bluuebunny/crossref_metadata_2025 huggingface dataset:
Premedication with corticosteroids does not impact the pharmacokinetics of infliximab in inflammatory bowel disease irrespective of azathioprine cotreatment
Authors: Larsen Lone , Jess Tine , Drewes Asbjørn M. , Dige Anders , Fallingborg Jan , Jacobsen Bent A. , Aagaard Bitten , Agnholt Jørgen
Published: May 2019

Objective

Loss of infliximab (IFX) effect is a clinical challenge in the management of patients with Crohn’s disease (CD), but this can potentially be reduced with azathioprine (AZA) or with corticosteroids (CS). We aimed to study whether CS premedication with or without cotreatment with AZA could reduce antibody formation and affect the IFX elimination rate.

Patients and methods

A cross-sectional observational study was conducted at two centers with CD patients receiving maintenance IFX therapy for 12–18 months. In addition to IFX, patients received either CS premedication or not, with or without concominant AZA.

Results

Fifty-seven patients were included in the study. Thirty-one patients received premedication with CSs, and 11 (35.5%) of these also received AZA, whereas this was the case for 22 of 26 (84.6%) patients in the non-CS group. No difference in IFX trough level (P=0.10) or halftime elimination (P=0.31) was observed with or without CS premedication. Concomitant AZA was associated with significantly longer mean half-life of IFX (P=0.04). Total IFX antibody concentrations were 15.8 and 12.9 with and without CS, respectively, in those not receiving AZA versus 4.3 and 6.1 AU/ml with and without CS, respectively, in those receiving AZA (P=0.004). Premedication with CS did not have any effect on the frequency of antibody formation (P=0.28).

Conclusion

In patients with CD and in maintenance IFX therapy, premedication with CS did not influence antibody formation, IFX trough levels or IFX halftime elimination, irrespective of concomitant AZA use. However, the use of AZA was associated with higher IFX trough levels and lower total IFX antibody concentrations.
Sleep disturbances in HIV-HCV coinfected patients: indications for clinical management in the HCV cure era (ANRS CO13 HEPAVIH cohort)
Authors: Costa Marie , Rojas Teresa Rojas , Lacoste Denis , Villes Virginie , Aumaitre Hugues , Protopopescu Camelia , Yaya Issifou , Wittkop Linda , Krause Jessica , Salmon-Céron Dominique , Marcellin Fabienne , Sogni Philippe , Carrieri Maria P.
Published: May 2019

Objectives

Although common among patients coinfected with HIV and hepatitis C virus (HCV), sleep disturbances (SD) are still poorly documented in this population in the HCV cure era. This longitudinal study aimed at analysing SD in HIV-HCV coinfected patients and identifying their clinical and sociobehavioural correlates.

Methods

We used 5-year annual follow-up data from 1047 participants in the French National Agency for Research on Aids and Viral Hepatitis Cohort 13 ‘Hépatite et VIH’ (ANRS CO13 HEPAVIH) cohort of HIV-HCV coinfected patients to identify clinical (medical records) and behavioural (self-administered questionnaires) correlates of SD (mixed-effects logistic regression). SD were identified using one item documenting the occurrence of insomnia or difficulty falling asleep (ANRS ‘Action Coordonnée 24’ self-reported symptoms checklist), and two items documenting perceived sleep quality (Center for Epidemiologic Studies Depression and WHO Quality of Life HIV-specific brief scales).

Results

Seven hundred and sixteen (68.4%) patients with completed self-administered questionnaires reported SD at their most recent follow-up visit. In the multivariable model, hazardous alcohol consumption (Alcohol Use Disorders Identification Test-Consumption score ≥ 4 for men, ≥ 3 for women) (adjusted odds ratio = 1.61; 95% confidence interval: 1.09–2.36), depressive symptoms (6.78; 4.36–10.55) and the number of other physical and psychological self-reported symptoms (1.10; 1.07–1.13) were associated independently with SD after adjustment for sex, age and employment status. HCV cure was not associated significantly with SD.

Conclusion

SD remain frequent in HIV-HCV coinfected patients and are associated with a series of modifiable behavioural risk factors. Independent of HCV cure, improved screening and comprehensive management of alcohol use, physical and psychological self-reported symptoms and depression are essential in this population. Closer investigation of these risk factors of SDs may both increase sleep quality and indirectly improve patients’ clinical outcomes.
The efficacy comparison of carvedilol plus endoscopic variceal ligation and traditional, nonselective β-blockers plus endoscopic variceal ligation in cirrhosis patients for the prevention of variceal rebleeding: a meta-analysis
Authors: Yang Jiao , Ge Ke , Chen Ling , Yang Jian-Le
Published: May 2019

Background

Currently, the first-line treatment regimen in cirrhotic patients for variceal rebleeding prophylaxis is still under debate.

Aim

This study aimed to compare the efficacy and safety of carvedilol plus endoscopic variceal ligation (EVL) and traditional, nonselective β-blockers (NSBBs) plus EVL in preventing variceal rebleeding.

Patients and methods

Studies were found in PubMed, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Med Online, and Wiper Database. Review Manager 5.3 was used to analyze the relevant data.

