Functional domains of a ribosome arresting peptide are affected by surrounding nonconserved residues.

Expression of the Escherichia coli tnaCAB operon, responsible for L-tryptophan (L-Trp) transport and catabolism, is regulated by L-Trp-directed translation arrest and the ribosome arresting peptide TnaC. The function of TnaC relies on conserved residues distributed throughout the peptide, which are involved in forming an L-Trp binding site at the ribosome exit tunnel and inhibiting the ribosome function. We aimed to understand whether nonconserved amino acids surrounding these critical conserved residues play a functional role in TnaC-mediated ribosome arrest. We have isolated two intragenic suppressor mutations that restore arrest function of TnaC mutants; one of these mutations is located near the L-Trp binding site, while the other mutation is located near the ribosome active site. We used reporter gene fusions to show that both suppressor mutations have similar effects on TnaC mutants at the conserved residues involved in forming a free L-Trp binding site. However, they diverge in suppressing loss-of-function mutations in a conserved TnaC residue at the ribosome active site. With ribosome toeprinting assays, we determined that both suppressor mutations generate TnaC peptides, which are highly sensitive to L-Trp. Puromycin-challenge assays with isolated arrested ribosomes indicate that both TnaC suppressor mutants are resistant to peptidyl-tRNA cleavage by puromycin in the presence of L-Trp; however, they differ in their resistance to puromycin in the absence of L-Trp. We propose that the TnaC peptide two functionally distinct segments, a sensor domain and a stalling domain, and that the functional versatility of these domains is fine-tuned by the nature of their surrounding nonconserved residues.

Clinical Features and Neurodevelopmental Outcomes for Infants with Perinatal Vertical Transmission of Zika Virus, Colombia.

Transplacental transmission of Zika virus has been reported during all trimesters of pregnancy and might lead to central nervous system anomalies, including microcephaly. We report 3 cases of perinatal Zika infection identified during the epidemic in Colombia and provide detailed descriptions of clinical features, diagnosis, and neurodevelopmental outcome at 18 months of age (corrected).

Fetal central nervous system anomalies according to RT-PCR and trimester of maternal infection with Zika virus: A prospective cohort study.

INTRODUCTION: In October 2015, an epidemic of Zika began in Colombia's geographic areas with a high population of mosquitoes of the genus Aedes. We aimed to describe the fetal brain ultrasound findings in pregnant women with active symptoms or a history of symptoms suggestive of Zika virus (ZIKV) infection. MATERIAL AND METHODS: Eligible pregnant women were tested with reverse transcriptase-polymerase chain reaction (RT-PCR) for ZIKV and followed prospectively using detailed anatomic ultrasound and transvaginal neurosonography to detect structural anomalies of the fetal central nervous system (CNS). RESULTS: A total of 115 symptomatic women with a positive ZIKV RT-PCR and 55 with a negative ZIKV RT-PCR were enrolled in the study; CNS compromise of the fetus occurred in 22% and 17%, respectively (p = 0.255). Callosal dysgenesis (14.5%) was the most frequent anomaly of the CNS, followed by microcephaly (13.6%) and neuronal migration disorders (8.3%). When symptomatic ZIKV RT-PCR-positive women were categorized by trimester of infection, CNS anomalies were present in 40% of first-trimester infections, compared with 21% and 7% in second- and third-trimester infections (p = 0.002). CNS anomalies were also more severe in first-trimester-infected fetuses than in second- and third-trimester-infected fetuses. The high prevalence of CNS anomalies in fetuses of symptomatic ZIKV RT-PCR negative women suggests a high rate of false-negative cases and an even higher prevalence of CNS anomalies than observed in this study. CONCLUSIONS: The prevalence of fetal CNS anomalies was higher than previously reported in the literature for both symptomatic RT-PCR-positive and -negative pregnant women. Corpus callosum anomalies, microcephaly, neuronal migration disorders, and brain parenchymal hyperechogenicities were the most frequent CNS anomalies detected. In addition, CNS anomalies were more frequent and severe in infected fetuses during the first trimester of pregnancy than during the second or third trimester.

