Miracle-dz/UniFAR-FTUs huggingface dataset:
Diverse fate of ubiquitin chain moieties: The proximal is degraded with the target, and the distal protects the proximal from removal and recycles

Significance The canonical targeting signal for degrading proteins by the ubiquitin (Ub) system—a chain composed of multiple Ub moieties—has remained a mystery. The structure of the proteasome, the enzyme that recognizes the signal and degrades the target substrate cannot explain why such a long chain is needed. To better understand this problem, we synthesized α-globin to which chains with different number of Ubs were attached. In long adducts, the proximal Ub remains on the substrate, likely securing its attachment to the proteasome, and is degraded with it. The distal Ub protects the proximal from removal by deubiquitinating enzymes and is then removed and recycled. In short adducts, the Ub moieties are rapidly removed, and the substrate remains stable. One of the enigmas in the ubiquitin (Ub) field is the requirement for a poly-Ub chain as a proteasomal targeting signal. The canonical chain appears to be longer than the distance between the two Ub-binding proteasomal receptors. Furthermore, genetic manipulation has shown that one receptor subunit is sufficient, which suggests that a single Ub can serve as a degradation signal. To shed light on this mystery, we chemically synthesized tetra-Ub, di-Ub (K48-based), and mono-Ub adducts of HA-α-globin, where the distal or proximal Ub moieties were tagged differentially with either Myc or Flag. When incubated in a crude cell extract, the distal Ub moiety in the tetra-Ub adduct was mostly removed by deubiquitinating enzymes (DUBs) and reconjugated to other substrates in the extract. In contrast, the proximal moiety was most likely degraded with the substrate. The efficacy of degradation was proportionate to the chain length; while tetra-Ub globin was an efficient substrate, with mono-Ub globin, we observed rapid removal of the Ub moiety with almost no degradation of the free globin. Taken together, these findings suggest that the proximal moieties are necessary for securing the association of the substrate with the proteasome along the proteolytic process, whereas the distal moieties are important in protecting the proximal moieties from premature deubiquitination. Interestingly, when the same experiment was carried out using purified 26S proteasome, mono- and tetra-Ub globin were similarly degraded, highlighting the roles of the entire repertoire of cellular DUBs in regulating the degradation of proteasomal substrates.
ClC-7 Regulates the Pattern and Early Development of Craniofacial Bone and Tooth

Human CLCN7 encodes voltage-gated chloride channel 7 (ClC-7); mutations of CLCN7 lead to osteopetrosis which is characterized by increased bone mass and impaired osteoclast function. In our previous clinical practice, we noticed that osteopetrosis patients with CLCN7 mutations had some special deformities in craniofacial morphology and tooth dysplasia. It is unclear whether these phenotypes are the typical features of CLCN7 involved osteopetrosis and whether ClC-7 could regulate the development of craniofacial bone and tooth in some signaling pathways. Methods: First, we collected 80 osteopetrosis cases from the literature and compared their craniofacial and dental phenotypes. Second, four osteopetrosis pedigrees with CLCN7 mutations were recruited from our clinic for gene testing and clinical analysis of their craniofacial and dental phenotypes. Third, we used a zebrafish model with clcn7 morpholino treatment to detect the effects of ClC-7 deficiency on the development of craniofacial and dental phenotypes. General observation, whole mount alcian blue and alizarin red staining, whole mount in situ hybridization, scanning electron microscope observation, lysoSensor staining, Q-PCR and western blotting were performed to observe the in vivo characteristics of craniofacial bone and tooth changes. Fourth, mouse marrow stromal cells were further primarily cultured to detect ClC-7 related mRNA and protein changes using siRNA, Q-PCR and western blotting. Results: Over 84% of osteopetrosis patients in the literature had some typical craniofacial and tooth phenotypes, including macrocephaly, frontal bossing, and changes in shape and proportions of facial skeleton, and these unique features are more severe and frequent in autosomal recessive osteopetrosis than in autosomal dominant osteopetrosis patients. Our four pedigrees with CLCN7 mutations confirmed the aforementioned clinical features. clcn7 knockdown in zebrafish reproduced the craniofacial cartilage defects and various dental malformations combined the decreased levels of col10a1, sp7, dlx2b, eve1, and cx43. Loss of clcn7 function resulted in lysosomal storage in the brain and jaw as well as downregulated cathepsin K (CTSK). The craniofacial phenotype severity also presented a dose-dependent relationship with the levels of ClC-7 and CTSK. ClC-7/CTSK further altered the balance of TGF-β/BMP signaling pathway, causing elevated TGF-β-like Smad2 signals and reduced BMP-like Smad1/5/8 signals in clcn7 morphants. SB431542 inhibitor of TGF-β pathway partially rescued the aforementioned craniofacial bone and tooth defects of clcn7 morphants. The ClC-7 involved CTSK/BMP and SMAD changes were also confirmed in mouse bone marrow stromal cells. Conclusion: These findings highlighted the vital role of clcn7 in zebrafish craniofacial bone and tooth development and mineralization, revealing novel insights for the causation of osteopetrosis with CLCN7 mutations. The mechanism chain of ClC-7/CTSK/ TGF-β/BMP/SMAD might explain the typical craniofacial bone and tooth changes in osteopetrosis as well as pycnodysostosis patients.
PARAMETER IDENTIFICATION-BASED DAMAGE DETECTION FOR LINEAR TIME-VARYING SYSTEMS