Results

Nine trials including 802 patients were identified (402 for carvedilol and 400 for traditional NSBBs). Carvedilol was more efficacious than traditional NSBBs in decreasing the variceal rebleeding rate [odds ratio (OR): 0.53; 95% confidence interval (CI): 0.38–0.75; P = 0.0003], lowering the degree of esophageal varices (OR: 4.40; 95% CI: 2.64–7.34; P < 0.00001), decreasing the mean arterial pressure (standard mean difference: − 0.35; 95% CI: − 0.56 to − 0.14; P = 0.0009), reducing the total adverse events occurrence (OR: 0.39; 95% CI: 0.28–0.53; P < 0.00001), and decreasing drug-related adverse events (OR: 0.37; 95% CI: 0.25–0.56; P < 0.00001). No difference was noted between carvedilol and traditional NSBBs with respect to mortality and heart rate (OR: 0.72; 95% CI: 0.43; 1.22; P = 0.22 and standard mean difference: 0.09; 95% CI: − 0.12 to 0.30; P = 0.40, respectively).

Conclusion

Combined with variceal ligation, carvedilol was more effective and safer than traditional NSBBs in the prevention of rebleeding in cirrhotic patients.
Interventional studies performed in emergency medical communication centres: systematic review
Authors: Reuter Paul-Georges , Chauvin Anthony , Javaud Nicolas , Adnet Frédéric , Lapostolle Frédéric , Yordanov Youri
Published: May 2019

We aimed to both quantitatively and qualitatively describe interventional research performed in emergency medical communication centres. We conducted a systematic review of articles published in MEDLINE, Cochrane Central Register of Controlled Trials and Web of Science. Studies evaluating therapeutic or organizational interventions directed by call centres in the context of emergencies were included. Studies of call centre management for general practice or nonhealthcare agencies were excluded. We assessed general characteristics and methodological information for each study. Quality was evaluated by the Cochrane Risk of Bias tool or the Newcastle-Ottawa Scale. Among 3896 articles screened, we retained 59; 41 studies were randomized controlled trials (69%) and 18 (31%) were before–after studies; 41 (69%) took place in a single centre. For 33 (56%), 22 (37%) and 4 (7%) studies, the models used were simulation training, patient-based or experimental, respectively. The main topic was cardiac arrests (n = 45, 76%), with outcome measures of cardiopulmonary resuscitation quality and dispatch assistance. Among randomized controlled trials, risk of bias was unclear or high for selective reporting for 37 (90%) studies, low for blinding of outcomes for 34 (83%) and low for incomplete outcomes for 31 (76%). Regarding before–after studies, quality was high in 9 (50%) studies. Few interventional studies have been performed in call centres. Studies mainly involved simulation and focussed on cardiac arrest. The quality of studies needs improvement to allow for a better recognition and understanding of emergency medical call control.
Upper Gastrointestinal Endoscopy in Adolescents With Severe Obesity Before Vertical Sleeve Gastrectomy
Authors: Colman Ruben J. , Woo Baidal Jennifer A. , Zitsman Jeffrey L. , Mencin Ali A.
Published: May 2019

Objectives:

Esophagogastroduodenoscopy (EGD) is often performed to evaluate for mucosal and anatomical abnormalities before vertical sleeve gastrectomy (SG). Little is known, however, about how prebariatric EGD in adolescents influences clinical management or outcome. Our aim was to assess if an abnormal prebariatric EGD resulted in interventions or modification of bariatric surgery.

Methods:

We performed a retrospective cohort study of adolescents undergoing evaluation for bariatric surgery. We obtained demographic and anthropometric data in addition to EGD findings, biopsy pathology, gastrointestinal symptoms, and surgical outcomes. An EGD was considered abnormal if either abnormal gross findings or abnormal pathology was reported. Patients were followed until a 6‐week postop visit.

Results:

Of 134 patients presenting for evaluation, 94 (70%) underwent preoperative EGD. Fifty‐one (54%) had a normal EGD and 43 (46%) had EGD abnormalities including 7 with an anatomical abnormality and 36 with mild mucosal abnormalities. Among patients with EGD abnormalities, 22% received medical intervention including proton pump inhibitor (PPI) administration (n = 10) and Helicobacter pylori eradication (n = 11). GI symptoms were the only predictor of EGD abnormalities (odds ratio [OR] 4.9: 95% confidence interval [CI] 1.6–15.0; P < 0.001). No factors predicted likelihood of a post‐EGD intervention. An abnormal EGD did not correlate with any postoperative complications.