The regulatory TnaC nascent peptide preferentially inhibits release factor 2-mediated hydrolysis of peptidyl-tRNA.

The tnaC regulatory gene from the tna operon of Escherichia coli controls the transcription of its own operon through an attenuation mechanism relying on the accumulation of arrested ribosomes during inhibition of its own translation termination. This free l-Trp-dependent mechanism of inhibition of translation termination remains unclear. Here, we analyzed the inhibitory effects of l-Trp on the function of two known E. coli translation termination factors, RF1 and RF2. Using a series of reporter genes, we found that the in vivo l-Trp sensitivity of tnaC gene expression is influenced by the identity of its stop codon, with the UGA stop codon producing higher expression efficiency of the tnaA-lacZ gene construct than the UAG stop codon. In vitro TnaC-peptidyl-tRNA accumulation and toe-printing assays confirmed that in the presence of l-Trp, the UGA stop codon generates higher accumulation of both TnaC-peptidyl-tRNA and arrested ribosomes than does the UAG stop codon. RF-mediated hydrolysis assays corroborated that l-Trp blocks RF2 function more than that of RF1. Mutational analyses disclosed that amino acids substitutions at the 246 and 256 residue positions surrounding the RF2-GGQ functional motif reduce l-Trp-dependent expression of the tnaC(UGA) tnaA-lacZ construct and the ability of l-Trp to inhibit RF2-mediated cleavage of the TnaC-peptidyl-tRNA. Altogether, our results indicate that l-Trp preferentially blocks RF2 activity during translation termination of the tnaC gene. This inhibition depends on the identities of amino acid residues surrounding the RF2-GGQ functional motif.

History and physical exam predictors of intracranial injury in the elderly fall patient: A prospective multicenter study.

OBJECTIVES: A prior single-center study demonstrated historical and exam features predicting intracranial injury (ICI) in geriatric patients with low-risk falls. We sought to prospectively validate these findings in a multicenter population. METHODS: This is a prospective observational study of patients ≥65 years presenting after a fall to three EDs. Patients were eligible if they were at baseline mental status and were not triaged to the trauma bay. Fall mechanism, head strike history, headache, loss of consciousness (LOC), anticoagulants/antiplatelet use, dementia, and signs of head trauma were recorded. Radiographic imaging was obtained at the discretion of treating physicians. Patients were called at 30 days to determine outcome in non-imaged patients. RESULTS: 723 patients (median age 83, interquartile range 74-88) were enrolled. Although all patients were at baseline mental status, 76 had GCS <15, and 154 had dementia. 406 patients were on anticoagulation/antiplatelet agents. Fifty-two (7.31%) patients had traumatic ICI. Two study variables were helpful in predicting ICI: LOC (odds ratio (OR) 2.02) and signs of head trauma (OR 2.6). The sensitivity of these items was 86.5% (CI 73.6-94) with a specificity of 38.8% (CI 35.1-42.7). The positive predictive value in this population was 10% (CI 7.5-13.3) with a negative predictive value of 97.3% (CI 94.4-98.8). Had these items been applied as a decision rule, 273 patients would not have undergone CT scanning, but 7 injuries would have been missed. CONCLUSION: In low-risk geriatric fall patients, the best predictors of ICI were physical findings of head trauma and history of LOC.

[Non-critical care hospital-acquired acute kidney injury. Analysis of 101 cases]. / Lesión renal aguda adquirida en el hospital: factores de riesgo y desenlaces clínicos.