Many damage detection methods assume the system is linear before and after damage occurrence. This assumption usually does not accord with fact and this cause difficulty to the successful application of many existing damage detection approaches. This paper presents a technique for parameter identification – based damage detection for linear time-varying discrete dynamical systems. First, the parameter identification of linear time-varying systems is developed based on the Hilbert-Huang transform and the empirical mode decomposition method via free vibration data. Then the approach is used in damage detection of linear time-varying discrete system with demonstration with numerical examples with singleand multi-degree-of-freedom discrete systems.
Cross‐sectional comparative study of pharmacokinetics and efficacy between sucrose‐formulated recombinant factor VIII (Kogenate®) and BAY 81‐8973 (Kovaltry®) in patients with severe or moderate haemophilia A in prophylaxis

1. World Federation of Hemophilia. Report on the Annual Global Survey 2016, 2017. http://www1.wfh. org/publication/files/pdf‐1690.pdf. Accessed June 2018. 2. Ghosh K, Ghosh K. Management of haemophilia in developing countries: challenges and options. Indian J Hematol Blood Transfus. 2016;32(3):347‐355. 3. O’Mahony B, Black C. Expanding hemophilia care in developing countries. Semin Thromb Hemost. 2005;31(5):561‐568. 4. Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388(10040):187‐197. 5. Global Alliance for Progress, 2017. http://www.wfh. org/en/page.aspx? pxml:id=814. Accessed February 2017. 6. Giangrande PL, Mariani G, Black C. The WFH Haemophilia Centre Twinning Programme: 10 years of growth, 1993–2003. Haemophilia. 2003;9(3):240-244. 7. Ozelo MC, Matta MA, Yang R. Meeting the challenges of haemophilia care and patient support in China and Brazil. Haemophilia. 2012;18(Suppl 5):33-38. 8. IHTC. IHTC alumni newsletter 2017(4). https://www.wfh. org/en/ IHTC_Fellowship_Program
Efficient Search-Based Weighted Model Integration

Weighted model integration (WMI) extends Weighted model counting (WMC) to the integration of functions over mixed discrete-continuous domains. It has shown tremendous promise for solving inference problems in graphical models and probabilistic programming. Yet, state-of-the-art tools for WMI are limited in terms of performance and ignore the independence structure that is crucial to improving efficiency. To address this limitation, we propose an efficient model integration algorithm for theories with tree primal graphs. We exploit the sparse graph structure by using search to performing integration. Our algorithm greatly improves the computational efficiency on such problems and exploits context-specific independence between variables. Experimental results show dramatic speedups compared to existing WMI solvers on problems with tree-shaped dependencies.
Assessing the Geographic Context of Risk Perception and Behavioral Response to Potential Ebola Exposure

