Role of palmitoylation on the neuronal glycine transporter GlyT2.

The neuronal glycine transporter GlyT2 removes glycine from the synaptic cleft through active Na+, Cl-, and glycine cotransport contributing to the termination of the glycinergic signal as well as supplying substrate to the presynaptic terminal for the maintenance of the neurotransmitter content in synaptic vesicles. Patients with mutations in the human GlyT2 gene (SLC6A5), develop hyperekplexia or startle disease (OMIM 149400), characterized by hypertonia and exaggerated startle responses to trivial stimuli that may have lethal consequences in the neonates as a result of apnea episodes. Post-translational modifications in cysteine residues of GlyT2 are an aspect of structural interest we analyzed. Our study is compatible with a reversible and short-lived S-acylation in spinal cord membranes, detectable by biochemical and proteomics methods (acyl-Rac binding and IP-ABE) confirmed with positive and negative controls (palmitoylated and non-palmitoylated proteins). According to a short-lived modification, direct labeling using click chemistry was faint but mostly consistent. We have analyzed the physiological properties of a GlyT2 mutant lacking the cysteines with high prediction of palmitoylation and the mutant is less prone to be included in lipid rafts, an effect also observed upon treatment with the palmitoylation inhibitor 2-bromopalmitate. This work demonstrates there are determinants of lipid raft inclusion associated with the GlyT2 mutated cysteines, which are presumably modified by palmitoylation.

DROUGHT-INDUCED BRANCHED-CHAIN AMINO ACID AMINOTRANSFERASE enhances drought tolerance in rice.

Plants accumulate several metabolites in response to drought stress, including branched-chain amino acids (BCAAs). However, the roles of BCAAs in plant drought responses and the underlying molecular mechanisms for BCAA accumulation remain elusive. Here, we demonstrate that rice (Oryza sativa) DROUGHT-INDUCED BRANCHED-CHAIN AMINO ACID AMINOTRANSFERASE (OsDIAT) mediates the accumulation of BCAAs in rice in response to drought stress. An in vitro enzyme activity assay indicated that OsDIAT is a branched-chain amino acid aminotransferase, and subcellular localization analysis revealed that OsDIAT localizes to the cytoplasm. The expression of OsDIAT was induced in plants upon exposure to abiotic stress. OsDIAT-overexpressing (OsDIATOX) plants were more tolerant to drought stress, whereas osdiat plants were more susceptible to drought stress compared with nontransgenic (NT) plants. Amino acid analysis revealed that BCAA levels were higher in OsDIATOX but lower in osdiat compared with in NT plants. Finally, the exogenous application of BCAAs improved plant tolerance to osmotic stress compared with that in control plants. Collectively, these findings suggest that OsDIAT mediates drought tolerance by promoting the accumulation of BCAAs.

Prediction of Redox Potentials for U, Np, Pu, and Am in Aqueous Solution.

The redox properties of the actinides in aqueous solution are important for fuel production/reprocessing and understanding the environmental impact of nuclear waste. The redox potentials for U, Np, Pu, and Am in oxidation states from 0 up to VII (as appropriate) in aqueous solutions have been predicted at the density functional theory level with the B3LYP functional, Stuttgart small core pseudopotential basis sets for the actinides, and explicit (30H2O molecules)/implicit treatment of the aqueous solvent using the self-consistent reaction field COSMO and SMD approaches for the implicit solvation. The predictions of the structural parameters of clusters incorporating first and second solvation shells are consistent with the available experimental data. Our results are typically within 0.2 V of the available experimental data using two explicit solvation shells with an implicit solvent model. The use of the PW91 functional substantially improved the prediction of the Pu(VI/V) redox couple. The redox couples for An(VI/IV) and An(V/IV) which involve the addition of protons and removal of the actinyl oxygens led to slightly larger differences from an experiment. The An(IV/0) and An(III/0) couples were reliably predicted with our approach. Predictions of the unknown An(II/I) redox potentials were negative, consistent with expectations, and predictions for unknown An(VII/VI), An(III/II), and An(II/0) redox couples improve prior estimates.

Use of 3D Anorectal Ultrasonography in the Preoperative Assessment of Complex Anal Fistulas and Patterns of Healing, Failure, and Recurrence After Ligation of the Intersphincteric Fistula Tract (LIFT).