BACKGROUND: Non-critical care Hospital-Acquired Acute Kidney Injury (Non-ICU HA-AKI) is a preventable common complication. AIM: To analyze its risk factors and outcomes in a general hospital ward. MATERIAL AND METHODS: A retrospective paired case-control 1:2 study was carried out from April to December 2014. Non-ICU HA-AKI was defined as those patients who experienced a 1.5-fold, or 0.3 mg/dl rise in serum creatinine after 24 hours of hospitalization. Controls were randomly selected, paired by date of hospital admission and specialty causing the admission. We analyzed short-term outcomes and risk factors. RESULTS: We included 101cases aged 65 ± 16 years (55% women). Mean length of stay at the time of diagnosis of AKI was 7.9 ± 8.9 days. Hospital length of stay was longer in patients with AKI (p < 0.01), The risk for intensive care unit (ICU) admission and mortality were also higher (odds ratio [OR], 2.43 [95% confidence intervals (CI), 1.24 to 4.75)p < 0.01 and OR, 26.2 [95% CI, 8.8 to 104, P < 0.01). In a multivariate analysis, sepsis (OR, 3.64 [95% CI, 1.30 to 10.16] p = 0.013), dehydration (OR, 14.4 [95% CI, 4.49 to 46.19), baseline glomerular filtration (OR, 0.96 [95% CI, 0.94-0.98), contrast medium exposure (OR, 4.33 [95% CI, 1.60 to 11.66), recent exposure to Nonsteroidal Anti-inflammatory Drugs (OR 3.23 [95% CI, 1.22 to 8.52 (p = 0.02)] and Charlson comorbidity index (OR, 1.23 [95% CI, 1.05 to 1.43 (p < 0.01) were independent risk factors for Non-ICU HA-AKI. CONCLUSIONS: Non-ICU HA-AKI is associated with a longer hospital stay and higher risk of ICU admission and mortality. Most risk factors are potentially preventable.

Interactions of the TnaC nascent peptide with rRNA in the exit tunnel enable the ribosome to respond to free tryptophan.

A transcriptional attenuation mechanism regulates expression of the bacterial tnaCAB operon. This mechanism requires ribosomal arrest induced by the regulatory nascent TnaC peptide in response to free L-tryptophan (L-Trp). In this study we demonstrate, using genetic and biochemical analyses, that in Escherichia coli, TnaC residue I19 and 23S rRNA nucleotide A2058 are essential for the ribosome's ability to sense free L-Trp. We show that the mutational change A2058U in 23S rRNA reduces the concentration dependence of L-Trp-mediated tna operon induction, whereas the TnaC I19L change suppresses this phenotype, restoring the sensitivity of the translating A2058U mutant ribosome to free L-Trp. These findings suggest that interactions between TnaC residue I19 and 23S rRNA nucleotide A2058 contribute to the creation of a regulatory L-Trp binding site within the translating ribosome.

Elderly fall patients triaged to the trauma bay: age, injury patterns, and mortality risk.

BACKGROUND: Falls in the elderly are a significant cause of morbidity and mortality. We sought to better categorize this patient population and describe factors contributing to their falls. METHODS: This is a retrospective review of geriatric patients presenting to a level 1 community trauma center. We queried our trauma database for all patients 65 years and older presenting with fall and triaged to the trauma bay from 2008 to 2013. Researchers reviewed the patients' trauma intake paperwork to assess mechanism, injury, and location of fall, whereas discharge summaries were reviewed to determine disposition, morbidity, and mortality. RESULTS: A total of 650 encounters were analyzed. Five hundred thirty-nine resided at home (82.9%), 110 presented from nursing homes or assisted living (16.9%), and 1 came from hospice (0.15%). Ninety-five patients died or were placed on hospice as a result of their falls (14.7%), of which 88 came from home. Controlling for Injury Severity Score, living at home was an independent risk factor for fall-related mortality (odds ratio, 3.0). Comparing the elderly (age 65-79 years; n = 274) and the very elderly (age ≥80 years; n = 376), there were no differences in Injury Severity Score (P = .33), likelihood of death (P = .49), likelihood of C-spine injury (P = 1.0), or likelihood of other axial or long bone skeletal injury (P = .23-1.0). There was a trend for increased likelihood of head injury in very elderly patients (P = 0.06). CONCLUSION: Prevention measures to limit morbidity and mortality in elderly fall patients should be aimed at the home setting, where most severe injuries occur. Very elderly patients may be at increased risk for intracranial fall-related injuries.

