Correlation of gene expression and protein production rate - a system wide study

<p>Abstract</p> <p>Background</p> <p>Growth rate is a major determinant of intracellular function. However its effects can only be properly dissected with technically demanding chemostat cultivations in which it can be controlled. Recent work on <it>Saccharomyces cerevisiae </it>chemostat cultivations provided the first analysis on genome wide effects of growth rate. In this work we study the filamentous fungus <it>Trichoderma reesei </it>(<it>Hypocrea jecorina</it>) that is an industrial protein production host known for its exceptional protein secretion capability. Interestingly, it exhibits a low growth rate protein production phenotype.</p> <p>Results</p> <p>We have used transcriptomics and proteomics to study the effect of growth rate and cell density on protein production in chemostat cultivations of <it>T. reesei</it>. Use of chemostat allowed control of growth rate and exact estimation of the extracellular specific protein production rate (SPPR). We find that major biosynthetic activities are all negatively correlated with SPPR. We also find that expression of many genes of secreted proteins and secondary metabolism, as well as various lineage specific, mostly unknown genes are positively correlated with SPPR. Finally, we enumerate possible regulators and regulatory mechanisms, arising from the data, for this response.</p> <p>Conclusions</p> <p>Based on these results it appears that in low growth rate protein production energy is very efficiently used primarly for protein production. Also, we propose that flux through early glycolysis or the TCA cycle is a more fundamental determining factor than growth rate for low growth rate protein production and we propose a novel eukaryotic response to this i.e. the lineage specific response (LSR).</p

Coarctation of the aorta in infants under one year of age: an analysis of 20 years of experience

Objetivo Revisão da experiência com diversas técnicas de correção empregadas, nos últimos 20 anos, em crianças menores de um ano de idade. Métodos No período de 1978 a 1998, foram operados 148 pacientes (pc) consecutivos com coartação de aorta (CoAo) com até um ano de idade, com ou sem defeitos intracardíacos associados. A idade apresentou mediana de 50 dias, 92 pc do sexo feminino (62,1%). O peso foi de 4.367±1.897 gramas. O seguimento foi em média de 1.152±1.462 dias. A população foi dividida em 3 grupos: Grupo I, CoAo isolada: 74 pc (50%); Grupo II, CoAo e comunicação interventricular (CIV): 41 pacientes (27,7%) e Grupo III, CoAo com malformações complexas: 33 pc (22,3%). Resultados Mortalidade total foi 43 pc (29%): com menos de 30 dias, foi 53%, p=0,009, OR=4,5, entre 31 e 90 dias, foi 14,7%, p=0,69, e acima de 91 dias, 15%, p=0,004. A probabilidade de sobrevida atuarial de toda a população foi de 67% aos 5 e 10 anos. Trinta e seis pacientes (24,3%) recoartaram, dos quais 18 pacientes (50%) tinham menos de 30 dias, OR=6,35. A incidência de recoartação foi com a técnica de Waldhausen em 4 pacientes (10%) e com a término-terminal clássica em 19 pacientes (26%) p=0.03, e a istmoplastia em 6 pacientes (37,5%). A probabilidade de sobrevida atuarial livre de recoartação aos 5 e 10 anos foi de 69% com a técnica de Waldhausen e 63% com a técnica término-terminal clássica. Conclusão Pacientes com menos de 30 dias apresentaram risco aumentado de mortalidade e recoartação. A técnica de Waldhausen em pacientes com mais de 30 dias mostrou-se efetiva. A técnica términoterminal clássica mostrou não ser uma boa opção em todas as faixas etárias, sendo imperativo executar variantes técnicas como término-terminal estendida.Objective A review of experience with techniques of correction used, in the last 20 years, in children younger than one year old. Methods In the period from 1978 to 1998, 148 patients (pt) with coarctation of the aorta (CoAo), under one year of age, with or without associated intracardiac defects, were submitted to surgery. Median age 50 days, 92 female pt (62.1%). The average weight was 4,367± 1,897 gr. The average follow-up was 1,152±1,462 days. The population was divided in 3 groups: Group I, isolated CoAo: 74 pt (50%); Group II, CoAo and interventricular communication (IVC): 41 pt (27.7%) and Group III, CoAo with complex intracardiac malformations: 33 pt (22.3%). Results The total mortality was of 43 patients (29%). In patients younger than 30 days, the mortality was 53%, p=0.009, DR=4.5, between 31 and 90 days, 14.7%, p=0.69, and over 91 days, 15%, p=0.004. The probability of actuarial survival of the whole population was 67% at 5 and 10 years. Thirty-six patients (24.3%) had recoarctation, from which 18 patients (50%) were younger than 30 days, DR=6.,35. The incidence of recoarctation was with Waldhausen technique in 4 patients (10%) and with the classic termino-terminal technique in 19 patients (26%) p=0.03, and isthmusplastic operation in 6 patients (37.5%). The patients younger than 30 days showed a relative risk for recoarctation de DR=6.35. The probability of actuarial survival, free of coarctation repair, at 5 and 10 years was of 69% with Waldhausen’s technique and 63% with the classic termino-terminal technique. Conclusion Patients younger than 30 days showed increased mortality and recoarctation risk. Waldhausen’s technique in patients older than 30 days showed effective. The classic termino-terminal technique did not show to be a good option in all age ranges, being imperative to carry out more radical technical variations, such as the extended termino-terminal

