Exploring the Biosynthesis of Unsaturated Fatty Acids in Bacillus cereus ATCC 14579 and Functional Characterization of Novel Acyl-Lipid Desaturases

At low temperatures, Bacillus cereus synthesizes large amounts of unsaturated fatty acids (UFAs) with double bonds in positions Δ5 and Δ10, as well as Δ5,10 diunsaturated fatty acids. Through sequence homology searches, we identified two open reading frames (ORFs) encoding a putative Δ5 desaturase and a fatty acid acyl-lipid desaturase in the B. cereus ATCC 14579 genome, and these were named BC2983 and BC0400, respectively. Functional characterization of ORFs BC2983 and BC0400 by means of heterologous expression in Bacillus subtilis confirmed that they both encode acyl-lipid desaturases that use phospholipids as the substrates and have Δ5 and Δ10 desaturase activities. Thus, these ORFs were correspondingly named desA (Δ5 desaturase) and desB (Δ10 desaturase). We established that DesA utilizes ferredoxin and flavodoxins (Flds) as electron donors for the desaturation reaction, while DesB preferably employs Flds. In addition, increased amounts of UFAs were found when B. subtilis expressing B. cereus desaturases was subjected to a cold shock treatment, indicating that the activity or the expression of these enzymes is upregulated in response to a decrease in growth temperature. This represents the first work reporting the functional characterization of fatty acid desaturases from B. cereus.Fil: Chazarreta Cifré, Lorena Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Alemany, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: de Mendoza, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Altabe, Silvia Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Biología Molecular y Celular de Rosario; Argentin

The biological function of the proto-oncogene Cot/tpl-2

Capítulo 2.-- Editor: Pedro A. Lazo.Cot, as well as its murine homologue tpl-2, was discovered in a COOH–terminal truncated form that unmasks the transformation capacity of the protein. The COOH-terminal domain of wt Cot contains an amino acid sequence that is a recognition signal for degradation via proteasome, besides, this domain of wt Cot is also an autoinhibitory domain of the specific activity of the wild type form. These data explain the transformation capacity of trunc-Cot/tpl-2, that when overexpressed is capable of activating several MAP kinases pathways as well as AP-1, NFAT, and NF-κB2 transcriptional activities. Earlier sobreexpression experiments lead to the proposal that Cot/tpl-2 could be involved in proliferative signalling, but the use of new technologies such as genetically modifies mice and interference RNA end up with the already accepted hypothesis that Cot/tpl-2 is involved in immune innate and adaptive processes. Cot/tpl-2 is activated in response to the activation of the TLR/IL-1 receptor superfamily as well as in response to the activation of some receptors of the TNF family. Independently of the cell system it is accepted that in resting cells Cot/tpl-2 forms a stable and inactive complex with p105 NF-κB among other proteins to protect it from degradation, adequate TLR/IL-1R stimulation induces the activation of the IKK complex that targets p105 NF-κB to be rapidly degraded by the proteasome pathway to p50 NF-κB, a subunit of the NF-κB transcription factor. Consequently Cot/tpl-2 is released from the complex and susceptible to transduce the activatory signal, leading to the activation of the MEK1-Erk1/Erk2 pathway. However, actually it is not completely understood all the requests that Cot/tpl-2 needs to be fully active and to this end it is also accepted that Cot/tpl2 requires to be phosphorylated. In addition the possibility that the requirements vary from cell system to cell system cannot be excluded. Physiologically, Cot/tpl-2 is involved in provoking innate immunity to establish adaptive immunity. In fact it is the unique MAP3K that activates Erk1/Erk2 when the TLRs/IL-1 receptors are activated and mediates the production of proinflammatory cytokines, such as TNFα, IL-1, or IL-6. More recently it has been shown that Cot/tpl-2 has the capacity to regulate the balance between Th1 and Th2 cytokines. All these data indicate that, although mutations in Cot gene result in the expression of a protein linked with cell malignancies, physiologically wt Cot/tpl-2 is involved in innate and adaptive immunity.Our research is supported by the Plan Nacional (SAF 2008-00819) and Mutua Madrileña.Peer Reviewe

The thyroid hormone receptors inhibit hepatic interleukin-6 signaling during endotoxemia