Application of National Emergency X-Ray Utilizations Study low-risk c-spine criteria in high-risk geriatric falls.

STUDY OBJECTIVES: We sought to validate National Emergency X-Radiography Utilizations Study low-risk cervical spine (C spine) criteria in a geriatric trauma population. We sought to determine whether patients' own baseline mental status (MS) could substitute for Glasgow Coma Scale (GCS) to meet the criteria "normal alertness." We further sought to refine the definition of "distracting injury." METHODS: This is a retrospective review of geriatric fall patients presenting to a level 1 trauma center and triaged to the trauma bay. We queried our database from 2008 to 2013. Abstractors recorded GCS, deviation from baseline MS, midline neck tenderness, intoxication, focal deficit, signs of trauma, and presence of other injury. Patients were considered at baseline MS if specific documentation was present on the chart, or if their GCS was 15. RESULTS: Six hundred sixty elderly fall patients were trauma alerts during the study period. Seventeen were excluded for incomplete records/death before imaging, leaving 647. The median age was 81 (interquartile range, 74-87). Fifty patients (8.0%) had C spine or cord injury. Two hundred ninety-four (44.5%) had baseline MS (including GCS 13-15), no spine tenderness, no intoxication, and no focal neurologic deficit. Of these, 18 had C-spine injury. Using physical findings of head trauma as the only "distracting injury," no injury would have been missed (sensitivity, 100% [confidence interval, 91.1-100]; specificity, 14.2%). CONCLUSIONS: Our study suggests that National Emergency X-Radiography Utilizations Study can be safely applied in elderly fall patients who are at their personal baseline MS. Furthermore, our data support a more narrow definition of distracting injury to include only patients with signs of trauma to the head.

Crucial elements that maintain the interactions between the regulatory TnaC peptide and the ribosome exit tunnel responsible for Trp inhibition of ribosome function.

Translation of the TnaC nascent peptide inhibits ribosomal activity in the presence of l-tryptophan, inducing expression of the tnaCAB operon in Escherichia coli. Using chemical methylation, this work reveals how interactions between TnaC and the ribosome are affected by mutations in both molecules. The presence of the TnaC-tRNA(Pro) peptidyl-tRNA within the ribosome protects the 23S rRNA nucleotide U2609 against chemical methylation. Such protection was not observed in mutant ribosomes containing changes in 23S rRNA nucleotides of the A748-A752 region. Nucleotides A752 and U2609 establish a base-pair interaction. Most replacements of either A752 or U2609 affected Trp induction of a TnaC-regulated LacZ reporter. However, the single change A752G, or the dual replacements A752G and U2609C, maintained Trp induction. Replacements at the conserved TnaC residues W12 and D16 also abolished the protection of U2609 by TnaC-tRNA(Pro) against chemical methylation. These data indicate that the TnaC nascent peptide in the ribosome exit tunnel interacts with the U2609 nucleotide when the ribosome is Trp responsive. This interaction is affected by mutational changes in exit tunnel nucleotides of 23S rRNA, as well as in conserved TnaC residues, suggesting that they affect the structure of the exit tunnel and/or the nascent peptide configuration in the tunnel.

Childhood Systemic Lupus Erythematosus: Clinical and Immunologic Patterns in Mexican Children.