OBJECTIVES: To use three-dimensional anorectal ultrasonography (3D-US) to evaluate the outcome of ligation of the intersphincteric fistula tract (LIFT) in patients with crypto-glandular transsphincteric fistula and describing the patterns of healing, failure, and recurrence rate. METHODS: After classifying the fistula and determining the length of the sphincter muscle to be transected, the patients were submitted to LIFT. The accuracy of pre- and postoperative 3D-US with 360° endoprobe (16 MHz) with automatic scanning and clinical findings was evaluated against surgical findings. Three outcomes were considered: healing, failure (persistent anal fistula through the original external opening or intersphincteric), and recurrence (reappearance of the anal fistula). RESULTS: Sixty-three patients of both sexes were evaluated. The 3D-US assessment revealed primary healing in 50 (79.3%) patients, although in 6 (9.5%) cases healing was delayed and the cavity was without communication with the anal canal. The procedure failed in 9 (15.9%) and fistula recurred in 4 (6.3%), all of whom underwent a second surgery based on a new 3D-US, resulting in a 92.3% (12/13) healing rate on 3D-US. CONCLUSIONS: A 3D-US was found to be useful in the preoperative assessment of fistulas by quantifying the percentage of muscle to be transected, and in the postoperative assessment by identifying healing, types of failure, and recurrence. The 3D-US was accurate and consistent with surgical findings.

Immune and endocrine alterations at the early stage of inflammatory assemblage in toads after stimulation with heat-killed bacteria (Aeromonas hydrophila).

The red-leg syndrome in amphibians is a condition commonly associated with the bacteria Aeromonas hydrophila and has led to population declines. However, there is little information concerning the inflammatory assemblage in infected anurans. We evaluated immune and endocrine alterations induced by stimulation with heat-killed A. hydrophila injected in Rhinella diptycha toads. Control animals were not manipulated, while the others were separated into groups that received intraperitoneal injection of 300 µl of saline or heat-killed bacteria: groups A1 (3 × 107 cells), A2 (3 × 108 cells), and A3 (3 × 109 cells). Animals were bled and euthanized six hours post-injection. We evaluated neutrophil: lymphocyte ratio (NLR), plasma bacterial killing ability (BKA), testosterone (T), melatonin (MEL), and corticosterone (CORT) plasma levels. Heat-killed A. hydrophila increased CORT and NLR, and decreased MEL, especially at higher concentrations. There was no effect of treatment on T and BKA. We then selected the saline and A3 groups to conduct mRNA expression of several genes including glucocorticoid receptor (GR), toll-like receptor-4 (TLR-4), interferon-γ (IFN-γ), interleukin (IL)-1ß, IL-6, and IL-10. We found higher expression of IL-6, IL-1ß, IL-10, and IFN-γ in group A3 compared to the saline group. These results indicate the beginning of an inflammatory assemblage, notably at the two highest concentrations of bacteria, and give a better understanding of how anurans respond to an infection within an integrated perspective, evaluating different physiological aspects. Future studies should investigate later phases of the immune response to elucidate more about the inflammation in amphibians challenged with A. hydrophila.

High infestation and phylogenetic position of Epistylis sp. (Ciliophora, Peritrichia) on Aegla serrana Buckup & Rossi (Crustacea, Anomura) from southern Brazil.

High infestations of epibiont ciliates on vertebrates or invertebrates are normally related to aquaculture tanks or similar environments, and the importance of this relationship in natural habitats is often disregarded. Here, we describe the first record of high infestation of ciliates on Aegla serrana in South America and conduct a brief morphological and phylogenetic characterization of these ciliates. Our findings confirm that cases of high infestation of ciliates on metazoans can indeed occur in natural environments.

Performance of the National Institute of Infectious Diseases disability scale in HTLV-1-associated myelopathy/tropical spastic paraparesis.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic disabling disease. However, there is a lack of an adequate and specific health measurement instrument validated and with good performance to assess their degree of physical disability. This led us to carry out this study and to evaluate the performance of Fiocruz's National Institute of Infectious Diseases (IDS) disability scale, a specific instrument for HAM/TSP. Ninety-two HAM/TSP patients participated in the study. One researcher applied the IDS, IPEC scale, Disability Status Scale (DSS), Expanded DSS (EDSS), Osame scale, Beck Depression Inventory, and the WHOQOL-BREF questionnaire. In parallel, blindly, and separately, other researchers applied the IDS. An inter-rater reliability analysis of the IDS, correlation analysis with the other scales, and depression and quality of life questionnaires were performed. The applicability of the IDS was also evaluated. The IDS showed high reliability in all scores. The inter-rater reliability test for the total IDS score was 0.94 (0.82-0.98) on its four dimensions. The scale adequately indicated the different degrees of disability, presenting a distribution similar to normal. There was a high correlation with the other scales (Spearman coefficients > 0.80, p < 0.001). The scale had good acceptance among users and a short application time. IDS for HAM/TSP was reliable, consistent, easy, and fast to use. It can be used for both prospective evaluations and clinical trials. The present study supports the IDS as a valid instrument to measure disability in patients with HAM/TSP compared to previously used scales.