Decreased thyroidal hormone production is found during lipopolysaccharide (LPS)-induced endotoxic shock in animals as well as in critically ill patients. Here we studied the role of the thyroid hormone receptors (TRs) in activation of STAT3, NF-ΰ B and ERK, which play a key role in the response to inflammatory cytokines during sepsis. TR knockout mice showed down-regulation of hepatic inflammatory mediators, including interleukin 6 (IL-6) in response to LPS. Paradoxically, STAT3 and ERK activity were higher, suggesting that TRs could act as endogenous repressors of these pathways. Furthermore, hyperthyroidism increased cytokine production and mortality in response to LPS, despite decreasing hepatic STAT3 and ERK activity. This suggested that TRs could directly repress the response of the cells to inflammatory mediators. Indeed, we found that the thyroid hormone T3 suppresses IL-6 signalling in macrophages and hepatocarcinoma cells, inhibiting STAT3 activation. Consequently, the hormone strongly antagonizes IL-6-stimulated gene transcription, reducing STAT3 recruitment and histone acetylation at IL-6 target promoters. In conclusion, TRs are potent regulators of inflammatory responses and immune homeostasis during sepsis. Reduced responses to IL-6 should serve as a negative feedback mechanism for preventing deleterious effects of excessive hormone signaling during infections.This work was supported by Grants: BFU2011-28058, BFU2014-53610P and SAF2015-71878-REDT from Ministerio de Economía y Competitividad; S2011/BMD-2328 from the Comunidad de Madrid and RD12/0036/0030 from the Instituto de Salud Carlos II

Expired Tidal Volume and Respiratory Rate During Postnatal Stabilization of Newborn Infants Born at Term via Cesarean Delivery

Objective To retrieve evolving respiratory measures in the first minutes after birth in normal neonates born at term using a respiratory function monitor. Study design We evaluated newborn babies delivered at term via cesarean after uncomplicated pregnancies. Immediately after birth, a respiratory function monitor with an adapted flowmeter and a face mask were applied at 2, 5, and 10 minutes after birth for 90 seconds in each period. We analyzed expired and inspired tidal volume, respiratory rate (RR), percentage of leakage, and number of analyzed breaths in each individual infant’s recording using a respiratory research software. Results A total of 243 infants completed the study. The final data set included 59 058 (48.35%) valid observations for each of the variables representing the analysis of 32 801 breaths. With these data, we constructed a reference range with 10th, 25th, 50th, 75th, and 90th percentiles for expired tidal volume and RR. Tidal volumes plateaued earlier in female than in male infants. No correlation with delayed cord clamping, gestational age, maternal morbidity, or indication for cesarean delivery were established. Conclusions We have constructed a reference range with percentiles for inspired and expired tidal volumes and RR in newborn babies born at term for the first 10 minutes after birth. Reference ranges can be employed for research and can be useful in the clinical setting to guide positive pressure ventilation in the delivery room.Enfermerí

Cytochrome P17 inhibition with ketoconazole as treatment for advanced granulosa cell ovarian tumor

Originally published by the American Society of Clinical Oncology. García-Donas et al.: Journal of Clinical Oncology Vol. 31.10, April 1 - 2013: e165-e16

A Network approach of gambling disorder profile with and without related illegal acts

Gambling disorder (GD) is a complex mental health condition that can cause many severe psychological, physical, and social impairment. Illegal acts have been recognized in quite a few cases because of the debts related with the gambling activity. This study used network methodology to visualize the relationships among patients seeking treatment for gambling related problems, separately for the patients with and without illegal behaviors. The aim is to identify the diverse and differentiate mechanisms, as well as the central nodes, that occur within GD patients depending on the presence/absence of illegal acts. The sample included N = 401 patients (age range 18 to 80 years). Network analysis was performed considering the nodes that measure gambling features (the core symptoms based on the DSM-5 taxonomy, global symptom severity, and forms of gambling), psychopathology distress, substance use (tobacco, alcohol, and illegal drugs), and personality traits. Two separate networks were adjusted for patients with illegal acts (n = 105) and without these behaviors (n = 296). The most relevant nodes among patients with GD plus illegal acts were self-transcendence and the GD DSM-5 symptom "A7-lies to conceal the extent of gambling" (these variables were also identified as the bridge nodes, those with the highest linkage capacity). Among the patients with GD without illegal acts, the node with the greatest authority was the GD DSM-5 symptom "A5-often gambles when feeling distressed" (this was also the variable with the highest linkage capacity). The study provides empirical evidence of the most relevant features and the linkage capacity among patients seeking treatment for problematic gambling, which can support the development of precise plans for treatment and prevention of the risk of GDRIA

First manic/hypomanic episode in obsessive-compulsive disorder patients treated with antidepressants: a systematic review

