Exploiting gene deletion fitness effects in yeast to understand the modular architecture of protein complexes under different growth conditions

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Understanding how individual genes contribute towards the fitness of an organism is a fundamental problem in biology. Although recent genome-wide screens have generated abundant data on quantitative fitness for single gene knockouts, very few studies have systematically integrated other types of biological information to understand how and why deletion of specific genes give rise to a particular fitness effect. In this study, we combine quantitative fitness data for single gene knock-outs in yeast with large-scale interaction discovery experiments to understand the effect of gene deletion on the modular architecture of protein complexes, under different growth conditions. Results Our analysis reveals that genes in complexes show more severe fitness effects upon deletion than other genes but, in contrast to what has been observed in binary protein-protein interaction networks, we find that this is not related to the number of complexes in which they are present. We also find that, in general, the core and attachment components of protein complexes are equally important for the complex machinery to function. However, when quantifying the importance of core and attachments in single complex variations, or isoforms, we observe that this global trend originates from either the core or the attachment components being more important for strain fitness, both being equally important or both being dispensable. Finally, our study reveals that different isoforms of a complex can exhibit distinct fitness patterns across growth conditions. Conclusion This study presents a powerful approach to unveil the molecular basis for various complex phenotypic profiles observed in gene deletion experiments. It also highlights some interesting cases of potential functional compensation between protein paralogues and suggests a new piece to fit into the histone-code puzzle.Published versio

Swiss Validation of the Enhanced Recovery After Surgery (ERAS) Database.

Enhanced recovery after surgery (ERAS) pathways have considerably improved postoperative outcomes and are in use for various types of surgery. The prospective audit system (EIAS) could be a powerful tool for large-scale outcome research but its database has not been validated yet. Swiss ERAS centers were invited to contribute to the validation of the Swiss chapter for colorectal surgery. A monitoring team performed on-site visits by the use of a standardized checklist. Validation criteria were (I) coverage (No. of operated patients within ERAS protocol; target threshold for validation: ≥ 80%), (II) missing data (8 predefined variables; target ≤ 10%), and (III) accuracy (2 predefined variables, target ≥ 80%). These criteria were assessed by comparing EIAS entries with the medical charts of a random sample of patients per center (range 15-20). Out of 18 Swiss ERAS centers, 15 agreed to have onsite monitoring but 13 granted access to the final dataset. ERAS coverage was available in only 7 centers and varied between 76 and 100%. Overall missing data rate was 5.7% and concerned mainly the variables "urinary catheter removal" (16.4%) and "mobilization on day 1" (16%). Accuracy for the length of hospital stay and complications was overall 84.6%. Overall, 5 over 13 centers failed in the validation process for one or several criteria. EIAS was validated in most Swiss ERAS centers. Potential patient selection and missing data remain sources of bias in non-validated centers. Therefore, simplified validation of other centers appears to be mandatory before large-scale use of the EIAS dataset

Correlation of postoperative fluid balance and weight and their impact on outcomes.

Normovolemia after major surgery is critical to avoid complications. The aim of the present study was to analyze correlation between fluid balance, weight gain, and postoperative outcomes. All consecutive patients undergoing elective or emergency major abdominal surgery needing intermediate care unit (IMC) admission from September 2017 to January 2018 were included. Postoperative fluid balances and daily weight changes were calculated for postoperative days (PODs) 0-3. Risk factors for postoperative complications (30-day Clavien) and prolonged length of IMC and hospital stay were identified through uni- and multinominal logistic regression. One hundred eleven patients were included, of which 55% stayed in IMC beyond POD 1. Overall, 67% experienced any complication, while 30% presented a major complication (Clavien ≥ III). For the entire cohort, median cumulative fluid balance at the end of PODs 0-1-2-3 was 1850 (IQR 1020-2540) mL, 2890 (IQR 1610-4000) mL, 3890 (IQR 2570-5380) mL, and 4000 (IQR 1890-5760) mL respectively, and median weight gain was 2.2 (IQR 0.3-4.3) kg, 3 (1.5-4.7) kg, and 3.9 (2.5-5.4) kg, respectively. Fluid balance and weight course showed no significant correlation (r = 0.214, p = 0.19). Extent of surgery, analyzed through Δ albumin and duration of surgery, significantly correlated with POD 2 fluid balances (p = 0.04, p = 0.006, respectively), as did POD 3 weight gain (p = 0.042). Prolonged IMC stay of ≥ 3 days was related to weight gain ≥ 3 kg at POD 2 (OR 2.8, 95% CI 1.01-8.9, p = 0.049). Fluid balance and weight course showed only modest correlation. POD 2 weight may represent an easy and pragmatic tool to optimize fluid management and help to prevent fluid-related postoperative complications

Preoperative Nutritional Conditioning of Crohn's Patients-Systematic Review of Current Evidence and Practice.