Conclusions:

In this cohort of adolescents undergoing evaluation for SG, 46% had an abnormal EGD, of which 22% received a medical intervention. Symptoms were the only predictor of EGD abnormalities. Abnormal EGD findings were not associated with modification of the surgery or any adverse outcome.
Body weight supported treadmill vs. overground gait training for acute stroke gait rehabilitation
Authors: Lura Derek J. , Venglar Mollie C. , van Duijn Arie J. , Csavina Kristine R.
Published: May 2019

The purpose of this study was to evaluate the clinical efficacy of body weight supported treadmill training for acute post-stroke rehabilitation, relative to conventional therapy. Forty individuals were randomized to receive either body weight supported treadmill training or conventional therapy as part of standard care at an acute rehabilitation facility. As part of normal care patients were evaluated using the Functional Independence Measure; gait units and length of stay were also recorded. Within 48 hours of discharge, participants were evaluated using a Qualisys motion capture system to measure spatiotemporal gait parameters. Participants allocated to the body weight supported treadmill training group had a significantly lower admission Functional Independence Measure, but had a longer length of stay, and did not have significantly different discharge Functional Independence Measure scores. Gait speed was the only spatiotemporal outcome that was significantly different at discharge, and was lower for the body weight supported treadmill training group. As seen in previous literature, the clinical efficacy of body weight supported treadmill training seems to be similar to that of conventional overground therapy. Accounting for difference in admission scores the body weight supported treadmill training and conventional therapy groups, both methods performed comparably.
Clinicopathologic Characterization of GREB1-rearranged Uterine Sarcomas With Variable Sex-Cord Differentiation
Authors: Lee Cheng-Han , Kao Yu-Chien , Lee Wan-Ru , Hsiao Yi-Wen , Lu Tzu-Pin , Chu Chia-Ying , Lin Yi-Jia , Huang Hsuan-Ying , Hsieh Tsung-Han , Liu Yun-Ru , Liang Cher-Wei , Chen Tom Wei-Wu , Yip Stephen , Lum Amy , Kuo Kuan-Ting , Jeng Yung-Ming , Yu Shih-Chen , Chung Yung-Chuan , Lee Jen-Chieh
Published: May 2019

Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5′-ESR1/GREB1 and 3′-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, α-inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.
The Prognostic Significance of the 8th Edition TNM Staging of Pulmonary Carcinoid Tumors
Authors: Dermawan Josephine K. , Farver Carol F.
Published: May 2019

Pulmonary carcinoid tumors are an uncommon tumor in the lung, representing <1% to 2% of all primary lung cancers, and have a relatively indolent clinical course. Because of their low incidence, these tumors do not have a specific staging system. However, since the 7th edition, the TNM Classification for Lung Cancer has been used in these tumors, though the ability of this staging classification to predict prognosis in carcinoid tumors is not well-studied. We report the largest single institution study of typical and atypical carcinoid tumors with recurrence as a measure of outcome and compared the ability of the 7th and 8th TNM Classification of Lung Cancer to predict recurrence in typical and atypical carcinoid tumors of the lung. All surgical lung resection cases from 1995 to 2016 with a diagnosis of primary lung carcinoid tumor were reviewed and clinicopathologic parameters, including tumor size, nodal status, histology (mitotic counts), and recurrence were recorded. The final cohort consists of 205 carcinoid tumors: 188 (92%) typical carcinoids and 17 (8%) atypical carcinoids. Pulmonary carcinoid tumors have an excellent prognosis with a low recurrence rate of 8%. Atypical carcinoids were significantly more likely to recur (median time to recurrence: 3 y) compared with typical carcinoids. By placing more emphasis on tumor size and nodal status in the staging classification, the TNM 8th edition was superior in predicting outcome compared with the TNM 7th edition.
Relationship Between Diaphragmatic Electrical Activity and Esophageal Pressure Monitoring in Children*
Authors: Essouri Sandrine , Baudin Florent , Mortamet Guillaume , Beck Jennifer , Jouvet Philippe , Emeriaud Guillaume
Published: May 2019

Objectives:

Mechanical ventilation is an essential life support technology, but it is associated with side effects in case of over or under-assistance. The monitoring of respiratory effort may facilitate titration of the support. The gold standard for respiratory effort measurement is based on esophageal pressure monitoring, a technology not commonly available at bedside. Diaphragmatic electrical activity can be routinely monitored in clinical practice and reflects the output of the respiratory centers. We hypothesized that diaphragmatic electrical activity changes accurately reflect changes in mechanical efforts. The objectives of this study were to characterize the relationship between diaphragmatic electrical activity and esophageal pressure.

Design:

Prospective crossover study.

Setting:

Esophageal pressure and diaphragmatic electrical activity were simultaneously recorded using a specific nasogastric tube in three conditions: in pressure support ventilation and in neurally adjusted ventilatory support in a random order, and then after extubation.

Patients:

Children in the weaning phase of mechanical ventilation.

Interventions:

The maximal swing in esophageal pressure and esophageal pressure-time product, maximum diaphragmatic electrical activity, and inspiratory diaphragmatic electrical activity integral were calculated from 100 consecutive breaths. Neuroventilatory efficiency was estimated using the ratio of tidal volume/maximum diaphragmatic electrical activity.

Measurements and Main Results:

Sixteen patients, with a median age of 4 months (interquartile range, 0.5–13 mo), and weight 5.8 kg (interquartile range, 4.1–8 kg) were included. A strong linear correlation between maximum diaphragmatic electrical activity and maximal swing in esophageal pressure (r
2 > 0.95), and inspiratory diaphragmatic electrical activity integral and esophageal pressure-time product (r
2 > 0.71) was observed in all ventilatory conditions. This correlation was not modified by the type of ventilatory support.

