Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional interrelationships between carbohydrate and lipid storage, and mitochondrial activity during sporulation in Saccharomyces cerevisiae

In Saccharomyces cerevisiae under conditions of nutrient stress, meiosis precedes the formation of spores. Although the molecular mechanisms that regulate meiosis, such as meiotic recombination and nuclear divisions, have been extensively studied, the metabolic factors that determine the efficiency of sporulation are less understood. Here, we have directly assessed the relationship between metabolic stores and sporulation in S. cerevisiae by genetically disrupting the synthetic pathways for the carbohydrate stores, glycogen (gsy1/2Δ cells), trehalose (tps1Δ cells), or both (gsy1/2Δ and tps1Δ cells). We show that storage carbohydrate‐deficient strains are highly inefficient in sporulation. Although glycogen and trehalose stores can partially compensate for each other, they have differential effects on sporulation rate and spore number. Interestingly, deletion of the G1 cyclin, CLN3, which resulted in an increase in cell size, mitochondria and lipid stores, partially rescued meiosis progression and spore ascus formation but not spore number in storage carbohydrate‐deficient strains. Sporulation efficiency in the carbohydrate‐deficient strain exhibited a greater dependency on mitochondrial activity and lipid stores than wild‐type yeast. Taken together, our results provide new insights into the complex crosstalk between metabolic factors that support gametogenesis.
Oxidative and inflammatory effects of pulmonary rehabilitation in patients with bronchiectasis. A prospective, randomized study.

BACKGROUND systemic inflammation and oxidative stress are important factors in the pathogenesis of bronchiectasis. Pulmonary rehabilitation (PR) is recommended for bronchiectasis, but there is no data about its effect on the inflammatory and REDOX status of these patients. AIMS to investigate the effect of PR in non-cystic-fibrosis bronchiectasis (NCFB) patients, and to compare it with the effect of PR plus a hyperproteic oral nutritional supplement (PRS) enriched with beta-hydroxy-beta-methylbutyrate (HMB) on serum inflammatory and oxidative biomarkers. MATERIALS AND METHODS this was an open randomized, controlled trial. Thirty individuals (65 years old or younger with a body mass index over 18.5, older than 65 years with a body mass index over 20) were recruited from September 2013 to September 2014, and randomly assigned to receive PR or PRS. Total neutrophils, and inflammatory and oxidative biomarker levels were measured at baseline, and then at 3 and 6 months. RESULTS in the PRS group neutrophil levels were decreased from baseline at 6 months. A significantly different fold change was found between the PR and PRS groups. In the PR group, IL-6 and adiponectin were increased by the end of the study while TNFα levels were decreased from baseline at 6 months. REDOX biomarkers remained stable throughout the study except for 8-isoprostane levels, which were increased from baseline at 6 months in both groups of patients. CONCLUSIONS a PR program induced a pro-oxidative effect accompanied by changes in circulating inflammatory cytokine levels in NCFB patients. Our results would also suggest a possible beneficial effect of the HMB enriched supplement on neutrophil level regulation in these patients. The information provided in this study could be useful for choosing the right therapeutic approach in the management of bronchiectasis.
Outcomes in Adulthood After Long-Term Foster Care: A Sibling Approach

When a child is removed from their home and placed in foster care, society takes over the responsibility for that child’s well-being and development. Failure to provide a child with a nurturing upbringing may have negative consequences for the child as well as for society. Using Swedish longitudinal registry data for a national cohort sample of siblings, in which some were placed in foster care and others remained in their birth parents’ care, this study asks whether long-term foster care ensures improved life chances. Results from multilevel regression analyses of a wide range of educational, social, and health-related outcomes in mature adult age (16 outcome constructs) support a row of previous studies indicating that traditional long-term foster care does not seem to improve maltreated children’s life chances.
Autoregressive repeatability model for genetic evaluation of longitudinal reproductive traits in dairy cattle

