Miracle-dz/UniFAR-FTUs huggingface dataset:
Members of the GADD45 Protein Family Show Distinct Propensities to form Toxic Amyloid-Like Aggregates in Physiological Conditions

The three members (GADD45α, GADD45β, and GADD45γ) of the growth arrest and DNA damage-inducible 45 (GADD45) protein family are involved in a myriad of diversified cellular functions. With the aim of unravelling analogies and differences, we performed comparative biochemical and biophysical analyses on the three proteins. The characterization and quantification of their binding to the MKK7 kinase, a validated functional partner of GADD45β, indicate that GADD45α and GADD45γ are strong interactors of the kinase. Despite their remarkable sequence similarity, the three proteins present rather distinct biophysical properties. Indeed, while GADD45β and GADD45γ are marginally stable at physiological temperatures, GADD45α presents the Tm value expected for a protein isolated from a mesophilic organism. Surprisingly, GADD45α and GADD45β, when heated, form high-molecular weight species that exhibit features (ThT binding and intrinsic label-free UV/visible fluorescence) proper of amyloid-like aggregates. Cell viability studies demonstrate that they are endowed with a remarkable toxicity against SHSY-5Y and HepG2 cells. The very uncommon property of GADD45β to form cytotoxic species in near-physiological conditions represents a puzzling finding with potential functional implications. Finally, the low stability and/or the propensity to form toxic species of GADD45 proteins constitute important features that should be considered in interpreting their many functions.
Esterase Activity of Serum Albumin Studied by 1H NMR Spectroscopy and Molecular Modelling

Serum albumin possesses esterase and pseudo-esterase activities towards a number of endogenous and exogenous substrates, but the mechanism of interaction of various esters and other compounds with albumin is still unclear. In the present study, proton nuclear magnetic resonance (1H NMR) has been applied to the study of true esterase activity of albumin, using the example of bovine serum albumin (BSA) and p-nitrophenyl acetate (NPA). The site of BSA esterase activity was then determined using molecular modelling methods. According to the data obtained, the accumulation of acetate in the presence of BSA in the reaction mixture is much more intense as compared with the spontaneous hydrolysis of NPA, which indicates true esterase activity of albumin towards NPA. Similar results were obtained for p-nitophenyl propionate (NPP) as substrate. The rate of acetate and propionate release confirms the assumption that there is a site of true esterase activity in the albumin molecule, which is different from the site of the pseudo-esterase activity Sudlow II. The results of molecular modelling of BSA and NPA interaction make it possible to postulate that Sudlow site I is the site of true esterase activity of albumin.
Systematic Review of Prognostic Models Compared to the Mayo Risk Score for Primary Sclerosing Cholangitis

Background: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with a variable clinical course that can ultimately lead to end-stage liver disease, cholangiocarcinoma, and the need for liver transplantation. Several prognostic models have been developed to predict clinical outcomes and have been compared to the revised Mayo Risk Score (rMRS). Aim: To conduct a systematic review comparing the rMRS to other non-invasive prognostic tests for PSC. Methods: A systematic review of studies from 2000 to 2020 was performed that compared non-invasive biochemical prognostic models to the rMRS in predicting outcomes in patients with PSC. Results: Thirty-seven studies were identified, of which five studies that collectively included 3230 patients were reviewed. Outcomes included transplant-free survival or composite clinical outcomes. The rMRS was better than the Amsterdam–Oxford model for predicting 1-year transplant-free survival, c-statistics 0.75 and 0.70, respectively. The UK-PSC score outperformed the rMRS for 10-year transplant-free survival, c-statistics 0.85 and 0.69, respectively. An enhanced liver fibrosis score was independently associated with transplant-free survival after adjusting for rMRS. PREsTo predicts 5-year hepatic decompensation with a c-statistic modestly higher than rMRS; 0.90 and 0.85, respectively. Conclusion: Newer prognostic models, including the UK-PSC score and PREsTo, are more accurate at predicting clinical endpoints in PSC compared to the rMRS. Time frames and clinical endpoints are not standard among studies.
Age-Related Changes in the Matrisome of the Mouse Skeletal Muscle

