julilili42/papers huggingface dataset:
The Scientific Evolution of Periacetabular Osteotomy: A Global Review
2022-10-17

It is well-known that hip disorders are frequently of bony origin related to an underlying pathomorphology. A fundamental understanding of morphology and biomechanics is therefore of essential importance for a targeted approach in defining treatment plans. Treatment is frequently based on altering bony morphology, for which a set of effective techniques have been proposed. Periacetabular osteotomy (PAO) allows for reorientation of the acetabulum and powerful correction of acetabular coverage. The revolutionary aspect of PAO compared to prior osteotomies lies in maintenance of the integrity of the posterior column. This allows for a substantial increase in primary stability, a larger bony surface for healing, and simple reorientation of the acetabular fragment that is free of posterior ligamentous restraints. The results for dysplasia are very promising. Indications have been refined by studies revealing that the presence of degenerative changes and age &gt; 40 years at the time of surgery represent prognostic factors of poorer outcome. Indications have also been broadened to include acetabular retroversion (with posterolateral dysplasia) and borderline hip dysplasia. A glimpse at the future would reflect major advances related to individual planning, surgical training, and precise surgical conduction. In the era of digitalization, augmented reality may assist in performing bony cuts and act as an aid for some of the blind ischial and retro-acetabular cuts. Innovations in perioperative management will enhance recovery after the procedure and allow for early recovery programs with optimized protocols of pain management. Considering that the success of PAO in the young is comparable to the success of hip arthroplasty in the old, PAO should be considered one of the pillars of modern orthopedic surgery.
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia
2022-10-17

Abstract Background Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia‐derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods We investigated the cerebrospinal fluid concentrations of TREM2, YKL‐40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation‐negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias‐corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini‐Mental State Examination (MMSE) score using non‐parametric partial correlations adjusting for age. Age‐adjusted z ‐scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL‐40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72 , 25% of GRN , and 14% of MAPT mutation carriers had a concentration above the 95 th percentile of controls. For YKL‐40 this was 8% C9orf72 , 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72 , 50% GRN , and 29% MAPT mutation carriers. Conclusions Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia‐derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.
Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives
2022-10-17

Approximately 60% of cancer patients receive curative or palliative radiation. Despite the significant role of radiotherapy (RT) as a curative approach for many solid tumors, tumor recurrence occurs, partially because of intrinsic radioresistance. Accumulating evidence indicates that the success of RT is hampered by activation of the DNA damage response (DDR). The intensity of DDR signaling is affected by multiple parameters, <i>e.g.,</i> loss-of-function mutations in tumor suppressor genes, gain-of-function mutations in protooncogenes as well as radiation-induced alterations in signal-transduction pathways. Therefore, the response to irradiation differs in tumors of different types, which makes the individualization of RT as a rational but challenging goal. One contributor to tumor cell radiation survival is signaling through the Ras pathway. Three RAS genes encode 4 Ras isoforms: K-Ras4A, K-Ras4B, H-Ras, and N-Ras. RAS family members are found to be mutated in approximately 19% of human cancers. Mutations in RAS lead to constitutive activation of the gene product and activation of multiple Ras-dependent signal-transduction cascades. Preclinical studies have shown that the expression of mutant KRAS affects DDR and increases cell survival after irradiation. Approximately 70% of RAS mutations occur in KRAS. Thus, applying targeted therapies directly against K-Ras as well as K-Ras upstream activators and downstream effectors might be a tumor-specific approach to overcome K-Ras-mediated RT resistance. In this review, the role of K-Ras in the activation of DDR signaling will be summarized. Recent progress in targeting DDR in KRAS-mutated tumors in combination with radiochemotherapy will be discussed.
Metabolic Modeling Elucidates Phenformin and Atpenin A5 as Broad-Spectrum Antiviral Drugs
2022-10-17

The SARS-CoV-2 pandemic has reemphasized the urgent need to develop broad-spectrum antiviral therapies. Wedeveloped a computational pipeline that uses scRNA-Seq data to reconstruct the metabolic state of cells and tissuesduring viral infection. Using this pipeline, we investigated the cellular capacity to produce SARS-CoV-2 virions invarious tissues and disease conditions. Subsequently, we expanded our analysis to influenza A and dengue virus andidentified several metabolic targets and their inhibitors for broad-spectrum antiviral treatment. Phenformin, an inhibitorof NADH:ubiquinone oxidoreductase, suppressed SARS-CoV-2 and dengue virus replication. Using Atpenin A5 toblock the succinate dehydrogenase inhibited SARS-CoV-2, dengue virus, influenza A virus and respiratory syncytialvirus with superior therapeutic indices. Thus, our work establishes host metabolism as druggable for broad antiviraltherapy. Moreover, our pipeline, the identified targets, and inhibitors are invaluable tools for pandemic preparedness.
Patients with completely resected nongenitourinary low‐risk embryonal rhabdomyosarcoma are candidates for reduced duration low‐intensity chemotherapy
2022-10-17