High doses of antidepressants, particularly clomipramine and selective serotonin reuptake inhibitors (SSRIs), are the well-established treatment for obsessive-compulsive disorder (OCD), but manic/hypomanic episodes are potential adverse events associated with this treatment. A systematic literature review was performed on manic/ hypomanic episodes in non-bipolar OCD patients. Clinical, sociodemographic and antidepressant characteristics during the manic/hypomanic switch were extracted using descriptive statistics. Data were obtained from 20 case reports and case series. Switching episodes mostly appeared in the first 12 weeks after antidepressant initiation and took place more frequently during SSRI use (mostly fluoxetine) in 64.3% of cases. Clomipramine and SSRI use differed non-significantly between the switching episodes that appeared during the first 12 weeks of antidepressant treatment and the episodes that appeared beyond 12 weeks. Switching episodes emerging before 12 weeks were associated with a lower defined daily dose of antidepressants than episodes emerging after 12 weeks. These findings suggest that there are two independent characteristics involved in manic/hypomanic switch in OCD: a) they appeared most frequently with SSRI use (fluoxetine) regardless of the time of it use, and b) episodes appeared in the first 12 weeks after SSRI or clomipramine initiation had a lower dose of antidepressant than episodes appeared after 12 weeks

Fasting plasma glucose is an independent predictor of survival in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy

Background: Diabetes is related with increased cancer mortality across multiple cancer types. Its role in lung cancer mortality is still unclear. We aim to determine the prognostic value of fasting plasma glucose (FPG) and diabetes mellitus in patients with locally advanced non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy. Methods: One-hundred seventy patients with stage III NSCLC received definitive concurrent chemoradiotherapy from 2010 to 2014. Clinico-pathological data and clinical outcome was retrospectively registered. Fifty-six patients (33%), met criteria for type 2 diabetes mellitus (T2DM) at baseline. The prognostic value of FPG and other clinical variables was assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and Cox proportional models and log-rank test were used. Results: With a median follow-up of 36 months, median PFS was 8.0 months and median OS was 15.0 months in patients with FPG ≥7 mmol/L compared to 20 months (HR 1.13; 95% CI 1.07-1.19, p  8.5%) (HR 4.53; 95% CI 2.21-9.30; p < 0.001) and those receiving insulin (HR 3.22; 95% CI 1.90-5.46 p < 0.001) had significantly independent worse OS. Conclusion: Baseline FPG level is an independent predictor of survival in our cohort of patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. Studies in larger cohorts of patients are warranted to confirm this relevant association

Hypothyroidism confers tolerance to cerebral malaria

The modulation of the host’s metabolism to protect tissue from damage induces tolerance to infections increasing survival. Here, we examined the role of the thyroid hormones, key metabolic regulators, in the outcome of malaria. Hypothyroidism confers protection to experimental cerebral malaria by a disease tolerance mechanism. Hypothyroid mice display increased survival after infection with Plasmodium berghei ANKA, diminishing intracranial pressure and brain damage, without altering pathogen burden, blood-brain barrier disruption, or immune cell infiltration. This protection is reversed by treatment with a Sirtuin 1 inhibitor, while treatment of euthyroid mice with a Sirtuin 1 activator induces tolerance and reduces intracranial pressure and lethality. This indicates that thyroid hormones and Sirtuin 1 are previously unknown targets for cerebral malaria treatment, a major killer of children in endemic malaria areas.This work was funded by grants SAF2017-83289-R to S.A. and A.A., SAF2017-90604REDT to A.A. supported by the The European Regional Development Fund (FEDER) and BIO2016-77430-R to J.M.B. from the Ministerio de Economía y Competitividad; B2017/BMD-3724 to S.A. and A.A. from the Comunidad de Madrid; and CIBERONC CB/16/00228 to A.A. from the Instituto de Salud Carlos III

Purging behavior modulates the relationships of hormonal and behavioral parameters in women with eating disorders

Background/aims: There is ample consensus that there is a neurophysiological basis for the eating disorders (ED). Traits of personality translate into behavioural traits, purging being a well defined transversal example. Direct implication of steroid hormones on ED has been seldom studied, despite their effects on behaviour. Methods: After psychological interview analysis 57 ED female patients (31 purgative and 26 non-purgative), and 17 female controls were studied. Metabolic parameters and analysis of androgen, estrogen and glucocorticoid hormones were determined in parallel to the psychopathological profile (EDI-2 and SCL-90-R) and anthropometric measurements. Results: Psychometric tests showed clear differences between ED and controls, but there were few hormonal-metabolic significant differences. In purgative ED there were repeated (significant) positive correlations with CBG, and negative with SHBG, versus eating and general psychopathology. In non-purging, there were positive correlations for deoxycortisol, free fatty acids, albumin and negative for aspartate aminotransferase and psychopathological traits. Conclusion: The data hint at CBG/corticosteroids and sexual hormones/SHBG to be involved in purging behaviour and its psychopathology and severity scores. Correlations of selected psychometric data and the CBG/SHBG levels in purging may eventually result in clinical markers. This approach may provide additional clues for understanding the pathogenesis of the ED