Introduction Systemic lupus erythematosus (SLE) is a complex autoimmune disease with heterogeneous clinical and laboratory features. The incidence increases markedly in women. The reason for the predominance of the female gender is still under study. The ethnicity could influence the clinical and serological features of SLE. Material and methods This is a retrospective, descriptive, and longitudinal study. We studied 89 patients diagnosed with childhood-onset systemic lupus erythematosus (cSLE) in our center in 2000-2020 for men and 2010-2020 for women. We investigated disease manifestations, ranging from clinical symptoms to renal involvement, at the time of diagnosis and compared them by gender. Results We studied 89 patients, comprising 23 males and 66 females. The mean age for both groups was 12 years. Concerning clinical manifestations, serositis exhibited a higher prevalence among males, while hair loss was more prominent among females. In the paraclinical evaluation, noteworthy differences were observed regarding average hemoglobin levels and the prevalence of positive anti-DNA antibodies. Males demonstrated an average hemoglobin level of 11.47 g/dL, whereas females displayed 9.84 g/dL (p=0.017). The prevalence of anti-DNA antibodies exhibited marked elevation in males, at 88.9%, compared to females' 42.9% (p=0.024). On a contrary note, our male cohort displayed heightened prevalence in using hydroxychloroquine, cyclophosphamide, and mycophenolate. Similarly, renal involvement presented a higher prevalence in males (100% against 83.3%), albeit lacking statistical significance. Nevertheless, significant disparities emerged in the occurrence of granular casts, proteinuria, and the average glomerular filtration rate, with males experiencing greater impact in each instance. Finally, it is noteworthy that the application of mycophenolate and azathioprine was more frequently observed among patients with renal involvement. Conclusion cSLE patients in our inception cohort showed statistical significance in dermatological and vascular manifestations, serositis, granular casts, low kidney glomerular filtration, and high proteinuria, which are predominant in male patients. Immunological features were predominantly positive in ds-DNA antibodies for male patients. Separation by gender for future studies might identify a better treatment strategy.

Optimizing Transitions of Care and Enhancing Surgical Education on Acute Care Surgery: A Multi-Institutional Survey Study.

OBJECTIVE: Critically ill and injured patients are routinely managed on the Trauma and Acute Care Surgery (ACS) service and receive care from numerous residents during hospital admission. The Clinical Learning Environment Review (CLER) program established by the ACGME identified variability in resident transitions of care (TC) while observing quality care and patient safety concerns. The aim of our multi-institutional study was to review surgical trainees' impressions of a specialty-specific handoff format in order to optimize patient care and enhance surgical education on the ACS service. DESIGN: A survey study was conducted with a voluntary electronic 20-item questionnaire that utilized a 5 point Likert scale regarding TC among resident peers, supervised handoffs by trauma attendings, and surgical education. It also allowed for open-ended responses regarding perceived advantages and disadvantages of handoffs. SETTING: Ten American College of Surgeons-verified Level 1 adult trauma centers. PARTICIPANTS: All general surgery residents and trauma/acute/surgical critical care fellows were surveyed. RESULTS: The study task was completed by 147 postgraduate trainees (125 residents, 14 ACS fellows, and 8 surgical critical care fellows) with a response rate of 61%. Institutional responses included: university hospital (67%), community hospital-university affiliate (16%), and private hospital-university affiliate (17%). A majority of respondents were satisfied with morning TC (62.6%) while approximately half were satisfied with evening TC (52.4%). Respondees believe supervised handoffs improved TC and prevented patient care delays (80.9% and 74.8%, respectively). A total of 35% of trainees utilized the open-ended response field to highlight specific best practices of their home institutions. CONCLUSIONS: Surgical trainees view ACS morning handoff as an effective standard to provide the highest level of clinical care and an opportunity to enhance surgical knowledge. As TC continue to be a focus of certifying bodies, identifying best practices and opportunities for improvement are critical to optimizing quality patient care and surgical education.

The Identity of the Constriction Region of the Ribosomal Exit Tunnel Is Important to Maintain Gene Expression in Escherichia coli.