Conclusions:

On a short-term basis, diaphragmatic electrical activity changes are strongly correlated with esophageal pressure changes. In clinical practice, diaphragmatic electrical activity monitoring may help to inform on changes in respiratory efforts.
Does bedtime matter among patients with chronic pain? A longitudinal comparison study
Authors: McHugh R. Kathryn , Edwards Robert R. , Ross Edgar L. , Jamison Robert N.
Published: May 2019

Introduction:

Chronic pain patients frequently report having sleep disturbances and many tend to stay up during the night and then sleep into the day.

Objectives:

This study was designed to compare a heterogeneous group of persons with chronic pain who reported typically going to bed between the hours of 9 pm and midnight with those who go to bed at other hours of the day and night.

Methods:

Two hundred seventy-nine participants were divided between those who reported going to bed between the hours of 9 pm and midnight (N = 205) and those who reported having atypical bedtimes (N = 74) based on pre–post questionnaire data and average pain assessments from a smartphone pain application (app).

Results:

Those individuals in the atypical bedtime group reported waking up more frequently and getting fewer hours sleep (P < 0.05). These individuals also reported significantly higher pain scores, activity interference, and taking more prescription opioid medication compared with those who had typical bedtimes (P < 0.05). Based on average 3-month daily assessments, those subjects with an atypical bedtime consistently reported more sleep disturbances, pain, activity interference, negative mood, and general worsening conditions over time, and elevated pain catastrophizing, pain-related disability, emotional distress scores, and more prescription medication for pain at 3-month follow-up (P < 0.01).

Conclusion:

These results support the importance of providers asking patients with pain about what time they typically go to bed at night to gain a greater understanding of their lifestyle habits. Future studies are needed to further determine the importance of maintaining a typical bedtime among patients with chronic pain.
Loneliness, Living Alone, and All-Cause Mortality: The Role of Emotional and Social Loneliness in the Elderly During 19 Years of Follow-Up
Authors: O'Súilleabháin Páraic S. , Gallagher Stephen , Steptoe Andrew
Published: May 2019

Objective

The aims of the study were to examine the predictive value of social and emotional loneliness for all-cause mortality in the oldest-old who do and do not live alone and to test whether these varied by functional status and personality.

Methods

Participants were 413 older adults from the Berlin Aging Study (M [SD] = 84.53 [8.61] years of age) who either lived alone (n = 253) or did not live alone (n = 160). Significance values for hazard ratios are reported having adjusted for age, sex, education, income, marital status, depressive illness, and both social and emotional loneliness.

Results

Although social loneliness was not associated with mortality in those living alone, emotional loneliness was; with each 1 SD increase in emotional loneliness, there was an 18.6% increased risk of all-cause mortality in the fully adjusted model (HR = 1.186, p = .029). No associations emerged for social or emotional loneliness among those not living alone. Examinations of potential moderators revealed that with each 1 SD increase in functional status, the risk associated with emotional loneliness for all-cause mortality increased by 17.9% (hazard ratiointeraction = 1.179, p = .005) in those living alone. No interaction between personality traits with loneliness emerged.

Conclusions

Emotional loneliness is associated with an increased risk of all-cause mortality in older adults who live alone. Functional status was identified as one potential pathway accounting for the adverse consequences of loneliness. Emotional loneliness that can arise out of the loss or absence of a close emotional attachment figure seems to be the toxic component of loneliness.
Perioperative Complications in Minimally Invasive Sacrocolpopexy Versus Transvaginal Mesh in the Management of Pelvic Organ Prolapse: Analysis of a National Multi-institutional Dataset
Authors: Kisby Cassandra K. , Occhino John A. , Bews Katherine A. , Habermann Elizabeth B. , Linder Brian J.
Published: May 2019

Objectives

The objective of this study was to evaluate perioperative complications in women who underwent minimally invasive sacrocolpopexy (MISC) versus mesh-augmented vaginal repair (vaginal mesh) for pelvic organ prolapse.

Methods

We identified patients undergoing MISC and vaginal mesh via Current Procedural Terminology codes from the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2016. Those undergoing concomitant hysterectomy were excluded. Univariate analyses were performed to compare baseline characteristics and 30-day complications. Multivariable logistic regression models were constructed to assess the association between surgical approach and complications, prolonged hospitalization, reoperation, and blood transfusion. A multivariable Cox proportional hazard model was used to evaluate hospital readmission.

Results

A total of 5722 patients were identified (2573 MISC [45%], 3149 vaginal mesh [55%]). Those undergoing MISC repairs had a significantly lower rate of urinary tract infection (3.1 vs 4.2%; P = 0.03) and blood transfusion (0.5 vs 1.4%; P < 0.001). There was no difference in reoperation rate (1.3 vs 1.6%; P = 0.35). Multivariable analysis showed no significant association of MISC with overall (odds ratio [OR], 0.91; P = 0.44), major (OR, 1.30; P = 0.31), or minor complication (OR, 0.85; P = 0.26). There were lower odds of receiving a blood transfusion (OR, 0.44; P = 0.02) and higher odds of prolonged hospitalization (>2 days; OR, 1.47; P = 0.003) for the MISC group. There was no difference in reoperation (OR, 0.79; P = 0.38) or hospital readmissions (hazard ratio, 1.25, P = 0.32).