Abstract We investigated the efficiency of the autoregressive repeatability model (AR) for genetic evaluation of longitudinal reproductive traits in Portuguese Holstein cattle and compared the results with those from the conventional repeatability model (REP). The data set comprised records taken during the first four calving orders, corresponding to a total of 416, 766, 872 and 766 thousand records for interval between calving to first service, days open, calving interval and daughter pregnancy rate, respectively. Both models included fixed (month and age classes associated to each calving order) and random (herd-year-season, animal and permanent environmental) effects. For AR model, a first-order autoregressive (co)variance structure was fitted for the herd-year-season and permanent environmental effects. The AR outperformed the REP model, with lower Akaike Information Criteria, lower Mean Square Error and Akaike Weights close to unity. Rank correlations between estimated breeding values (EBV) with AR and REP models ranged from 0.95 to 0.97 for all studied reproductive traits, when the total bulls were considered. When considering only the top-100 selected bulls, the rank correlation ranged from 0.72 to 0.88. These results indicate that the re-ranking observed at the top level will provide more opportunities for selecting the best bulls. The EBV reliabilities provided by AR model was larger for all traits, but the magnitudes of the annual genetic progress were similar between two models. Overall, the proposed AR model was suitable for genetic evaluations of longitudinal reproductive traits in dairy cattle, outperforming the REP model.
TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination.

Increased rates of locoregional recurrence are observed in patients with basal-like breast cancer (BC) despite the use of radiation therapy (RT); therefore, approaches that result in radiosensitization of basal-like BC are critically needed. Using patients' tumor gene expression data from 4 independent data sets, we correlated gene expression with recurrence to find genes significantly correlated with early recurrence after RT. The highest-ranked gene, TTK, was most highly expressed in basal-like BC across multiple data sets. Inhibition of TTK by both genetic and pharmacologic methods enhanced radiosensitivity in multiple basal-like cell lines. Radiosensitivity was mediated, at least in part, through persistent DNA damage after treatment with TTK inhibition and RT. Inhibition of TTK impaired homologous recombination (HR) and repair efficiency, but not nonhomologous end-joining, and decreased the formation of Rad51 foci. Reintroduction of wild-type TTK rescued both radioresistance and HR repair efficiency after TTK knockdown, however, reintroduction of kinase-dead TTK did not. In vivo, TTK inhibition combined with RT led to a significant decrease in tumor growth in both heterotopic and orthotopic, including patient-derived xenograft, BC models. These data support the rationale for clinical development of TTK inhibition as a radiosensitizing strategy for patients with basal-like BC, and efforts toward this end are currently underway.
A polyomavirus peptide binds to the capsid VP1 pore and has potent antiviral activity against BK and JC polyomaviruses

In pursuit of therapeutics for human polyomaviruses, we identified a peptide derived from the BK polyomavirus (BKV) minor structural proteins VP2/3 that is a potent inhibitor of BKV infection with no observable cellular toxicity. The thirteen-residue peptide binds to major structural protein VP1 with single-digit nanomolar affinity. Alanine-scanning of the peptide identified three key residues, substitution of each of which results in ~1000 fold loss of binding affinity with a concomitant reduction in antiviral activity. Structural studies demonstrate specific binding of the peptide to the pore of pentameric VP1. Cell-based assays demonstrate nanomolar inhibition (EC50) of BKV infection and suggest that the peptide acts early in the viral entry pathway. Homologous peptide exhibits similar binding to JC polyomavirus VP1 and inhibits infection with similar potency to BKV in a model cell line. Lastly, these studies validate targeting the VP1 pore as a novel strategy for the development of anti-polyomavirus agents.
Quantitative optical coherence tomography angiography: A review