The 2014–2016 Ebola Virus Disease (EVD) epidemic outbreak reached over 28,000 cases and totaled over 11,000 deaths with 4 confirmed cases in the United States, which sparked widespread public concern about nationwide spread of EVD. Concern was elevated in locations connected to the infected people, which included Kent State University in Kent, Ohio. This threat of exposure enabled a unique opportunity to assess self-reported knowledge about EVD, risk perception, and behavior response to EVD. Unlike existing studies, which often survey one point in time across geographically coarse scales, this work offers insights into the geographic context of risk perception and behavior at finer-grained spatial and temporal scales. We report results from 3138 respondents comprised of faculty, staff, and students at two time periods. Results reveal increased EVD knowledge, decreased risk perception, and reduction in protective actions during this time. Faculty had the lowest perceived risk, followed by staff and then students, suggesting the role of education in this outcome. However, the most impactful result is the proof-of-concept for this study design to be deployed in the midst of a disease outbreak. Such geographically targeted and temporally dynamic surveys distributed during an outbreak can show where and when risk perception and behaviors change, which can provide policy-makers with rapid results that can shape intervention practices.
Exposure to Elevated Concentrations of Major Ions Decreases Condition Index of Freshwater Mussels: Comparison of Metrics

ABSTRACT Energy storage is critical for gametogenesis and successful spawning in bivalve mollusks. However, it often is overlooked as an endpoint in toxicological studies of freshwater mussels. Energy storage can be assessed through direct measurement of energy substrates or the use of the condition index (CI) as an indicator of overall nutritional status. Our study focused on the CI of adult Lampsilis fasciola exposed to treatment conditions designed to mimic the Powell River (Virginia, USA), which historically supported an exceptionally diverse freshwater mussel community. Coal mining operations have impacted the upper Powell River, and low-flow specific conductance frequently exceeds 900 µS/cm. We used four treatments in a full-factorial design to evaluate mussel responses to diluted pond water (control), simulated Powell River water, control sediment, and Powell River sediment. We measured glycogen content of mantle tissue and CI and compared several CI metrics. Exposure to simulated Powell River water caused a significant decrease in several CI metrics compared to control water. There was no effect of sediment type, nor was there any effect of sex; both males and females lost body mass in simulated Powell River water. However, males had significantly lower glycogen content of mantle tissue, indicating females likely were using other sources of energy to compensate for salinity stress. Comparison of CI metrics demonstrated that dissection was necessary to discern the effect of major ions on energy storage and that the use of tissue weight (g)/shell cavity capacity (g) had lower variability than tissue weight (g)/shell cavity volume (mL). The observed decrease in CI of adult L. fasciola after exposure to elevated concentrations of major ions has implications for maintaining mussel populations in the Powell River and in other rivers with rapidly increasing salinity.
Students' Constructions of Mental Illness: Using Discourse Analysis to Develop Critical Language Awareness

Discourses actively construct the objects of which they speak and these constructions have implications for subjectivity and power dynamics. Research has shown that hegemonic discourses of mental illness are problematic because they are implicated in the legitimization of unequal power relations and the perpetuation of stereotypes. In light of this, the need for the critical appraisal of the discursive practices within psychology in South Africa has been identified. This study, therefore, sought to facilitate the development of critical language awareness by identifying the discourses that psychology students draw on when talking about mental illness. Three semi-structured focus group discussions were conducted on the topic. These groups consisted of between five and seven undergraduate psychology students from the University of Cape Town. A Foucauldian discourse analysis approach was used to analyse the data because of its focus on power relations. The findings of the study show that students drew predominantly on a biomedical discourse and a romantic discourse when talking about mental illness. Both discourses, although via different discursive practices, construct mental illness as a Western, biomedical phenomenon. Thus, the intersection of these two discourses serves to disempower non-Western groups twice over. The use of these discourses in South African psychology is problematic as they locate the majority of the population in a position of powerlessness. This study therefore highlights the need for the development of new discursive practices within psychology in South Africa.
HopRank: How Semantic Structure Influences Teleportation in PageRank (A Case Study on BioPortal)