Conclusions

Minimally invasive sacrocolpopexy was associated with a lower rate of blood transfusion than transvaginal mesh placement. There was no significant difference in 30-day complication rates, reoperation, or readmission between these prolapse procedures when performed without concomitant hysterectomy.
Size and structure of the sequence space of repeat proteins
Authors: Marchi Jacopo , Galpern Ezequiel A. , Espada Rocio , Ferreiro Diego U. , Walczak Aleksandra M. , Mora Thierry
Published: May 2019

The coding space of protein sequences is shaped by evolutionary constraints set by requirements of function and stability. We show that the coding space of a given protein family —the total number of sequences in that family— can be estimated using models of maximum entropy trained on multiple sequence alignments of naturally occuring amino acid sequences. We analyzed and calculated the size of three abundant repeat proteins families, whose members are large proteins made of many repetitions of conserved portions of ∼30 amino acids. While amino acid conservation at each position of the alignment explains most of the reduction of diversity relative to completely random sequences, we found that correlations between amino acid usage at different positions significantly impact that diversity. We quantified the impact of different types of correlations, functional and evolutionary, on sequence diversity. Analysis of the detailed structure of the coding space of the families revealed a rugged landscape, with many local energy minima of varying sizes with a hierarchical structure, reminiscent of fustrated energy landscapes of spin glass in physics. This clustered structure indicates a multiplicity of subtypes within each family, and suggests new strategies for protein design.
RNA strand invasion activity of the Polycomb complex PRC2
Authors: Alecki Célia , Chiwara Victoria , Sanz Lionel A. , Grau Daniel , Pérez Osvaldo Arias , Armache Karim-Jean , Chédin Fréderic , Francis Nicole J.
Published: May 2019

Epigenetic regulation is conveyed through information encoded by specific chromatin features. Non-canonical nucleic acid structures could in principle also convey biological information but their role(s) in epigenetic regulation is not known. Polycomb Group (PcG) proteins form memory of transient transcriptional repression events that is necessary for development. In Drosophila, PcG proteins are recruited to specific DNA sequences, Polycomb Response Elements (PREs). PREs are switchable memory elements that can exist in repressed, active, or unengaged states 1,2. How PcG activities are targeted to PREs to maintain repressed states only in appropriate developmental contexts has been difficult to elucidate. Biochemically, PcG protein complexes modify chromatin to maintain gene repression 1,3,4. However, PcG proteins also interact with both RNA and DNA, and RNA is implicated in the targeting of PcG function. We find that R-loops, three-stranded nucleic acid structures formed when an RNA hybridizes to its complementary DNA and displaces the other DNA strand 5, form at many PREs in Drosophila embryos, and correlate with the repressive state. R-loops are recognized by the PcG complex PRC1 in vitro. Unexpectedly, we find that the PcG complex PRC2 has RNA strand invasion activity, which can drive formation of RNA-DNA hybrids, the key component of R-loops. Our results suggest a new mechanism for targeting PcG function through R-loop formation by PRC2 and recognition by PRC1. More generally, our findings suggest formation and recognition 6 of non-canonical nucleic acid structures as an epigenetic mechanism.
Loss of F-box Motif Encoding Gene SAF1 and RRM3 Together Leads to Synthetic Growth Defect and Sensitivity to HU, MMS inS.cerevisiae
Authors: Sharma Meenu , Verma V. , Bairwa Narendra K
Published: May 2019

Unearthing of novel genetic interaction which leads to synthetic growth defects due to inactivation of genes are needed for applications in precision medicine. The genetic interactions among the molecular players involving different biological pathways need to be investigated. The SAF1 gene ofS.cerevisiaeencodes for a protein product which contain N-terminal F-box motif and C-terminal RCC1 domain. The F-box motif interacts with Skp1subunit of the SCF-E3 ligase and C-terminus with Aah1 (adenine deaminase) for ubiquitination and subsequent degradation by 26S proteasome during phase transition from proliferation state to quiescence phase due to nutrient limitation stress. The replication fork associated protein Rrm3 ofS.cerevisiaebelongs to Pif1 family helicase and function in removal of the non-histone proteins during replication fork movement. Here we have investigated the genetic interaction among both the genes (SAF1 and RRM3) and their role in growth fitness and genome stability. The single and double gene knockout strains of SAF1and RRM3 genes was constructed in BY4741 genetic background and checked for the growth fitness in presence of genotoxic stress causing agents such as hydroxyurea and methyl methanesulfonate. The strains were also evaluated for nuclear migration defect by DAPI staining and for HIS3AI marked Ty1 retro-transposition. Thesaf1Δrrm3Δshowed the extremely slow growth phenotype in rich medium and sensitivity to genotoxic agents such as HU and MMS in comparison to single gene mutant (saf1Δ,rrm3Δ) and WT cells. Thesaf1Δrrm3Δalso showed the defects in nuclear migration as evident by multi-nuclei phenotype. Thesaf1Δrrm3Δalso showed the elevated frequency of Ty1 retro-transposition in JC2326 background in comparison to eithersaf1Δ or rrm3Δ. Based on these observations we report that thatSAF1 and RRM3 functions in parallel pathway for growth fitness and stability of the genome.
Quantitative analysis of ZFY and CTCF reveals dependent recognition of tandem zinc finger proteins
Authors: Zuo Zheng , Billings Timothy , Walker Michael , Petkov Petko M. , Stormo Gary D. , Fordyce Polly M.
Published: May 2019