As a new optical coherence tomography (OCT) modality, OCT angiography (OCTA) provides a noninvasive method to detect microvascular distortions correlated with eye conditions. By providing unparalleled capability to differentiate individual plexus layers in the retina, OCTA has demonstrated its excellence in clinical management of diabetic retinopathy, glaucoma, sickle cell retinopathy, diabetic macular edema, and other eye diseases. Quantitative OCTA analysis of retinal and choroidal vasculatures is essential to standardize objective interpretations of clinical outcome. Quantitative features, including blood vessel tortuosity, blood vessel caliber, blood vessel density, vessel perimeter index, fovea avascular zone area, fovea avascular zone contour irregularity, vessel branching coefficient, vessel branching angle, branching width ratio, and choroidal vascular analysis have been established for objective OCTA assessment. Moreover, differential artery–vein analysis has been recently demonstrated to improve OCTA performance for objective detection and classification of eye diseases. In this review, technical rationales and clinical applications of these quantitative OCTA features are summarized, and future prospects for using these quantitative OCTA features for artificial intelligence classification of eye conditions are discussed. Impact statement OCT angiography (OCTA) provides a noninvasive method to detect microvascular distortions correlated with eye conditions. Quantitative analysis of OCTA is essential to standardize objective interpretations of clinical outcome. This review summarizes technical rationales and clinical applications of quantitative OCTA features.
Short and long-term efficacy of adalimumab in ulcerative colitis: a real-life study

Abstract Objective: Randomized controlled trials have shown the effectiveness of Adalimumab in ulcerative colitis. However, real-life data is scarce. We aimed to assess the effectiveness and predictive factors of effectiveness in a large Swedish cohort. Methods: Retrospective capture of data from local registries at five Swedish IBD centers. Clinical response and remission rates were assessed at three months after starting adalimumab treatment and patients were followed until colectomy or need for another biological. Bio-naive patients were compared to bio experienced patients. Factors associated with short term responses were assessed using logistic regression model. Failure on drug was assessed using a Cox proportional hazards regression model. Results: 118 patients (59 males, 59 females) with median age 34.4 years (IQR 27.0–51.4) were included. Median disease duration was 4.3 years (IQR 2.0–9.0) and follow-up 1.27 years (IQR 0.33–4.1). A clinical corticosteroid-free remission was achieved by 38/118 (32.2%) and response by 91/118 (77%) after three months. CRP >3 mg/l at baseline was predictive of short-term failure to reach corticosteroid-free remission. Factors associated with survival on the drug were male gender, CRP <3 mg/l and absence of primary sclerosing cholangitis. Patients >42 years of age at diagnosis were more likely to respond to adalimumab and remain on treatment compared to patients <20 years. Conclusions: An elevated CRP-level, primary sclerosing cholangitis and female gender were predictors of treatment failure. In contrast older age at diagnosis was a predictor of short-term clinical response and drug survival. Prior infliximab failure, regardless of cause, did not influence the outcome of adalimumab treatment.
Cost-effectiveness of a patient-centred approach to managing multimorbidity in primary care: a pragmatic cluster randomised controlled trial

Objective Patients with multiple chronic health conditions are often managed in a disjointed fashion in primary care, with annual review clinic appointments offered separately for each condition. This study aimed to determine the cost-effectiveness of the 3D intervention, which was developed to improve the system of care. Design Economic evaluation conducted alongside a pragmatic cluster-randomised trial. Setting General practices in three centres in England and Scotland. Participants 797 adults with three or more chronic conditions were randomised to the 3D intervention, while 749 participants were randomised to receive usual care. Intervention The 3D approach: comprehensive 6-monthly general practitioner consultations, supported by medication reviews and nurse appointments. Primary and secondary outcome measures The primary economic evaluation assessed the cost per quality-adjusted life year (QALY) gained from the perspective of the National Health Service (NHS) and personal social services (PSS). Costs were related to changes in a range of secondary outcomes (QALYs accrued by both participants and carers, and deaths) in a cost–consequences analysis from the perspectives of the NHS/PSS, patients/carers and productivity losses. Results Very small increases were found in both QALYs (adjusted mean difference 0.007 (−0.009 to 0.023)) and costs (adjusted mean difference £126 (£−739 to £991)) in the intervention arm compared with usual care after 15 months. The incremental cost-effectiveness ratio was £18 499, with a 50.8% chance of being cost-effective at a willingness-to-pay threshold of £20 000 per QALY (55.8% at £30 000 per QALY). Conclusions The small differences in costs and outcomes were consistent with chance, and the uncertainty was substantial; therefore, the evidence for the cost-effectiveness of the 3D approach from the NHS/PSS perspective should be considered equivocal. Trial registration number ISCRTN06180958
Advances in the laboratory diagnosis of prosthetic joint infection