In a marine teleost, the significance of oxygen supply for acute thermal tolerance depends upon the context and the endpoint used.

Eight juvenile European seabass were exposed to two thermal ramping protocols with different levels of aerobic activity and tolerance endpoint: the critical thermal maximum for swimming (CTSmax) while exercising aerobically until fatigue and the critical thermal maximum (CTmax) under static conditions until loss of equilibrium (LOE). In the CTSmax protocol, warming caused a profound increase in the rate of oxygen uptake (MO2), culminating in a gait transition from steady aerobic towards unsteady anaerobic swimming, then fatigue at 30.3±0.4°C (mean±s.e.m.). Gait transition and fatigue presumably indicate an oxygen limitation, which reflects the inability to meet the combined demands of swimming plus warming. The CTmax protocol also elicited an increase in MO2, culminating in LOE at 34.0±0.4°C, which is significantly warmer than fatigue at CTSmax. The maximum MO2 achieved in the CTmax protocol was, however, less than 30% of that achieved in the CTSmax protocol. Therefore, the static CTmax did not exploit full cardiorespiratory capacity for oxygen supply, indicating that LOE was not caused by systemic oxygen limitation. Consequently, systemic oxygen supply can be significant for tolerance of acute warming in seabass but this depends upon the physiological context and the endpoint used.

Hiatal hernia repair with biosynthetic mesh reinforcement: a qualitative systematic review.

INTRODUCTION: Reinforcement of crural closure with synthetic resorbable mesh has been proposed to decrease recurrence rates after hiatal hernia repair, but continues to be controversial. This systematic review aims to evaluate the safety, efficacy, and intermediate-term results of using biosynthetic mesh to augment the hiatus. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed throughout this systematic review. The Risk of Bias in Non-Randomized Studies of Interventions and Risk of Bias in Randomized Trials tools were used to perform qualitative assessment of all studies included in this review. Recommendations were then summarized for the following pre-defined key items: protocol, research question, search strategy, study eligibility, data extraction, study design, risk of bias, publication bias, and statistical analysis. RESULTS: The systematic literature search found 520 articles, 101 of which were duplicates and 355 articles were determined to be unrelated to our study and excluded. The full text of the remaining 64 articles was thoroughly assessed. A total of 18 articles (1846 patients) were ultimately included for this review, describing hiatal hernia repair using three different biosynthetic meshes-BIO-A, Phasix ST, and polyglactin mesh. Mean operative time varied from 127 to 223 min. Mean follow up varied from 12 to 54 months. There were no mesh erosions or explants. One mesh-related complication of stenosis requiring reoperation was reported with BIO-A. Studies showed significant improvement in symptom and quality-of-life scores, as well as satisfaction with surgery. Recurrence was reported as radiologic or clinical recurrence. Overall, recurrence rate varied from 0.9 to 25%. CONCLUSION: The use of biosynthetic mesh is safe and effective for hiatal hernia repair with low complications rates and high symptom resolution. The reported recurrence rates are highly variable due to significant heterogeneity in defining and evaluating recurrences. Further randomized controlled trials with larger samples and long-term follow-up should be performed to better analyze outcomes and recurrence rates.

What are the correlates of intention to be physically active in Brazilian adolescents? A network analysis.

OBJECTIVE: The current study aimed to explore the association of individual characteristics, social and environmental factors - school and region - in the intention to be physically active in Brazilian adolescents. METHODS: This is a cross sectional study based on the third edition of the National School Health Survey. The study included a total of 53,937 adolescents. To assess the intention to be physically active, only who engaged in less than 300 min of physical activity per week were included. Participants were asked: "If you had the opportunity to practice physical activity most days of the week, what would your attitude be?" Individual characteristics, physical activity domains, social factors, school, and regional environments were used as exposures. Network analysis was utilized to evaluate the associations. RESULTS: We observed that boys had higher intentions to be physically active compared to their peers, as did adolescents who perceived themselves as fat. In addition, students from private schools show a higher intention to regularly engage in physical activities, and in general, private schools offer more extracurricular physical activities. CONCLUSION: In conclusion, individual factors such as sex and body image perception, and environmental factors such as school administrative dependency and availability of extracurricular activities had a significant contribution to the intention to be physically active among Brazilian adolescents.