Mutational changes in bacterial ribosomes often affect gene expression and consequently cellular fitness. Understanding how mutant ribosomes disrupt global gene expression is critical to determining key genetic factors that affect bacterial survival. Here, we describe gene expression and phenotypic changes presented in Escherichia coli cells carrying an uL22(K90D) mutant ribosomal protein, which displayed alterations during growth. Ribosome profiling analyses revealed reduced expression of operons involved in catabolism, indole production, and lysine-dependent acid resistance. In general, translation initiation of proximal genes in several of these affected operons was substantially reduced. These reductions in expression were accompanied by increases in the expression of acid-induced membrane proteins and chaperones, the glutamate-decarboxylase regulon, and the autoinducer-2 metabolic regulon. In agreement with these changes, uL22(K90D) mutant cells had higher glutamate decarboxylase activity, survived better in extremely acidic conditions, and generated more biofilm in static cultures compared to their parental strain. Our work demonstrates that a single mutation in a non-conserved residue of a ribosomal protein affects a substantial number of genes to alter pH resistance and the formation of biofilms. IMPORTANCE All newly synthesized proteins must pass through a channel in the ribosome named the exit tunnel before emerging into the cytoplasm, membrane, and other compartments. The structural characteristics of the tunnel could govern protein folding and gene expression in a species-specific manner but how the identity of tunnel elements influences gene expression is less well-understood. Our global transcriptomics and translatome profiling demonstrate that a single substitution in a non-conserved amino acid of the E. coli tunnel protein uL22 has a profound impact on catabolism, cellular signaling, and acid resistance systems. Consequently, cells bearing the uL22 mutant ribosomes had an increased ability to survive acidic conditions and form biofilms. This work reveals a previously unrecognized link between tunnel identity and bacterial stress adaptation involving pH response and biofilm formation.

Prevalence of Housing Insecurity in Survivors of Traumatic Injury.

BACKGROUND: Almost 20% of the US population are housing insecure (HI) due to inadequate living conditions, imbalanced costs to income, nonsustainable shelter, or overcrowding. Housing insecure and physical trauma share similar risk factors, but their direct association is not well elucidated. The objective of our study was to determine the prevalence of HI in survivors of traumatic injury. METHODS: We conducted a prospective cohort study at an urban, level 1 trauma center. A survey on social determinants of health was administered to adult patients, and demographic, injury specifics, and clinical outcomes data were collected. HI was defined by affirmative answers to questions related to history of homelessness or concern about sustainable shelter. The cohort was stratified by HI; groups were compared using the Mann-Whitney U and Fisher exact tests, as appropriate. RESULTS: Of 116 study participants, four were excluded due to missing data. Of the 112, 42 (37.8%) reported HI and most were black (69%) males (73.8%). There were no demographic differences between groups. Conversely, HI patients had a higher rate of penetrating traumatic injury (34.1% vs 14.5%, P-value = .03) and were significantly less educated compared to secure participants (P-value = .03) [no degree (26.2% vs 10.3%), high school degrees (21.4% vs 41.2%)] with concomitant illicit drug use (63.4% vs 27.9%, P < .001), and history of addiction (52.4% vs 7.2%, P < .001). CONCLUSION: HI far exceeds national averages in our cohort. Although difficult to ascertain a cause-effect relationship, HI may be a modifiable risk factor for trauma that negatively influences outcomes.

Neurodevelopmental outcome of infants without central nervous system anomalies born to symptomatic RT-PCR ZIKV positive women.