Prosthetic joint implant surgery (arthroplasty) provides restoration of movement to almost half a million people each year in the USA, with major health and economic benefits. While the majority of recipients experience dramatic relief of preoperative pain at the arthroplasty site, some prostheses fail to achieve this result. This is most commonly the result of aseptic biomechanical failure or prosthetic joint infection (PJI), both of which are associated with significant morbidity. Because the management of PJI differs from that of aseptic failure, it is important to accurately differentiate these two entities. Current laboratory methods for diagnosis of PJI depend on isolation of a pathogen by culture from a clinical specimen (e.g., synovial fluid, periprosthetic tissue). However, as PJI is typically a low organism burden and focal infection caused by commensal micro-organisms, these methods have neither ideal sensitivity nor ideal specificity. Therefore, culture-independent molecular methods have been used to improve the diagnosis of PJI. In the research setting, detection of 16S ribosomal DNA (rDNA) by polymerase chain reaction has been the prime focus of the molecular diagnosis of PJI. In this article, advantages and limitations of conventional and molecular methods for the laboratory diagnosis of PJI are reviewed, as is the use of methods that may improve detection of organisms in the biofilm environment. The diagnosis of PJI remains challenging and a rapid, sensitive and specific method is needed for appropriate surgical and medical treatment decisions in the growing arthroplasty population.
Protein and DNA methylation-based scores as surrogate markers for interferon system activation in patients with primary Sjögren’s syndrome

Objective Standard assessment of interferon (IFN) system activity in systemic rheumatic diseases depends on the availability of RNA samples. In this study, we describe and evaluate alternative methods using plasma, serum and DNA samples, exemplified in the IFN-driven disease primary Sjögren’s syndrome (pSS). Methods Patients with pSS seropositive or negative for anti-SSA/SSB and controls were included. Protein-based IFN (pIFN) scores were calculated from levels of PD-1, CXCL9 and CXCL10. DNA methylation-based (DNAm) IFN scores were calculated from DNAm levels at RSAD2, IFIT1 and IFI44L . Scores were compared with mRNA-based IFN scores measured by quantitative PCR (qPCR), Nanostring or RNA sequencing (RNAseq). Results mRNA-based IFN scores displayed strong correlations between B cells and monocytes (r=0.93 and 0.95, p<0.0001) and between qPCR and Nanostring measurements (r=0.92 and 0.92, p<0.0001). The pIFN score in plasma and serum was higher in patients compared with controls (p<0.0001) and correlated well with mRNA-based IFN scores (r=0.62–0.79, p<0.0001), as well as with each other (r=0.94, p<0.0001). Concordance of classification as ‘high’ or ‘low’ IFN signature between the pIFN score and mRNA-based IFN scores ranged from 79.5% to 88.6%, and the pIFN score was effective at classifying patients and controls (area under the curve, AUC=0.89–0.93, p<0.0001). The DNAm IFN score showed strong correlation to the RNAseq IFN score (r=0.84, p<0.0001) and performed well in classifying patients and controls (AUC=0.96, p<0.0001). Conclusions We describe novel methods of assessing IFN system activity in plasma, serum or DNA samples, which may prove particularly valuable in studies where RNA samples are not available.
Show Don’t Tell: Diversity Dishonesty Harms Racial/Ethnic Minorities at Work