Aging is characterized by a progressive decline of skeletal muscle (SM) mass and strength which may lead to sarcopenia in older persons. To date, a limited number of studies have been performed in the old SM looking at the whole, complex network of the extracellular matrix (i.e., matrisome) and its aging-associated changes. In this study, skeletal muscle proteins were isolated from whole gastrocnemius muscles of adult (12 mo.) and old (24 mo.) mice using three sequential extractions, each one analyzed by liquid chromatography with tandem mass spectrometry. Muscle sections were investigated using fluorescence- and transmission electron microscopy. This study provided the first characterization of the matrisome in the old SM demonstrating several statistically significantly increased matrisome proteins in the old vs. adult SM. Several proteomic findings were confirmed and expanded by morphological data. The current findings shed new light on the mutually cooperative interplay between cells and the extracellular environment in the aging SM. These data open the door for a better understanding of the mechanisms modulating myocellular behavior in aging (e.g., by altering mechano-sensing stimuli as well as signaling pathways) and their contribution to age-dependent muscle dysfunction.
Zebrafish and Medaka: Important Animal Models for Human Neurodegenerative Diseases

Animal models of human neurodegenerative disease have been investigated for several decades. In recent years, zebrafish (Danio rerio) and medaka (Oryzias latipes) have become popular in pathogenic and therapeutic studies about human neurodegenerative diseases due to their small size, the optical clarity of embryos, their fast development, and their suitability to large-scale therapeutic screening. Following the emergence of a new generation of molecular biological technologies such as reverse and forward genetics, morpholino, transgenesis, and gene knockout, many human neurodegenerative disease models, such as Parkinson’s, Huntington’s, and Alzheimer’s, were constructed in zebrafish and medaka. These studies proved that zebrafish and medaka genes are functionally conserved in relation to their human homologues, so they exhibit similar neurodegenerative phenotypes to human beings. Therefore, fish are a suitable model for the investigation of pathologic mechanisms of neurodegenerative diseases and for the large-scale screening of drugs for potential therapy. In this review, we summarize the studies in modelling human neurodegenerative diseases in zebrafish and medaka in recent years.
The DNA Recognition Motif of GapR Has an Intrinsic DNA Binding Preference towards AT-rich DNA

The nucleoid-associated protein GapR found in Caulobacter crescentus is crucial for DNA replication, transcription, and cell division. Associated with overtwisted DNA in front of replication forks and the 3′ end of highly-expressed genes, GapR can stimulate gyrase and topo IV to relax (+) supercoils, thus facilitating the movement of the replication and transcription machines. GapR forms a dimer-of-dimers structure in solution that can exist in either an open or a closed conformation. It initially binds DNA through the open conformation and then undergoes structural rearrangement to form a closed tetramer, with DNA wrapped in the central channel. Here, we show that the DNA binding domain of GapR (residues 1–72, GapRΔC17) exists as a dimer in solution and adopts the same fold as the two dimer units in the full-length tetrameric protein. It binds DNA at the minor groove and reads the spatial distribution of DNA phosphate groups through a lysine/arginine network, with a preference towards AT-rich overtwisted DNA. These findings indicate that the dimer unit of GapR has an intrinsic DNA binding preference. Thus, at the initial binding step, the open tetramer of GapR with two relatively independent dimer units can be more efficiently recruited to overtwisted regions.
Persistent Post-COVID-19 Syndrome in Hemodialyzed Patients—A Longitudinal Cohort Study from the North of Poland

Background: After recovery from COVID-19, patients frequently face so-called “Post-COVID-19 Syndrome” defined by clusters of persistent symptoms lasting for >12 weeks which may arise from any system in the body. The long-term health consequences of COVID-19 in maintenance hemodialyzed (HD) patients remain to be investigated. Methods: In this longitudinal cohort study we described the health consequences in HD patients requiring hospitalization due to COVID-19. They were interviewed three and six months (M3 and M6) after discharge with a series of standardized questionnaires. Results: Of 144 HD patients discharged from the 7th Naval Hospital in Gdansk, 79 participants were enrolled, 39 m (49.4%) and 40 f (50.6%) with a median age of 70.0 (64.0–76.5) and an HD vintage of 40 months (17.5–88). After discharge, 93.7% and 81% reported at least one persistent symptom at M3 and M6, respectively. The most common symptoms were fatigue or muscle weakness (60.76% and 47.04%) and palpitations (40.51% and 30.14%). Dyspnea with an mMRC scale grade of at least 1 was reported by 21.5% before infection, and by 43.03% and 34.25% at M3 and M6, respectively. A decrease in the quality of life was reported in all domains of the EQ-5D-5L questionnaire but mainly in the pain/discomfort and anxiety dimensions. Mean EQ-VAS scores were 69.05, 61.58 and 64.38, respectively. Conclusion: Our study showed that HD patients may still experience persistent symptoms six months after recovery from COVID-19, which can further reduce their already poor health-related quality of life. This study highlights the need for long-term follow-up on these patients for diagnostic and rehabilitation programs.
Interactions of Aminopropyl–Azithromycin Derivatives, Precursors in the Synthesis of Bioactive Macrozones, with E. coli Ribosome: NMR and Docking Studies