Abstract Background The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites. Methods A total of 113 patients aged 0–18 years were identified who were enrolled from January 1995 to December 2016 in Children's Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin‐D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols. Results The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow‐up of 97.5 months, the 5‐year progression‐free and overall survival was 80.0% (71.2%–86.4%) and 92.5% (85.6%–96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size ( &lt; or &gt;5 cm) significantly influenced overall survival: 96.2% (88.6%–98.8%) vs. 80.6% (59.5%–91.4%), respectively ( p = .01). Conclusions Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low‐intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors &lt; 5 cm.
A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis — A phase I clinical trial
2022-10-17

Uveitis is a T cell-mediated, intraocular inflammatory disease and one of the main causes of blindness in industrialized countries. There is a high unmet need for new immunomodulatory, steroid-sparing therapies, since only ciclosporin A and a single TNF-α-blocker are approved for non-infectious uveitis. A new small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme pivotal for de novo synthesis of pyrimidines, has a high potency for suppressing T and B cells and has already proven highly effective for treating uveitis in experimental rat models. Systemic and intraocular application of KIO-100 (PP-001) (previously called PP-001, now KIO-100) could efficiently suppress rat uveitis in a preventive as well as therapeutic mode. Here we describe the outcome of the first clinical phase 1 trial comparing three different doses of a single intraocular injection of KIO-100 (PP-001) in patients with non-infectious posterior segment uveitis. No toxic side effects on intraocular tissues or other adverse events were observed, while intraocular inflammation decreased, and visual acuity significantly improved. Macular edema, a sight-threatening complication in uveitis, showed regression 2 weeks after intraocular KIO-100 (PP-001) injection in some patients, indicating that this novel small molecule has a high potential as a new intraocular therapy for uveitis. Clinical trial registration [ https://www.clinicaltrials.gov/ct2/show/NCT03634475 ], identifier [NCT03634475].
Human organoid model of PCH2a recapitulates brain region-specific pathology
2022-10-17

Abstract Pontocerebellar hypoplasia type 2 a (PCH2a) is a rare, autosomal recessive pediatric disorder with limited treatment options. Its anatomical hallmark is the hypoplasia of the cerebellum and pons accompanied by progressive microcephaly. PCH2a results from a homozygous founder variant in TSEN54 , which encodes a tRNA splicing endonuclease (TSEN) complex subunit. Despite the ubiquitous expression of the TSEN complex, the tissue-specific pathological mechanism of PCH2a remains unknown due to a lack of model system. In this study, we developed human models of PCH2a using brain region-specific organoids. We therefore obtained skin biopsies from three affected males with genetically confirmed PCH2a and derived induced pluripotent stem cells (iPSCs). Proliferation and cell death rates were not altered in PCH2a iPSCs. We subsequently differentiated cerebellar and neocortical organoids from control and PCH2a iPSCs. Mirroring clinical neuroimaging findings, PCH2a cerebellar organoids were reduced in size compared to controls starting early in differentiation. We observed milder growth deficits in neocortical PCH2a organoids. While PCH2a cerebellar organoids did not upregulate apoptosis, their stem cell zones showed altered proliferation kinetics, with increased proliferation at day 30 and reduced proliferation at day 50 compared to controls. In summary, we have generated a human model of PCH2a, which provides the foundation for deciphering brain region-specific disease mechanisms.
Development of a highly sensitive immunoassay to measure ataxin2 as a target engagement marker in Spinocerebellar Ataxia Type 2
2022-10-17