Econometric model of iron ore through principal component analysis and multiple linear regression.

Price of iron ore is affected by instabilities of microeconomic balance between supply and demand. Periods of equilibrium adjustment result in huge swings, growth or global recession. They also impact the viability of mineral enterprises and generate consequences to important global economic scenarios. This research aims to evaluate the market variables capable of influencing the price of iron ore through multivariate statistical techniques. Principal component analysis and multiple linear regression, booth multivariate statistical techniques were used. The studied variables were rate export of iron ore and concentrates from Brazil, steel production from China, steel production from Japan, production from Europe, steel production from the United States, steel production from India, steel price, coal price, China's Construction Gross Domestic Production, United States construction index, oil price and global oil production. First three components explained 89.12% of the variability of the data matrix. Multiple linear regression highlighted the significance of five variables. They are export iron ore from Brazil, steel production from China, price of coal, steel production from India and price of steel.

Tolerance of an acute warming challenge declines with body mass in Nile tilapia: evidence of a link to capacity for oxygen uptake.

It has been proposed that larger individuals within fish species may be more sensitive to global warming, as a result of limitations in their capacity to provide oxygen for aerobic metabolic activities. This could affect size distributions of populations in a warmer world but evidence is lacking. In Nile tilapia Oreochromis niloticus (n=18, mass range 21-313 g), capacity to provide oxygen for aerobic activities (aerobic scope) was independent of mass at an acclimation temperature of 26°C. Tolerance of acute warming, however, declined significantly with mass when evaluated as the critical temperature for fatigue from aerobic swimming (CTSmax). The CTSmax protocol challenges a fish to meet the oxygen demands of constant aerobic exercise while their demands for basal metabolism are accelerated by incremental warming, culminating in fatigue. CTSmax elicited pronounced increases in oxygen uptake in the tilapia but the maximum rates achieved prior to fatigue declined very significantly with mass. Mass-related variation in CTSmax and maximum oxygen uptake rates were positively correlated, which may indicate a causal relationship. When fish populations are faced with acute thermal stress, larger individuals may become constrained in their ability to perform aerobic activities at lower temperatures than smaller conspecifics. This could affect survival and fitness of larger fish in a future world with more frequent and extreme heatwaves, with consequences for population productivity.

COVID-19 diagnosis by SARS-CoV-2 Spike protein detection in saliva using an ultrasensitive magneto-assay based on disposable electrochemical sensor.

The outbreak of the COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome of Coronavirus 2 (SARS-CoV-2), has fueled the search for diagnostic tests aiming at the control and reduction of the viral transmission. The main technique used for diagnosing the Coronavirus disease (COVID-19) is the reverse transcription-polymerase chain reaction (RT-PCR) technique. However, considering the high number of cases and the underlying limitations of the RT-PCR technique, especially with regard to accessibility and cost of the test, one does not need to overemphasize the need to develop new and less expensive testing techniques that can aid the early diagnosis of the disease. With that in mind, we developed an ultrasensitive magneto-assay using magnetic beads and gold nanoparticles conjugated to human angiotensin-converting enzyme 2 (ACE2) peptide (Gln24-Gln42) for the capturing and detection of SARS-CoV-2 Spike protein in human saliva. The technique applied involved the use of a disposable electrochemical device containing eight screen-printed carbon electrodes which allow the simultaneous analysis of eight samples. The magneto-assay exhibited an ultralow limit of detection of 0.35 ag mL-1 for the detection of SARS-CoV-2 Spike protein in saliva. The magneto-assay was tested in saliva samples from healthy and SARS-CoV-2-infected individuals. In terms of efficiency, the proposed technique - which presented a sensitivity of 100.0% and specificity of 93.7% for SARS-CoV-2 Spike protein-exhibited great similarity with the RT-PCR technique. The results obtained point to the application potential of this simple, low-cost magneto-assay for saliva-based point-of-care COVID-19 diagnosis.

Day vs. night variation in the LPS effects on toad's immunity and endocrine mediators.