This paper introduces HopRank, an algorithm for modeling human navigation on semantic networks. HopRank leverages the assumption that users know or can see the whole structure of the network. Therefore, besides following links, they also follow nodes at certain distances (i.e., k-hop neighborhoods), and not at random as suggested by PageRank, which assumes only links are known or visible. We observe such preference towards k-hop neighborhoods on BioPortal, one of the leading repositories of biomedical ontologies on the Web. In general, users navigate within the vicinity of a concept. But they also “jump” to distant concepts less frequently. We fit our model on 11 ontologies using the transition matrix of clickstreams, and show that semantic structure can influence teleportation in PageRank. This suggests that users-to some extent-utilize knowledge about the underlying structure of ontologies, and leverage it to reach certain pieces of information. Our results help the development and improvement of user interfaces for ontology exploration.
Colistin resistance in Parisian inpatient faecal Escherichia coli as the result of two distinct evolutionary pathways.

BACKGROUND Beyond plasmid-encoded resistance (mcr genes) prevalence in strain collections, large epidemiological studies to estimate the human burden of colistin-resistant Escherichia coli gut carriage are lacking. OBJECTIVES To evaluate the prevalence of colistin-resistant E. coli carriage in inpatients and decipher the molecular support of resistance and the genetic background of the strains. METHODS During a 3 month period in 2017, we prospectively screened patients in six Parisian hospitals for rectal carriage of colistin-resistant E. coli using a selective medium, a biochemical confirmatory test and MIC determination. WGS of the resistant strains and their corresponding plasmids was performed. RESULTS Among the 1217 screened patients, 153 colistin-resistant E. coli strains were isolated from 152 patients (12.5%). The mcr-1 gene was identified in only seven isolates (4.6%) on different plasmid scaffolds. The genetic background of these MCR-1 producers argued for an animal origin. Conversely, the remaining 146 colistin-resistant E. coli exhibited a phylogenetic distribution corresponding to human gut commensal/clinical population structure (B2 and D phylogroup predominance); 72.6% of those isolates harboured convergent mutations in the PmrA and PmrB proteins, constituting a two-component system shown to be associated with colistin resistance. CONCLUSIONS We showed that the occurrence at a high rate of colistin resistance in human faecal E. coli is the result of two distinct evolutionary pathways, i.e. the occurrence of chromosomal mutations in an endogenous E. coli population and the rare acquisition of exogenous mcr-1-bearing strains probably of animal origin. The involved selective pressures need to be identified in order to develop preventative strategies.
Procopio G,Verzoni E,Bracarda S,Ricci S,Sacco C,Ridolfi L,Porta C,Miceli R,Zilembo N,Bajetta E,Italian Trials in Medical Oncology (ITMO) group Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC

Background The ROSORC trial, a randomised, phase II trial comparing sorafenib plus interleukin (IL-2) versus sorafenib alone as first-line treatment of metastatic renal cell carcinoma (mRCC) failed to demonstrate differences in progression-free survival (PFS). Updated overall survival (OS) results are reported. Patients and methods In this study, 128 patients were randomised to receive sorafenib 400 mg twice daily plus subcutaneous IL-2 4.5 million international units (MIU) five times per week for 6 weeks every 8 weeks (arm A) or sorafenib alone (arm B). OS was estimated with the Kaplan–Meier method and compared with the two-sided log-rank test. Results After a median follow-up of 58 months (interquartile range: 28–63 months), the median OS was 38 and 33 months in arms A and B, respectively (P = 0.667). The 5-year OS was 26.3% [95% confidence interval (CI) 15.9–43.5) and 23.1% (95% CI 13.2–40.5) for the combinationand single-agent arm, respectively. Most of the patients who were refractory to first-line treatment were subsequently treated with different targeted agents; they had a median survival greater than expected. Conclusions This outcome suggests a synergistic effect of the subsequent therapies following sorafenib failure. ClinicalTrials.gov Identifier NCT00609401.
Polyarthritis, Tenosynovitis and Dry Eyes after Treatment by Immune Check-Point Inhibitors