The structure and interactions of several aminopropyl–azithromycin derivatives (1a–c) have been studied by using NMR spectroscopy and docking calculations. Compounds 1a–c are precursors in the synthesis of macrozones, novel bioactive azithromycin–thiosemicarbazone conjugates active against some resistant bacterial strains. Today, bacterial resistance is considered as one of the major threats to human health. Knowledge on drug binding mode and conformations is one of the key factors in the process of designing molecules to fight resistance. In solution state, compounds 1a and 1c exist in the 3-endo-folded-out conformation, while 1b adopts a classical folded-out conformation. 13C and 15N CPMAS NMR spectra pointed towards similar structures in the solid state. The transferred NOESY NMR spectra confirmed binding to the E. coli ribosome and suggest that dominant conformations in the bound state resemble those in the free one. STD experiments identified reactive groups of 1a–c in close contact with the ribosome resembling binding epitopes observed for the related 15-membered macrolides. Docking studies revealed that the studied compounds bind to the same ribosome binding pocket similarly to erythromycin in the crystal state, and that the binding is achieved through H-bonds and van der Waals interactions. The bound conformation is the same as determined by NMR. STD enhancements observed for methylene protons in the aminopropyl side chain indicate additional interactions which contribute to the overall binding energy.
Individual and Synergistic Relationships of Low Muscle Mass and Low Muscle Function with Depressive Symptoms in Korean Older Adults

This study examined the relationship of low appendicular skeletal muscle mass and low muscle function with depressive symptoms in Korean older adults. Community-dwelling Korean older adults aged 65 years and older (n = 521) participated in this study. Appendicular muscle mass (ASM) and muscle function (MF) scores were assessed using dual-energy X-ray absorptiometry (DXA) scanning and sit-to-stand mean power based on a 30 s chair stand test, respectively. Depressive symptoms were evaluated using the Korean form of the Center for Epidemiologic Studies Depression Scale. Logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of depressive symptoms according to ASM- and MF-based subgroups; normal ASM/normal MF, low ASM/normal MF, normal ASM/low MF, and low ASM/low MF. The prevalence of depressive symptoms was 21.3% in all patients: 20.7% in women and 21.5% in men. Compared to the normal ASM/normal MF participants (OR = 1), the risk of depressive symptoms rose incrementally in subjects with low ASM/normal MF (OR = 2.963, p = 0.019), normal AMS/low MF (OR = 3.843, p = 0.002), and low ASM/low MF (OR = 7.907, p < 0.001), respectively. The current findings suggest that the coexistence of low ASM and low MF is significantly and independently associated with an increased risk for depressive symptoms, with dynapenia having a stronger relationship.
Ecuadorian Journalists Mental Health Influence on Changing Job Desire: A Cross Sectional Study

Journalist’s mental health could predict their job change. This study aims at determining the prevalence of mental health issues and their association with perception of aptitude for covering emergencies and difficulty in seeing a corpse, and also to determine the mental health factors associated with job change. An ad hoc survey, GHQ-28 (Somatization, Anxiety-Insomnia, Social Dysfunction, Depression), MBI-P (Burnout, Emotional Exhaustion, Depersonalization, personal accomplishment) and Brief scale to diagnose Post-Traumatic Stress Disorder and Suicide Risk were applied to 196 journalists (female = 51.6%). Descriptive analysis, correlations (Pearson and Spearman), T-test and binary logistic regression were performed. It was found that one third part of journalists perceive themselves as having low aptitude to cover emergencies and difficulty in seeing a corpse, 17.3% would consider changing jobs and 42.1% could only access free mental health services. The most frequent mental health problems are: low personal accomplishment, emotional exhaustion and post-traumatic stress disorder (11.2 to 17.3%). People who want to change jobs present more: social dysfunction, depression, emotional exhaustion, depersonalization, low personal accomplishment, post-traumatic stress disorder and suicide risk. The two mental health factors associated with desire of changing jobs are high emotional exhaustion, and low personal accomplishment. These results guide the psychosocial risk prevention processes for journalists, as well as the training needs that universities could consider to protect the mental health of this vulnerable group.
The Antagonism of the Prokineticin System Counteracts Bortezomib Induced Side Effects: Focus on Mood Alterations