Organizations aim to convey that they are diverse and inclusive, in part, to recruit racial minorities. We investigate a previously unexamined downside of this recruitment strategy: diversity dishonesty, that is, belief that an organization is falsely or incorrectly inflating its actual diversity. In four studies (total N = 871), we found that diversity dishonesty heightened minorities’ concerns about fitting in, being authentic, and performing well at the organization. We also found that evidence-based cues (which “show” observers whether the organization has a positive or negative diversity climate), but not expressed cues (which “tell” observers about the organization’s diversity), affect these expectations. Using correlational methodologies, Study 1 found these effects were pertinent to African American and Latinx participants’ beliefs about their current workplaces, holding other diversity-related measures constant. Studies 2 to 4 used experimental methods to replicate these findings with African American participants, using a hypothetical workplace setting.
O-Benzylhydroxylamine (BHA) as a Cleavable Tag for Isolation and Purification of Reducing Glycans

Glycoscience has been recognized as an important area in biomedical research. Currently, a major obstacle for glycoscience study is the lack of diverse, biomedically relevant, and complex glycans in quantities sufficient for exploring their structural and functional aspects. Complementary to chemoenzymatic synthesis, natural glycans could serve as a great source of biomedically relevant glycans if they are available in sufficient quantities. We have recently developed oxidative release of natural glycans (ORNG) for large-scale release of N-glycans as free reducing glycans. While free reducing glycans can be readily derivatized with ultraviolet or fluorescent tags for high-performance liquid chromatography (HPLC) and mass spectrometry (MS) analysis, it is difficult to remove tags for the regeneration of free reducing glycans without affecting the structural integrity of glycans. To address this inconvenience, we explored the use of a cleavable tag, O-benzylhydroxylamine (BHA). Free reducing glycans are easily and efficiently labeled with BHA under mild conditions, enabling UV detection during HPLC purification. Individual glycan–BHA conjugates can then be separated using multidimensional HPLC and characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and MS/MS. The BHA tag can then be easily removed by palladium-on-carbon (Pd/C)-catalyzed hydrogenation to efficiently regenerate free reducing glycans with little effect on glycan structures. This procedure provides a simple and straightforward way to tag free reducing glycans for purification at a preparative scale using multidimensional HPLC and subsequently recover purified free reducing glycans.
A crucial RNA-binding lysine residue in the Nab3 RRM domain undergoes SET1 and SET3-responsive methylation

Abstract The Nrd1–Nab3–Sen1 (NNS) complex integrates molecular cues to direct termination of noncoding transcription in budding yeast. NNS is positively regulated by histone methylation as well as through Nrd1 binding to the initiating form of RNA PolII. These cues collaborate with Nrd1 and Nab3 binding to target RNA sequences in nascent transcripts through their RRM RNA recognition motifs. In this study, we identify nine lysine residues distributed amongst Nrd1, Nab3 and Sen1 that are methylated, suggesting novel molecular inputs for NNS regulation. We identify mono-methylation of one these residues (Nab3-K363me1) as being partly dependent on the H3K4 methyltransferase, Set1, a known regulator of NNS function. Moreover, the accumulation of Nab3-K363me1 is essentially abolished in strains lacking SET3, a SET domain containing protein that is positively regulated by H3K4 methylation. Nab3-K363 resides within its RRM and physically contacts target RNA. Mutation of Nab3-K363 to arginine (Nab3-K363R) decreases RNA binding of the Nab3 RRM in vitro and causes transcription termination defects and slow growth. These findings identify SET3 as a potential contextual regulator of Nab3 function through its role in methylation of Nab3-K363. Consistent with this hypothesis, we report that SET3 exhibits genetic activation of NAB3 that is observed in a sensitized context.