Abstract Background Spinocerebellar Ataxia Type 2 (SCA2) belongs to a group of neurodegenerative diseases, inherited as an autosomal dominant trait. SCA2 is a trinucleotide repeat disease with a CAG repeat expansion in exon 1 of the ATXN2 gene resulting in an ataxin-2 protein with an expanded polyglutamine (polyQ)-stretch. The disease is late manifesting leading to premature death. Today, therapeutic interventions to cure the disease or even to decelerate disease progression are not available yet. Furthermore, primary readout parameter for disease progression and therapeutic intervention studies are limited. Thus, there is an urgent need for quantifiable molecular biomarkers such as ataxin-2 becoming even more important due to numerous potential protein reducing therapeutic intervention strategies. Objective Aim of this study was to establish a sensitive technique to measure the amount of polyQ-expanded ataxin-2 in human biofluids to evaluate ataxin-2 protein levels as prognostic and/ -or therapeutic biomarker in SCA2. Methods Time-Resolved Fluorescence Energy Transfer (TR-FRET) was used to establish a polyQ-expanded ataxin-2-specific immunoassay. Two different ataxin-2 antibodies and two different polyQ-binding antibodies were validated in three different concentrations and tested in cellular and animal tissue as well as in human cell lines, comparing different buffer conditions as well as total protein concentrations to evaluate the best assay conditions. Results We established a TR-FRET-based immunoassay for polyQ-expanded ataxin-2 and validated measurements in human cell lines including primary skin fibroblasts, induced pluripotent stem cells (iPSCs) and iPSC-derived cortical neurons. Additionally, our immunoassay was sensitive enough to monitor small ataxin-2 expression changes by siRNA or starvation treatment. Conclusion We successfully established the first sensitive ataxin-2 immunoassay to measure specifically polyQ-expanded ataxin-2 in human biomaterials.
Dysfunctional neuro-muscular mechanisms explain gradual gait changes in prodromal spastic paraplegia
2022-10-17

Abstract In Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) a length-dependent axonal degeneration in the cortico-spinal tract leads to progressing symptoms of hyperreflexia, muscle weakness, and spasticity of lower extremities. Even before the manifestation of spastic gait, in the prodromal phase, axonal degeneration leads to subtle gait changes. These gait changes – depicted by digital gait recording – are related to disease severity in prodromal and early-to-moderate manifest SPG4 subjects. We hypothesize that dysfunctional neuro-muscular mechanisms such as hyperreflexia and muscle weakness explain these disease severity-related gait changes of prodromal and early-to-moderate manifest SPG4 subjects. We test our hypothesis in computer simulation with a neuro-muscular model of human walking. We introduce neuro-muscular dysfunction by gradually increasing sensory-motor reflex sensitivity based on increased velocity feedback and gradually increasing muscle weakness by reducing maximum isometric force. By increasing hyperreflexia of plantarflexor and dorsiflexor muscles, we found gradual muscular and kinematic changes in neuro-musculoskeletal simulations that are comparable to subtle gait changes found in prodromal SPG4 subjects. Predicting kinematic changes of prodromal and early-to-moderate manifest SPG4 subjects by gradual alterations of sensory-motor reflex sensitivity allows us to link gait as a directly accessible performance marker to emerging neuro-muscular changes for early therapeutic interventions.
Isotopic insights into the Early Acheulean (1.95 Ma-1.66 Ma) high-elevation paleoenvironments at Melka Kunture (Upper Awash, Ethiopia)
2022-10-17

Abstract In this paper, we present carbon and oxygen stable isotope analysis of fauna tooth enamel from Garba IVD (~1.95 Ma) and Gombore IB (~1.66 Ma), two Early Acheulean sites of Melka Kunture (Upper Awash, Ethiopia) and discuss faunal taxonomy and fossil pollen. Our aim is to infer the diet, habitat, and environment at both sites and provide a broader paleoecological reconstruction. During the Pleistocene, the vegetation of the highlands of Ethiopia belonged to the “Dry evergreen Afromontane Forest and grassland complex”, distinct from the savanna of lower elevations in East Africa. Our carbon isotopic results indicate that all the analyzed faunal taxa were grazers, consuming C 4 grasses, while oxygen isotopic results clearly discriminate the taxa according to their semi-aquatic or terrestrial habitats. These results are consistent with the analysis of the faunal assemblages and the palynological results, suggesting extended mountain grasslands in the landscape at Garba IVD. In contrast, the carbon isotopic results do not totally agree with the pollen paleoenvironmental reconstruction at Gombore IB, where the open vegetation was interrupted by forests and bushy vegetation. Stable isotopes and pollen data provide different outcomes (feeding strategies vs. nearby plants) and have different temporal and spatial resolutions. This is relevant when reconstructing past environments by exclusively using independent proxies. Furthermore, isotopic comparisons with other East African archaeological sites of the Lower Pleistocene age indicate that all the analyzed taxa fed on C 4 grasses, and that their dietary strategies were not affected by differences linked to various elevations.
Multinational data show that conspiracy beliefs are associated with the perception (and reality) of poor national economic performance
2022-10-18