The development of neuropathy and of mood alterations is frequent after chemotherapy. These complications, independent from the antitumoral mechanism, are interconnected due to an overlapping in their processing pathways and a common neuroinflammatory condition. This study aims to verify whether in mice the treatment with the proteasome inhibitor bortezomib (BTZ), at a protocol capable of inducing painful neuropathy, is associated with anxiety, depression and supraspinal neuroinflammation. We also verify if the therapeutic treatment with the antagonist of the prokineticin (PK) system PC1, which is known to contrast pain and neuroinflammation, can prevent mood alterations. Mice were treated with BTZ (0.4 mg/kg three times/week for 4 weeks); mechanical allodynia and locomotor activity were evaluated over time while anxiety (dark light and marble burying test), depression (sucrose preference and swimming test) and supraspinal neuroinflammation were checked at the end of the protocol. BTZ treated neuropathic mice develop anxiety and depression. The presence of mood alterations is related to the presence of neuroinflammation and PK system activation in prefrontal cortex, hippocampus and hypothalamus with high levels of PK2 and PKR2 receptor, IL-6 and TNF-α, TLR4 and an upregulation of glial markers. PC1 treatment, counteracting pain, prevented the development of supraspinal inflammation and depression-like behavior in BTZ mice.
The Epidemiologic Characteristics of Malignant Mesothelioma Cases in Korea: Findings of the Asbestos Injury Relief System from 2011–2015

(1) Background: The purpose of this study was to investigate the epidemiological characteristics of malignant mesothelioma in Korea by investigating cases compensated under the asbestos injury relief system. (2) Methods: A total of 407 compensated cases between 2011 and 2015 were reviewed using medical records and resident registrations in order to investigate the dates of diagnosis and death. Asbestos exposure and patients’ general characteristics were investigated through face-to-face interviews. The standardized incidence ratio was calculated as the number of observations from 2005 to 2014 per exposure region in Korea, using the mid-annual population of each region in 2009 as the standard population. (3) Results: Among the 407 cases, 65.1% were male. The pleura and peritoneum were affected in 76.9% and 23.1% of cases, respectively. For peritoneal mesothelioma, the median survival duration was longer (p = 0.005), and the proportion of affected women was higher than that in pleural mesothelioma. The standardized incidence ratio (95% CI) by province of primary exposure was Chungnam 3.33 (2.51–4.35), Ulsan 1.85 (0.97–3.21), and Seoul 1.32 (1.06–1.63). (4) Conclusions: Although the representativeness of the data is limited, it is sufficient to assume the epidemiologic characteristics of malignant mesothelioma, help improve the compensation system, and contribute to future policies.
Alterations in HLA Class I-Presented Immunopeptidome and Class I-Interactome upon Osimertinib Resistance in EGFR Mutant Lung Adenocarcinoma