Coarctation of the aorta in infants under one year of age : an analysis of 20 years of experience

Objetivo Revisão da experiência com diversas técnicas de correção empregadas, nos últimos 20 anos, em crianças menores de um ano de idade. Métodos No período de 1978 a 1998, foram operados 148 pacientes (pc) consecutivos com coartação de aorta (CoAo) com até um ano de idade, com ou sem defeitos intracardíacos associados. A idade apresentou mediana de 50 dias, 92 pc do sexo feminino (62,1%). O peso foi de 4.367±1.897 gramas. O seguimento foi em média de 1.152±1.462 dias. A população foi dividida em 3 grupos: Grupo I, CoAo isolada: 74 pc (50%); Grupo II, CoAo e comunicação interventricular (CIV): 41 pacientes (27,7%) e Grupo III, CoAo com malformações complexas: 33 pc (22,3%). Resultados Mortalidade total foi 43 pc (29%): com menos de 30 dias, foi 53%, p=0,009, OR=4,5, entre 31 e 90 dias, foi 14,7%, p=0,69, e acima de 91 dias, 15%, p=0,004. A probabilidade de sobrevida atuarial de toda a população foi de 67% aos 5 e 10 anos. Trinta e seis pacientes (24,3%) recoartaram, dos quais 18 pacientes (50%) tinham menos de 30 dias, OR=6,35. A incidência de recoartação foi com a técnica de Waldhausen em 4 pacientes (10%) e com a término-terminal clássica em 19 pacientes (26%) p=0.03, e a istmoplastia em 6 pacientes (37,5%). A probabilidade de sobrevida atuarial livre de recoartação aos 5 e 10 anos foi de 69% com a técnica de Waldhausen e 63% com a técnica término-terminal clássica. Conclusão Pacientes com menos de 30 dias apresentaram risco aumentado de mortalidade e recoartação. A técnica de Waldhausen em pacientes com mais de 30 dias mostrou-se efetiva. A técnica términoterminal clássica mostrou não ser uma boa opção em todas as faixas etárias, sendo imperativo executar variantes técnicas como término-terminal estendida.Objective A review of experience with techniques of correction used, in the last 20 years, in children younger than one year old. Methods In the period from 1978 to 1998, 148 patients (pt) with coarctation of the aorta (CoAo), under one year of age, with or without associated intracardiac defects, were submitted to surgery. Median age 50 days, 92 female pt (62.1%). The average weight was 4,367± 1,897 gr. The average follow-up was 1,152±1,462 days. The population was divided in 3 groups: Group I, isolated CoAo: 74 pt (50%); Group II, CoAo and interventricular communication (IVC): 41 pt (27.7%) and Group III, CoAo with complex intracardiac malformations: 33 pt (22.3%). Results The total mortality was of 43 patients (29%). In patients younger than 30 days, the mortality was 53%, p=0.009, DR=4.5, between 31 and 90 days, 14.7%, p=0.69, and over 91 days, 15%, p=0.004. The probability of actuarial survival of the whole population was 67% at 5 and 10 years. Thirty-six patients (24.3%) had recoarctation, from which 18 patients (50%) were younger than 30 days, DR=6.,35. The incidence of recoarctation was with Waldhausen technique in 4 patients (10%) and with the classic termino-terminal technique in 19 patients (26%) p=0.03, and isthmusplastic operation in 6 patients (37.5%). The patients younger than 30 days showed a relative risk for recoarctation de DR=6.35. The probability of actuarial survival, free of coarctation repair, at 5 and 10 years was of 69% with Waldhausen’s technique and 63% with the classic termino-terminal technique. Conclusion Patients younger than 30 days showed increased mortality and recoarctation risk. Waldhausen’s technique in patients older than 30 days showed effective. The classic termino-terminal technique did not show to be a good option in all age ranges, being imperative to carry out more radical technical variations, such as the extended termino-terminal

Effect of lung recruitment and titrated Positive End-Expiratory Pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome - A randomized clinical trial

IMPORTANCE: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. OBJECTIVE: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. INTERVENTIONS: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. RESULTS: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, −1.1; 95% CI, −2.1 to −0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. CONCLUSIONS AND RELEVANCE: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01374022