Abstract While a great deal is known about the individual difference factors associated with conspiracy beliefs, much less is known about the country‐level factors that shape people's willingness to believe conspiracy theories. In the current article we discuss the possibility that willingness to believe conspiracy theories might be shaped by the perception (and reality) of poor economic performance at the national level. To test this notion, we surveyed 6723 participants from 36 countries. In line with predictions, propensity to believe conspiracy theories was negatively associated with perceptions of current and future national economic vitality. Furthermore, countries with higher GDP per capita tended to have lower belief in conspiracy theories. The data suggest that conspiracy beliefs are not just caused by intrapsychic factors but are also shaped by difficult economic circumstances for which distrust might have a rational basis.
Aesthetics and Cartography: Post-Critical Reflections on Deviance in and of Representations
2022-10-18

Cartographic representations are subject to sensory perception and rely on the translation of sensory perceptions into cartographic symbols. In this respect, cartography is closely related to aesthetics, as it represents an academic discipline of sensory perceptions. The scholarly concern with cartographic aesthetics, by today, has strongly been focused on the aesthetic impact of cartographic representations. The consideration of the philosophical sub-discipline of aesthetics however is rather restrained. This is also true for the connection between sociological questions and the social construction of aesthetic judgments. We address both topics in this article. We refer to post-critical cartographic theory. It accepts the socially constructed nature and power-bound nature of maps but does not reject “traditional” and widely established positivist cartography. Drawing on the theory of deviant cartographies related to this, we understand cartography designed according to aesthetic criteria as meta-deviant, as it makes the contingency of world interpretations clear. Especially augmented and virtual environments show a great potential to generate aesthetically constructed cartographic representations. Participatory cartography enables many people to reflect on the contingency of their spatial experiences and spatial abstractions without expert-like special knowledge. A prerequisite, however, is the greatest possible openness to topics and representations. This is not subject to a moral restriction.
PKC-mediated phosphorylation and activation of the MEK/ERK pathway as a mechanism of acquired trastuzumab resistance in HER2-positive breast cancer
2022-10-18

Protein expression, activation and stability are regulated through inter-connected signal transduction pathways resulting in specific cellular states. This study sought to differentiate between the complex mechanisms of intrinsic and acquired trastuzumab resistance, by quantifying changes in expression and activity of proteins (phospho-protein profile) in key signal transduction pathways, in breast cancer cellular models of trastuzumab resistance. To this effect, we utilized a multiplex, bead-based protein assay, DigiWest ® , to measure around 100 proteins and protein modifications using specific antibodies. The main advantage of this methodology is the quantification of multiple analytes in one sample, utilising input volumes of a normal western blot. The intrinsically trastuzumab-resistant cell line JIMT-1 showed the largest number of concurrent resistance mechanisms, including PI3K/Akt and RAS/RAF/MEK/ERK activation, β catenin stabilization by inhibitory phosphorylation of GSK3β, cell cycle progression by Rb suppression, and CREB-mediated cell survival. MAPK (ERK) pathway activation was common to both intrinsic and acquired resistance cellular models. The overexpression of upstream RAS/RAF, however, was confined to JIMT 1; meanwhile, in a cellular model of acquired trastuzumab resistance generated in this study (T15), entry into the ERK pathway seemed to be mostly mediated by PKCα activation. This is a novel observation and merits further investigation that can lead to new therapeutic combinations in HER2-positive breast cancer with acquired therapeutic resistance.
Combinatorial interactions between viral proteins expand the potential functional landscape of the tomato yellow leaf curl virus proteome
2022-10-18

Viruses manipulate the cells they infect in order to replicate and spread. Due to strict size restrictions, viral genomes have reduced genetic space; how the action of the limited number of viral proteins results in the cell reprogramming observed during the infection is a long-standing question. Here, we explore the hypothesis that combinatorial interactions may expand the functional landscape of the viral proteome. We show that the proteins encoded by a plant-infecting DNA virus, the geminivirus tomato yellow leaf curl virus (TYLCV), physically associate with one another in an intricate network, as detected by a number of protein-protein interaction techniques. Importantly, our results indicate that intra-viral protein-protein interactions can modify the subcellular localization of the proteins involved. Using one particular pairwise interaction, that between the virus-encoded C2 and CP proteins, as proof-of-concept, we demonstrate that the combination of viral proteins leads to novel transcriptional effects on the host cell. Taken together, our results underscore the importance of studying viral protein function in the context of the infection. We propose a model in which viral proteins might have evolved to extensively interact with other elements within the viral proteome, enlarging the potential functional landscape available to the pathogen.