The immune-endocrine interactions following an immune challenge have been demonstrated in amphibians. When considering immune challenges, the immune-endocrine implications can vary with the injection time (day or night), a pattern not explored in amphibians. We investigated the immune response following a lipopolysaccharide - LPS injection, measured as plasma bacterial killing ability - BKA, phagocytosis of blood cells - PP, and neutrophil to lymphocyte ratio - NLR, splenic proinflammatory cytokines mRNA (IL-1ß and IL-6), and also endocrine mediators (corticosterone - CORT and melatonin - MEL plasma levels) in Rhinella icterica adult male toads injected at day (10 am) or night (10 pm). LPS induced increases in CORT, NLR, PP, and IL-1ß mRNA compared with amphibian phosphate-buffer saline-injected individuals. For plasma CORT, the response was more pronounced during the night. While for the PP and IL-1ß mRNA, the effect was more evident during the day. For NLR, the increase happened at both times, day and night, in the LPS-injected toads. Meanwhile, no changes were observed in BKA, IL-6 mRNA, and MEL levels. Overall, our results demonstrated an LPS-induced inflammatory response in R. icterica toads, characterized by higher PP, NLR, and IL-1ß mRNA, followed by activation of the hypothalamic-pituitary-interrenal axis (higher CORT levels). The time in which the toads received the LPS injection affected the endocrine and immune mediators. The higher CORT and lower inflammatory response at night suggested a potential functional interaction between CORT and immune reactivity associated with the differences in night vs. day in R. icterica toads. These results highlight the relevance of investigating different injection times and mechanistic pathways to understand LPS-induced immunomodulation in anurans.

Occurrence of methicillin-resistant Staphylococcus aureus (MRSA) in 'coalho' cheese produced in Brazil.

The experiments reported in this research communication analysed the presence of methicillin-resistant Staphylococcus aureus (MRSA) in 112 samples of 'coalho' cheese, from 56 dairy producing farms in 28 cities in all mesoregions of the State of Ceará, Brazil. To assess antimicrobial resistance we also examined the presence of genes encoding enterotoxins and toxic shock syndrome toxin, as well as the presence of the blaZ gene for ß-lactamases, and resistance to oxacillin. The research found 69 isolates of S. aureus, of which 13.04% had the mecA gene encoding the penicillin-binding protein, which confers resistance to methicillin, in cheese samples from 6 different cities. This included the state capital, Fortaleza, which had the largest prevalence (23.19%) of mecA positive isolates. It was also found that 55.07% of the isolates of S. aureus had the blaZ gene, and 7.25% demonstrated resistance to oxacillin in the plate disc diffusion tests. We did not show the presence of isolates carrying toxigenic genes. The findings suggest that strict supervision of production processes in the dairy industry is necessary in all production scale processes, thus preventing contamination and possible problems for consumers.

New records of soft ticks (Acari: Argasidae) in the Caatinga biome of Brazil, with a phylogenetic analysis of argasids using the nuclear Histone 3 (H3) gene.

In Brazil, 19 species of the genus Ornithodoros (Acari: Argasidae) have been reported. The medical and veterinary importance of Ornithodoros ticks has increased substantially in recent decades, with the discovery of various relapsing fever Borrelia infecting Ornithodoros ticks. Herein, argasid ticks were collected during 2019-2020 from caves, abandoned nests and homes in various regions of Ceará State, Brazilian semiarid-Caatinga biome. In total, 289 ticks were collected and identified into five species: Ornithodoros cavernicolous (176 specimens), Ornithodoros fonsecai (81), Ornithodoros mimon (12), Ornithodoros rietcorreai (4), and a fifth species provisionally retained as Ornithodoros sp. Ubajara. Tick identifications were corroborated by a phylogenetic analysis inferred using the 16S rRNA gene. To extend the molecular characterization, DNA samples were tested by an additional PCR assay targeting the nuclear Histone 3 (H3) gene. Because there were no H3 sequences of argasids in GenBank, we extended this PCR assay for additional Ornithodoros species, available in our laboratory. In total, 15 partial sequences of the H3 gene were generated for 10 Ornithodoros species, showing 0% intraspecific polymorphism, and 1.5-11.6% interspecific polymorphism. Phylogenetic analyses inferred segregated Ornithodoros sp. Ubajara as a potential novel species. Our results also highlight the potential of the H3 gene for deeper phylogenetic analyses of argasids. The present study provides new data for argasid ticks of the genus Ornithodoros in the Caatinga biome. Because some of these tick species are human-biting ticks, active surveillance for the incidence of human infection due to Ornithodoros-borne agents is imperative in the Caatinga biome.

Dealing with complex contamination scenarios: using a multi-geochemical approach to assess environmental quality and identify pollution sources in a semi-arid estuary from Brazil.