Simple Summary We sought to identify molecular mechanisms of lower efficacy of immunotherapy in epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma and the differences in those mechanisms with the emergence of tyrosine kinase inhibitor (TKI)-resistance. To this end, we conducted affinity purification and quantitative mass spectrometry-based proteomic profiling of human leukocyte antigen (HLA) Class I-presented immunopeptides and Class I-interacting proteins. This large-scale dataset revealed that the Class I-presented immunopeptidome was suppressed in two third-generation EGFR TKI, osimertinib-resistant lung adenocarcinoma cell lines compared to their isogenic TKI-sensitive counterparts. The whole-cell proteomic profiling show that antigen presentation complex proteins and immunoproteasome were downregulated upon EGFR TKI resistance. Furthermore, HLA class I-interactome profiling demonstrated altered interaction with key apoptosis and autophagy pathway proteins. In summary, our comprehensive multi-proteomic characterization in antigen presentation machinery provides potentially novel evidence of poor immune response in osimertinib-resistant lung adenocarcinoma. Abstract Immune checkpoint inhibitor (ICI) therapy has been a paradigm shift in the treatment of cancer. ICI therapy results in durable responses and survival benefit for a large number of tumor types. Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has shown great efficacy treating EGFR mutant lung cancers; however, all patients eventually develop resistance. ICI therapy has not benefitted EGFR mutant lung cancer. Herein, we employed stable isotope labeling by amino acids in cell culture (SILAC) quantitative mass spectrometry-based proteomics to investigate potential immune escape molecular mechanisms in osimertinib resistant EGFR mutant lung adenocarcinoma by interrogating the alterations in the human leukocyte antigen (HLA) Class I-presented immunopeptidome, Class I-interactome, and the whole cell proteome between isogenic osimertinib-sensitive and -resistant human lung adenocarcinoma cells. Our study demonstrates an overall reduction in HLA class I-presented immunopeptidome and downregulation of antigen presentation core complex (e.g., TAP1 and ERAP1/2) and immunoproteasome in osimertinib resistant lung adenocarcinoma cells. Several key components in autophagy pathway are differentially altered. S100 proteins and SLC3A2 may play critical roles in reduced antigen presentation. Our dataset also includes ~1000 novel HLA class I interaction partners and hundreds of Class I-presented immunopeptides in EGFR mutant lung adenocarcinoma. This large-scale unbiased proteomics study provides novel insights and potential mechanisms of immune evasion of EGFR mutant lung adenocarcinoma.
Effect of Core Mass and Alloy on Cyclic Fatigue Resistance of Different Nickel-Titanium Endodontic Instruments in Matching Artificial Canals

Instrument failure during root canal preparation is still a concern among endodontists. However, it remains unclear whether the use of more martensitic alloys or the cross-sectional design parameters (i.e., core mass) significantly improve fracture resistance. The aim of the study was to evaluate the impact of core mass and alloy on dynamic cyclic fatigue resistance of nickel-titanium endodontic instruments in matching artificial canals at body temperature. Two groups were tested. (A) taper 0.04: F360 (Komet, Lemgo, Germany), Twisted file (Sybron Endo, Glendora, CA, USA) (=TF), JIZAI (Mani, Tochigi, Japan) (=J_04) (all size #25) and the variable tapered TruNatomy (Dentsply, Ballaigues, Switzerland) (size #26) (=TN). (B) size #25; taper 0.06: (Mtwo (VDW, Munich, Germany), JIZAI (Mani) (=J_06), and variable tapered Hyflex EDM OneFile (Coltene Whaledent, Altstätten, Switzerland) (=HF). Time, number of cycles to fracture (NCF), and number and length of fractured fragments were recorded and statistically analysed using ANOVA Student-Newman-Keuls, Kruskal–Wallis or Chi-square test (significance level = 0.05). (A) TN showed the significantly shortest time until fracture, followed by TF, F360 and J_04 which also differed significantly, while NCF showed the following order: F360 < TN < TF < J_04 (p < 0.05). Only one J_04 but all instruments of the other groups fractured within the test-limit of 10 min. (B) Mtwo was significantly inferior concerning time until fracture and NCF, compared to J_06 and HF (p < 0.05), which did not differ significantly (p > 0.05). While all Mtwo instruments fractured, only four instruments failed in the other groups (p < 0.05). Within the limitations of this study, alloy and cross-sectional design (i.e., core mass) were critical factors regarding instrument failure, but none of these factors could be determined as a main parameter for increased or decreased time, and cycles to fracture. Rather, it seemed to be the interaction of multiple factors (e.g., longitudinal and cross-sectional design, alloy, and rotational speed) that was responsible for differences in the time and cycles to fracture. Nonetheless, all instruments had lifetimes that allow safe clinical use. However, the superiority or inferiority of an instrument with regard to cyclic fatigue based on laboratory results—even when identical trajectories are guaranteed—may be considered questionable, as the characteristics and design parameters of the instruments vary considerably, and the experimental setups lack additional clinical parameters and thus clinical relevance.