Introduction: Immune checkpoint inhibitors targeting programmed death protein-1 and cytotoxic-T-lymphocyte-antigen-4 have revolutionized the treatment of various cancers. Despite their effectiveness, these therapies can lead to immune related adverse events. Observation: We reported a case of a 43- year-old white woman who was referred to our department for a management of acute polyarthritis. She was followed for a relapsing metastatic melanoma (stage IIIb) by surgery and Pembrolizumab, an immune checkpoint inhibitor targeting programmed death protein-1. After receiving her 4th cycle of this therapy she developed arthritis of the knees and the ankles, tenosynovitis and dry eyes with keratitis. After exclusion of other causes of polyarthritis such as connective-tissue disease, the diagnosis of rheumatologic immunerelated adverse events was retained. She was treated by 20 mg of prednisone daily, Pembrolizumab was discontinued. The evolution was favorable. Conclusion: Rheumatologic manifestations secondary to immune checkpoint inhibitors have been less well described in the literature. Their management requires the collaboration of oncologists and rheumatologists to limit the diagnostic delay and for an appropriate therapeutic choice according to their severity.
Enrichment of phosphate solubilizing bacteria during late developmental stages of eggplant (Solanum melongena L.)

&NA; Understanding the ecology of phosphate solubilizing bacteria (PSBs) is critical for developing better strategies to increase crop productivity. In this study, the diversity of PSBs and of the total bacteria in the rhizosphere of eggplant (Solanum melongena L.) cultivated in organic, integrated and conventional farming systems was compared at four developmental stages of its lifecycle. Both selective culture and high‐throughput sequencing analysis of 16S rRNA amplicons indicated that Enterobacter with strong or very strong in vivo phosphate solubilization activities was enriched in the rhizosphere during the fruiting stage. The high‐throughput sequencing analysis results demonstrated that farming systems explained 23% of total bacterial community variation. Plant development and farming systems synergistically shaped the rhizospheric bacterial community, in which the degree of variation influenced by farming systems decreased over the plant development phase from 56% to 26.3% to 16.3%, and finally to no significant effect as the plant reached at fruiting stage. Pangenome analysis indicated that two‐component and transporter systems varied between the rhizosphere and soil PSBs. This study elucidated the complex interactions among farming systems, plant development and rhizosphere microbiomes. &NA; Graphical Abstract Figure. The rhizospheric microbial community structure of eggplant was susceptible to soil type during early plant development stages, and was largely shaped by plant development and recruitment of Enterobacter PSBs during the fruiting stage.
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy Dovepress

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A novel strain of Planomicrobium isolated from paper mill and its capacity of cellulose degradation

A novel strain, designated WH2-56, was isolated from a slime sample collected from a paper company along the Yangtze River during March, 2018. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain WH2-56 was related to members of the genus Planomicrobium. Cellulolytic activity of the sample was screened and confirmed by Congo red-polysaccharide interactions and examined by broth culture using filter paper (FP) with no starch as the sole carbon source. Field emission scanning electron microscopy (FE-SEM) was used to confirm the delicate morphological changes of FP during bio-degradation. Different cellulosic materials were used to measure biodegradation effects and optimum incubation conditions. The activity of FPase and carboxymethyl cellulase (CMCase) were checked by 3,5-dinitrosalicylic acid (DNS agents) with different carbon sources, which showed a peak at 0.62 U/mL of CMCase on day 4, and at 0.38 U/mL of FPase on day 5.