The human genome contains around 800 C2H2 Zinc Finger Proteins (ZFPs), and many of them are composed of long tandem arrays of zinc fingers. Current motif prediction models assume longer finger arrays correspond to longer DNA-binding motifs and higher specificity. However, recent experimental efforts to identify ZFP binding sitesin vivocontradict this assumption, with many having short motifs. Here, we systematically test how multiple zinc fingers contribute to binding for three model ZFPs: Zinc Finger Y (ZFY), CTCF, and ZNF343. Using ZFY, which contains 13 fingers, we quantitatively characterize its binding specificity with several methods, including Affinity-seq, HT-SELEX, Spec-seq and fluorescence anisotropy, and find evidence for ‘dependent recognition’ where downstream fingers can recognize some extended motifs only in the presence of an intact core site. For the genomic insulator CTCF, additional high-throughput affinity measurements reveal that its upstream specificity profile depends on the strength of the core, violating presumed additivity and positionindependence. Moreover, the effect of different epigenetic modifications within the core site depends on the strength of flanking upstream site, providing new insight into how the previously identified intellectual disability-causing and cancer-related mutant R567W disrupts upstream recognition and deregulates CTCF’s methylation sensitivity. Lastly, we used ZNF343 as example to show that a simple iterative motif analysis strategy based on a small set of prefixed cores can reveal the dependent relationship between cores and upstream motifs. These results establish that the current underestimation of ZFPs motif lengths is due to our lack of understanding of intrinsic properties of tandem zinc finger recognition, including irregular motif structure, variable spacing, and dependent recognition between sub-motifs. These results also motivate a need for better recognition models beyond additive, position-weight matrix to predict ZFP specificities, occupancies, and the molecular mechanisms of disease mutations.
Gene-experience correlation during cognitive development: Evidence from the Adolescent Brain Cognitive Development (ABCD) StudySM
Authors: Loughnan Robert J. , Palmer Clare E. , Thompson Wesley K. , Dale Anders M. , Jernigan Terry L. , Fan Chun Chieh
Published: May 2019

Background

Findings in adults have shown more culturally sensitive ‘crystallized’ measures of intelligence have greater heritability, these results were not able to be shown in children.

Methods

With data from 8,518 participants, aged 9 to 11, from the Adolescent Brain Cognitive Development (ABCD) Study®, we used polygenic predictors of intelligence test performance (based on genome-wide association meta-analyses of data from 269,867 individuals) and of educational attainment (based on data from 1.1 million individuals), associating these predictors with neurocognitive performance. We then assessed the extent of mediation of these associations by a measure of recreational reading.

Results

more culturally sensitive ‘crystallized’ measures were more strongly associated with the polygenic predictors than were less culturally sensitive ‘fluid’ measures. This mirrored heritability differences reported previously in adults and suggests similar associations in children. Recreational reading more strongly statistically mediated the genetic associations with crystallized than those with fluid measures of cognition.

Conclusion

This is consistent with a prominent role of gene-environment correlation in cognitive development measured by “crystallized” intelligence tests. Such experiential mediators may represent malleable targets for improving cognitive outcomes.
Ablation of tanycytes of the arcuate nucleus and median eminence increases visceral adiposity and decreases insulin sensitivity in male mice
Authors: Yoo Sooyeon , Cha David , Kim Soohyun , Jiang Lizhi , Adebesin Mobolanie , Wolfe Andrew , Riddle Ryan , Aja Susan , Blackshaw Seth
Published: May 2019

Tanycytes are radial glial cells located in the mediobasal hypothalamus. Recent studies have proposed that tanycytes play an important role in hypothalamic control of energy homeostasis, although this has not been directly tested. Here, we report the phenotype of mice in which tanycytes of the arcuate nucleus and median eminence were conditionally ablated. Although the CSF-hypothalamic barrier was rendered more permeable, the blood-hypothalamic barrier was not altered. The metabolic effects of tanycyte ablation were likewise moderate. However, we consistently observed a significant increase in visceral fat distribution accompanying insulin insensitivity, but only in male mice, and without an effect on either body weight or food intake. A high-fat diet accelerated overall body weight gain in tanycyte-ablated mice, but the development of visceral adiposity and insulin insensitivity was attenuated. These results clarify the extent to which tanycytes regulate energy metabolism, and indicate a role for tanycytes in controlling body adiposity.
Clinical Efficacy and Adverse Effects of Antibiotics Used to Treat Mycobacterium abscessus Pulmonary Disease
Authors: Chen Jianhui , Zhao Lan , Mao Yanhua , Ye Meiping , Guo Qi , Zhang Yongjie , Xu Liyun , Zhang Zhemin , Li Bing , Chu Haiqing
Published: May 2019