The Jundiaí-Potengi Estuary (EJP) is located on the semi-arid coast of northeastern Brazil and is influenced by multiple sources of contamination. The sediment quality of EJP was assessed by using a multi-geochemical approach during the dry and wet seasons. Sediments were analyzed for concentrations of nutrients, metals, polycyclic aromatic hydrocarbons (PAHs), pesticides, hormones (natural and synthetic), and sterols. The results were integrated by multivariate methods. The sediment was altered by the presence of contaminants from anthropogenic and natural sources. The middle and lower estuarine areas were considered more degraded in both seasons. In these regions, metals, hormones, sterols, and PAHs were found, indicating that these regions are severely affected by industrial, sanitary and aquaculture effluents, combustion of fossil fuels, and oil spills. The upstream region was contaminated by pesticides. The contamination pattern along the EJP shows the prevalence of local sources which continuously release the chemicals into the estuary. Worse conditions occurred during the rainy season, when the runoff from urban and rural areas is more intense and carries a greater load of contaminants to the EJP.

Relapsing Fever Group Borreliae in Human-Biting Soft Ticks, Brazil.

We conducted a molecular survey for Borrelia spp. in Ornithodoros ticks previously reported as biting humans. We collected specimens in natural ecosystems and inside human dwellings in 6 states in Brazil. Phylogenetic analyses unveiled the occurrence of 4 putatively new species of relapsing fever group borreliae.

Diagnostic accuracy of FDG-PET/MRI versus pelvic MRI and thoracic and abdominal CT for detecting synchronous distant metastases in rectal cancer patients.

PURPOSE: We compared the diagnostic accuracy of detecting distant metastases for baseline rectal cancer staging between PET/MRI and conventional staging (CS). MATERIALS AND METHODS: This prospective study from November 2016 to April 2018 included 101 rectal adenocarcinoma patients for primary staging. These patients underwent whole-body PET/MRI in addition to CS (pelvic MRI and thoracic and abdominal contrast-enhanced CT). Different readers analyzed CS and PET/MRI findings for primary tumor, nodal, and metastatic staging. The presence, number, and location of metastases were recorded according to the organ involved (non-regional lymph nodes (LNs), liver, lungs, or others). Lesions were defined as positive, negative, or indeterminate. The number of lesions per organ was limited to 10. The McNemar test was used to compare the accuracies. RESULTS: PET/MRI exhibited a higher accuracy in detecting metastatic disease than CS in all patients (88.4% vs. 82.6%, p = 0.003) and in patients with extramural vascular invasion (EMVI) (88.9% vs. 85.5%, p = 0.013). The detection rate of PET/MRI was superior to that of CS for all lesions [84.1% vs. 68.9%, p = 0.001], as well as those in the liver (89.2% vs. 84.2%), non-regional LNs (90.0% vs. 36.7%), and lungs (76.4% vs. 66.9%). PET/MRI correctly classified 19/33 (57.5%) patients with indeterminate lesions on CS. CONCLUSION: PET/MRI yields higher accuracy than CS for detecting distant synchronous metastases in the baseline staging of patients with rectal cancer and EMVI. PET/MRI exhibited a higher detection rate than CS for identifying non-regional LNs, hepatic lesions, and pulmonary lesions as well as correctly classifying patients with indeterminate lesions. TRIAL REGISTRATION: NCT02537340.

Fbxl17 is rearranged in breast cancer and loss of its activity leads to increased global O-GlcNAcylation.

In cancer, many genes are mutated by genome rearrangement, but our understanding of the functional consequences of this remains rudimentary. Here we report the F-box protein encoded by FBXL17 is disrupted in the region of the gene that encodes its substrate-binding leucine rich repeat (LRR) domain. Truncating Fbxl17 LRRs impaired its association with the other SCF holoenzyme subunits Skp1, Cul1 and Rbx1, and decreased ubiquitination activity. Loss of the LRRs also differentially affected Fbxl17 binding to its targets. Thus, genomic rearrangements in FBXL17 are likely to disrupt SCFFbxl17-regulated networks in cancer cells. To investigate the functional effect of these rearrangements, we performed a yeast two-hybrid screen to identify Fbxl17-interacting proteins. Among the 37 binding partners Uap1, an enzyme involved in O-GlcNAcylation of proteins was identified most frequently. We demonstrate that Fbxl17 binds to UAP1 directly and inhibits its phosphorylation, which we propose regulates UAP1 activity. Knockdown of Fbxl17 expression elevated O-GlcNAcylation in breast cancer cells, arguing for a functional role for Fbxl17 in this metabolic pathway.