Crohn's disease is an incurable and frequently progressive entity with major impact on affected patients. Up to half of patients require surgery in the first 10 years after diagnosis and over 75% of operated patients require at least one further surgery within lifetime. In order to minimize surgical risk, modifiable risk factors such as nutritional status need to be optimized. This systematic review on preoperative nutritional support in adult Crohn's patients between 1997 and 2017 aimed to provide an overview on target populations, screening modalities, routes of administration, and expected benefits. Pertinent study characteristics (prospective vs. retrospective, sample size, control group, limitations) were defined a priori. Twenty-nine studies were retained, of which 14 original studies (9 retrospective, 4 prospective, and 1 randomized controlled trial) and 15 reviews. Study heterogeneity was high regarding nutritional regimens and outcome, and meta-analysis could not be performed. Most studies were conducted without matched control group and thus provide modest level of evidence. Consistently, malnutrition was found to be a major risk factor for postoperative complications, and both enteral and parenteral routes were efficient in decreasing postoperative morbidity. Current guidelines for nutrition in general surgery apply also to Crohn's patients. The route of administration should be chosen according to disease presentation and patients' condition. Further studies are needed to strengthen the evidence

Methodological assessment of HCC literature

Despite the fact that the hepatocellular carcinoma (HCC) represents a major health problem, very few interventions are available for this disease, and only sorafenib is approved for the treatment of advanced disease. Of note, only very few interventions have been thoroughly evaluated over time for HCC patients compared with several hundreds in other, equally highly lethal, tumours. Additionally, clinical trials in HCC have often been questioned for poor design and methodological issues. As a consequence, a gap between what is measured in clinical trials and what clinicians have to face in daily practice often occurs. As a result of this scenario, even the most recent guidelines for treatment of HCC patients use low strength evidence to make recommendations. In this review, we will discuss some of the potential methodological issues hindering a rational development of new treatments for HCC patient

Pressurized IntraPeritoneal Aerosol Chemotherapy - Practical aspects.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) has been introduced as novel treatment for peritoneal carcinomatosis. Only proper patient selection, stringent safety protocol and careful surgery allow for a secure procedure. We hereby report the essentials for safe implementation. All consecutive procedures within 20 months after PIPAC implementation were analyzed with regards to practical and surgical aspects. Special emphasis was laid on modifications of technique and safety measures during the implementation process with systematic use of a dedicated checklist. Further, surgical difficulty was documented by use of a visual analogue scale (VAS). 127 PIPAC procedures were performed in 58 patients from January 2015 until October 2016. 81% of patients had at least one previous laparotomy. Median operation time was 91 min (87-103) for the first 20 cases, 93 min (IQR 88-107) for PIPAC21-50, and 103 min (IQR 91-121) for the following 77 procedures. Primary and secondary non-access occurred in 3 patients (2%), all of them having prior hyperthermic intraperitoneal chemotherapy (HIPEC). Using open Hasson technique, one single bowel lesion occurred, which was the only intraoperative complication. One 5 mm and another 10/12 mm trocar were used in 88% of procedures while additional trocars were needed in 12%. No leak of cytostatics was observed and no procedure needed to be stopped. VAS for overall difficulty of the procedure was 3 ± 2.4, and 3 ± 2.9 and 3 ± 2.5, respectively, for abdominal access and intraoperative staging. With standardized surgical approach and dedicated safety checklist, PIPAC can be safely introduced in clinical routine with minimal learning curve

Influencia de las características petrofísicas en la penetración de consolidantes en rocas monumentales porosas

This paper describes a study of the penetration capacity of a consolidant frequently used in restoration —ethyl silicate— applied to two monumental stones with different porosities and pore geometries: the Hontoria limestone (Burgos) and the Laspra dolomite (Asturias). The relation between mode of application and penetration into the rock, and changes in porosity and pore geometry in the treated rocks, are discussed. Mercury porosimetry has been employed to measure both the depth of penetration of the treatment and its influence on the void spaces in the rock. The results obtained reveal that the most porous rock is not always that which most easily admits the treatment solution, and that the penetration of a treatment product is also influenced by the petrophysical properties of the rock.En este trabajo se estudia la capacidad de penetración de un tratamiento consolidante, de uso frecuente en restauración —silicato de etilo—, aplicado a dos rocas monumentales con porosidades y configuraciones del sistema poroso diferentes; la caliza de Hontoria (Burgos) y la dolomía de Laspra (Asturias). Se pretende tener una idea precisa de las relaciones entre: modo de aplicación del producto, profundidad de penetración y cambios inducidos en la porosidad y configuración del sistema poroso de las rocas mencionadas. La técnica empleada para controlar, tanto la profundidad de penetración del tratamiento, como su influencia en los espacios vacíos de la piedra, ha sido la porosimetría de mercurio. Los resultados obtenidos revelan que no siempre la roca más porosa es la que mejor admite el tratamiento, y que la penetración de un producto de este tipo en la roca, está condicionada también por las características petrofísicas de la misma