Treatment of Mycobacterium abscessus pulmonary infection requires long-term administration of multiple antibiotics. Little is known, however, about the impact of each antibiotic on treatment outcomes. A retrospective analysis was conducted to evaluate the efficacy and adverse effects of antibiotics administered in 244 cases of M. abscessus pulmonary disease. Only 110 (45.1%) patients met the criteria for treatment success. Treatment with amikacin (AOR, 3.275; 95% CI, 1.221 - 8.788), imipenem (AOR, 2.078; 95% CI, 1.151 - 3.753), linezolid (AOR, 2.231; 95% CI, 1.078 - 4.616) and tigecycline (AOR, 2.040; 95% CI, 1.079 - 3.857) was successful. The incidence of adverse effects was high (192/244, 78.7%). Severe adverse effects were primarily: ototoxicity (14/60, 23.3%) caused by amikacin; gastrointestinal (14/60, 23.3%) caused by tigecycline; and myelosuppression (5/60, 8.3%) caused by linezolid. In conclusion, the rate of success in treating M. abscessus pulmonary disease is still unsatisfactory; the administration of amikacin, imipenem, linezolid and tigecycline correlated with increased treatment success. Adverse side effects are common due to the long-term and combined antibiotic therapy. Ototoxicity, gastrointestinal and myelosuppression are the most severe.
Nutritional Immunity and Antibiotic Drug Treatments Influence Microbial Composition but Fail to Eliminate Urethral Catheter Biofilms in Recurrently Catheterized Patients
Authors: Yu Yanbao , Singh Harinder , Tsitrin Tamara , Kwon Keehwan , Bekele Shiferaw , Eguez Rodrigo V. , Lin Yi-Han , Sikorski Patricia , Moncera Kelvin J. , Torralba Manolito G. , Morrow Lisa , Wolcott Randall , Nelson Karen E. , Pieper Rembert
Published: May 2019

Polymicrobial biofilms that form on indwelling urethral catheters used by neurogenic bladder patients are known to recur following catheter replacements. Uropathogens dominate in catheter biofilms (CBs), grow and disperse as multi-cellular aggregates. Their microbial complexity, the characteristics of host immune responses and the molecular crosstalk in this ecosystem are incompletely understood. By surveying eight patients over up to six months with meta-omics analysis methods, we shed new light on the longitudinal microbial dynamics in CBs and the microbial-host crosstalk. There was evidence of chronic innate immune responses in all patients. Pathogens dominated the microbial contents.Proteus mirabilisoften out-competed other species in cases of salt encrustation of catheters. The examination of proteomes in CBs and associated urinary pellets revealed many abundant bacterial systems for transition metal ion (TMI) acquisition. TMIs are sequestered by effector proteins released by activated neutrophils and urothelial cells, such as lactotransferrin and calgranulins, which were abundant in the host proteomes. We identified positive quantitative correlations among systems responsible for siderophore biosynthesis, TMI/siderophore uptake and TMI cellular import in bacterial species, suggesting competition for TMIs to support their metabolism and growth in CBs.Enterococcus faecaliswas prevalent as a cohabitant of CBs and expressed three lipoproteins with apparent TMI acquisition functions. Fastidious anaerobic bacteria such asVeillonella,Actinobaculum, andBifidobacteriumgrew in CB communities that appeared to be oxygen starved. Finally, antibiotic drug treatments were shown to influence microbial composition of CBs but failed to prevent re-colonization of urethral catheters with persisting and/or drug-resistant newly emerging pathogens.
A microparticulate based formulation to protect therapeutic enzymes from proteolytic digestion: phenylalanine ammonia lyase as case study
Authors: de Sousa Irene Pereira , Gourmel Charlotte , Berkovska Olena , Burger Michael , Leroux Jean-Christophe
Published: May 2019

Phenylketonuria is a genetic disorder affecting the metabolism of phenylalanine (phe) due to a deficiency in the enzyme phenylalanine hydroxylase. This disorder is characterized by an elevated phe blood level, which can lead to severe intellectual disabilities in newborns. The current strategy to prevent these devastating consequences is limited to a life-long phe-free diet, which implies major lifestyle changes and restrictions. Recently, an injectable enzyme replacement therapy, Pegvaliase, has been approved for treating phenylketonuria, but is associated with significant side-effects. In this study a phe-metabolizing system suitable for oral delivery is designed to overcome the need for daily injections. Active phenylalanine ammonia-lyase (PAL), an enzyme that catalyzes phe metabolism, is loaded into mesoporous silica microparticles (MSPs) with pore sizes ranging from 10 to 35 nm. The surface of the MSPs is lined with a semipermeable barrier to allow permeation of phe while blocking digestive enzymes that degrade PAL. The enzymatic activity can be partially preserved in vitro by coating the MSPs with poly(allylamine) and poly(acrylic acid)-bowman birk (protease inhibitor) conjugate. The carrier system presented herein may provide a general approach to overcome gastro-intestinal proteolytic digestion and to deliver active enzymes to the intestinal lumen for prolonged local action.
Chromatin accessibility established by Pou5f3, Sox19b and Nanog primes genes for activity during zebrafish genome activation
Authors: Pálfy Máté , Schulze Gunnar , Valen Eivind , Vastenhouw Nadine L.
Published: May 2019

