. In this study, we consider the relevance of the interactional sociolinguistic concept of relationality for symbolic interactionist theories of authenticity. We first disambiguate two forms of authenticity that are commonly studied but not clearly differentiated in symbolic interactionist research—self‐authenticity, which emphasizes selves, and social authenticity, which emphasizes social identities. We then argue that relationality and its three pairs of interactional tactics—verification and denaturalization, adequation and distinction, and authorization and illegitimation—are particularly useful in conceptualizing social authenticity. We draw on data from an interethnic internet forum to show how members of two ethnic groups, Hungarian and Romanian, employ these relational tactics to authenticate their own ethnicity as the rightful inheritors of a place‐based Transylvanian identity, and to limit the other ethnicity's similar identity work. We then clarify the significance of social authenticity for the interactional study of category‐based identities by widening our discussion to other contestations over social identities in everyday life.Accepted versio

Truth Social Dataset

Formally announced to the public following former President Donald Trump’s bans and suspensions from mainstream social networks in early 2022 following his role in the January 6 Capitol Riots, Truth Social was launched as an ``alternative'' social media platform that claims to be a refuge for free speech, offering a platform for those disaffected by the content moderation policies of then existing, mainstream social networks. The subsequent rise of Truth Social has been driven largely by hard-line supporters of the former president as well as those affected by the content moderation of other social networks. These distinct qualities combined with the its status as the main mouthpiece of the former president positions Truth Social as a particularly influential social media platform and give rise to several research questions. However, outside of a handful of news reports, little is known about the new social media platform partially due to a lack of well-curated data. In the current work, we describe a dataset of over 823,000 posts to Truth Social and and social network with over 454,000 distinct users. In addition to the dataset itself, we also present some basic analysis of its content, certain temporal features, and its network

Assessment of a novel biomechanical fracture model for distal radius fractures

Background: Distal radius fractures (DRF) are one of the most common fractures and often need surgical treatment, which has been validated through biomechanical tests. Currently a number of different fracture models are used, none of which resemble the in vivo fracture location. The aim of the study was to develop a new standardized fracture model for DRF (AO-23.A3) and compare its biomechanical behavior to the current gold standard. Methods: Variable angle locking volar plates (ADAPTIVE, Medartis) were mounted on 10 pairs of fresh-frozen radii. The osteotomy location was alternated within each pair (New: 10 mm wedge 8 mm / 12 mm proximal to the dorsal / volar apex of the articular surface; Gold standard: 10 mm wedge 20 mm proximal to the articular surface). Each specimen was tested in cyclic axial compression (increasing load by 100 N per cycle) until failure or -3 mm displacement. Parameters assessed were stiffness, displacement and dissipated work calculated for each cycle and ultimate load. Significance was tested using a linear mixed model and Wald test as well as t-tests. Results: 7 female and 3 male pairs of radii aged 74 +/- 9 years were tested. In most cases (7/10), the two groups showed similar mechanical behavior at low loads with increasing differences at increasing loads. Overall the novel fracture model showed a significant different biomechanical behavior than the gold standard model (p < 0,001). The average final loads resisted were significantly lower in the novel model (860 N +/- 232 N vs. 1250 N +/- 341 N; p = 0.001). Conclusion: The novel biomechanical fracture model for DRF more closely mimics the in vivo fracture site and shows a significantly different biomechanical behavior with increasing loads when compared to the current gold standard

Feasibility of Osseous Landmarks for ACL Reconstruction—A Macroscopic Anatomical Study

During knee arthroscopy, easy orientation is important, and possible landmarks include the lateral intercondylar ridge (LIR) and the lateral bifurcate ridge (LBR). The objective was to show the feasibility of the LIR and the LBR as landmarks of the femoral attachment of the anterior cruciate ligament (ACL) among subjects with different levels of training. Thirty-six formalin-phenol-fixed lower extremities were acquired for this prospective macroscopic anatomical study. All soft tissue apart from the ligaments was removed. The two bundles of the ACL and their origins were identified, marked and photographed. Photographs were taken in an arthroscopic setting. An orthopedic surgeon, an anatomist and a medical student identified the ridges. The LIR existed in 80.6% of samples, while the LBR existed in 13.8% of samples. A significant difference existed between the raters in correctly identifying the LIR (p < 0.01). Due to its high frequency, the LIR seems more reliable than the LBR, especially as the LBR has the potential for false positive identification. Nevertheless, as these ridges are not easily discernible, the surgeon has to know the anatomy of the intercondylar notch perfectly to stand even a small chance of correctly placing drill holes in ACL reconstruction. New guidelines for more easily recognizing LIR and LBR arthroscopically are proposed