In many organisms, early embryonic development is driven by maternally provided factors until the controlled onset of transcription during zygotic genome activation. The regulation of chromatin accessibility and its relationship to gene activity during this transition remains poorly understood. Here, we generated chromatin accessibility maps from genome activation until the onset of lineage specification. During this period, chromatin accessibility increases at regulatory elements. This increase is independent of RNA polymerase II-mediated transcription, with the exception of the hyper-transcribed miR-430 locus. Instead, accessibility often precedes the transcription of associated genes. Loss of the maternal transcription factors Pou5f3, Sox19b, and Nanog, which are known to be required for zebrafish genome activation, results in decreased accessibility at regulatory elements. Importantly, the accessibility of regulatory regions, especially when established by Pou5f3, Sox19b and Nanog, is predictive for future transcription. Our results show that the maternally provided transcription factors Pou5f3, Sox19b, and Nanog open up chromatin and prime genes for activity during zygotic genome activation in zebrafish.
Spatial and semantic regularities produce interactive effects in early stages of visual orientation
Authors: Notaro Giuseppe , Hasson Uri
Published: May 2019

Learning environmental regularities allows predicting multiple dimensions of future events such as their location and semantic features. However, few studies have examined how multi-dimensional predictions are implemented, and mechanistic accounts are absent. Using eye tracking study, we evaluated whether predictions of object-location and object-category interact during the earliest stages of orientation. We presented stochastic series so that across four conditions, participants could predict either the location of the next image, its semantic category, both dimensions, or neither. Participants observed images in absence of any task. We modeled saccade latencies using ELATER, a rise-to-threshold model that accounts for accumulation rate (AR), variance of AR over trials, and decision threshold. The main findings were: 1) accumulation-rate scaled with the degree of surprise associated with location of target-presentation (confirmatory result); 2) predictability of semantic-category hindered latencies, but only when images were presented at a surprising location, suggesting a bottleneck in implementing joint predictions; 3) saccades to images that satisfied semantic expectations were associated with larger variance of accumulation-rate than saccades to semantically-surprising images, consistent with a richer repertoire of early evaluative processes for semantically-expected images. Joint impacts of location and target-identity regularity were also identified in analyses of anticipatory fixation offsets. The results indicate a strong interaction between the processing of regularities in object location and identity during stimulus-guided saccades, and suggest these regularities also impact anticipatory, non-stimulus-guided processes.
Cerebral oxygenation during locomotion is modulated by respiration
Authors: Zhang Qingguang , Roche Morgane , Gheres Kyle W. , Chaigneau Emmanuelle , Haselden William D. , Charpak Serge , Drew Patrick J.
Published: May 2019

In the brain, increased neural activity is correlated with an increase of cerebral blood flow and increased tissue oxygenation. However, how cerebral oxygen dynamics are controlled in the behaving animals remains unclear. Here, we investigated to what extent the cerebral oxygenation varies during natural behaviors that change the whole-body homeostasis, specifically exercise. We measured oxygen levels in the cortex of awake, head-fixed mice during locomotion using polarography, spectroscopy, and two-photon phosphorescence lifetime measurements of oxygen sensors. We found that locomotion significantly and globally increases cerebral oxygenation, specifically in areas involved in locomotion, as well as in the frontal cortex and the olfactory bulb. The oxygenation increase persisted when neural activity and functional hyperemia were blocked, occurred both in the tissue and in arteries feeding the brain, and was tightly correlated with respiration rate and the phase of respiration cycle. Thus, respiration provides a dynamic pathway for modulating cerebral oxygenation.
Integrins control tissue morphogenesis and homeostasis by sustaining the different types of intracellular actin networks
Authors: Mateos Carmen Santa-Cruz , Valencia-Expósito Andrea , Míguez David G. , Palacios Isabel M. , Martín-Bermudo María D.
Published: May 2019

Forces generated by the actomyosin cytoskeleton are key contributors to the generation of tissue shape. Within the cell, the actomyosin cytoskeleton organizes in different types of networks, each of them performing distinct roles. In addition, although they normally localize to precise regions of the cells, they are rarely independent and often their dynamics influence each other. In fact, the reorganization of a given structure can promote the formation of another, conversions that govern many morphogenetic processes. In addition, maintenance of a specific actomyosin network organization in a differentiated tissue might be equally important. Failure to do so could lead to undesired cell state transitions, which in turn would have drastic consequences on the homeostasis of the tissue. Still, little is known about the mechanisms that ensure controlled transitions between actomyosin networks during morphogenesis or their maintenance in a differentiated tissue. Here, we use theDrosophilafollicular epithelium to show that cell-ECM interactions mediated by integrins are necessary for the establishment and maintenance of the different actomyosin networks present in these epithelial cells. Elimination of integrins in a group of follicle cells results in changes in the F-actin levels and physical properties of their intracellular actomyosin networks. Integrin mutant follicle cells have reduced number of basal stress fibers. They also show increased cortical F-actin levels and tension, which interferes with proper basal surface growth. Finally, clonal elimination of integrins also triggers non-autonomous behavioural changes in neighbouring wild types cells, which now reorganize their actin cytoskeleton and spread and overlay the mutant ones. Based on these results, we propose that cell-ECM interactions mediated by integrins regulate epithelia morphogenesis and homesostasis by preserving the different types of intracellular actin networks.