An epidemic of Zika virus (ZIKV) infection began in Colombia in October 2015. Previous studies have identified a cause-effect relationship between fetal exposure to the ZIKV and the development of microcephaly and other central nervous system (CNS) anomalies with variable degrees of neurodevelopmental delay. Less is known about the neurodevelopmental outcome of infants without CNS anomalies born to symptomatic ZIKV RT-PCR-positive women. We aimed to compare the neurodevelopmental outcome of these infants to a control group of infants without CNS anomalies born to asymptomatic ZIKV RT-PCR negative women who did not seroconvert during pregnancy. Participating infants were categorized according to ZIKV maternal exposure. Women with symptomatology suggestive of ZIKV infection and a positive RT-PCR for ZIKV were categorized as ZIKV-exposed. Maternal controls (ZIKV unexposed) from the same geographic area were subsequently captured during the tail end of the epidemic through a partner project, the ZIKAlliance, whose aim was to determine the prevalence of ZIKV in pregnant women. Infant survivors from these two groups of pregnant women had a neurodevelopmental evaluation at 12, 18, and 24 months corrected age (CA). The ZIKV-exposed women were found to be older, had less subsidized health care, had a higher percentage of women in middle-class socioeconomic strata, had higher technical and university education, were less likely to be living with a partner, and had higher rates of pregnancy comorbidity and premature births than ZIKV unexposed women. Compared to infants born to ZIKV unexposed women (unexposed), infants born to ZIKV exposed women (exposed) were of lower gestational age and required more speech and occupational therapy services. No differences between groups were observed in the proportion of cut-off scores <70 on the Bayley-III Scale at 12, 18, and 24 months for motor, language, and cognitive domains. When a cut-off of <85 was used, a higher percentage of motor and cognitive impairment was observed in unexposed infants at 12 and 24 months CA, respectively. Median and IQR score on the Bayley-III scale showed higher scores in favor of exposed infants for motor development at 12 and 18 months CA, language at 12 months, and cognitive domain at 12, 18, and 24 months. The adjusted median and IQR compound score of the difference between exposed and unexposed was higher in favor of exposed infants at 12 to 24 months CA for motor (3.8 [95% CI 1.0 to 6.7]) and cognitive domains (10.6 [95% CI 7.3 to 13.9]). We observed no differences in the language domain (1.9 [95% CI -1.2 to 5.0]). We conclude that infants with no evidence of microcephaly or other CNS anomalies born to ZIKV-exposed women had normal neurodevelopment up to 24 months of CA, supporting an all-or-nothing effect with maternal ZIKV exposure. Long-term follow-up to evaluate school performance is required. Clinical Trial Registration: www.clinicaltrials.gov, NCT02943304.

A protein folding robot driven by a self-taught agent.

This paper presents a computer simulation of a virtual robot that behaves as a peptide chain of the Hemagglutinin-Esterase protein (HEs) from human coronavirus. The robot can learn efficient protein folding policies by itself and then use them to solve HEs folding episodes. The proposed robotic unfolded structure inhabits a dynamic environment and is driven by a self-taught neural agent. The neural agent can read sensors and control the angles and interactions between individual amino acids. During the training phase, the agent uses reinforcement learning to explore new folding forms that conduce toward more significant rewards. The memory of the agent is implemented with neural networks. These neural networks are noise-balanced trained to satisfy the look for future conditions required by the Bellman equation. In the operating phase, the components merge into a wise up protein folding robot with look-ahead capacities, which consistently solves a section of the HEs protein.

Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling.

Free L-tryptophan (L-Trp) stalls ribosomes engaged in the synthesis of TnaC, a leader peptide controlling the expression of the Escherichia coli tryptophanase operon. Despite extensive characterization, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a TnaC variant (R23F) with greatly enhanced sensitivity for L-Trp. We show that the TnaC-ribosome complex captures a single L-Trp molecule to undergo termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. Importantly, the L-Trp binding site is not altered by the R23F mutation, suggesting that the relative rates of L-Trp binding and peptidyl-tRNA cleavage determine the tryptophan sensitivity of each variant. Thus, our study reveals a strategy whereby a nascent peptide assists the ribosome in detecting a small metabolite.

[Irrational anxiety: obsessive-compulsive disorder]. / Anxiété obsessionnelle: trouble obsessionnel-compulsif.

Obsessive-compulsive disorder is an exemplar of an anxiety disorder where irrational thoughts and compulsive behaviors succeed each other in a mental system where every negative outcome can occur. Affects like doubt and guilt reinforce the need to prevent catastrophic consequences from occurring. Magical thinking replaces logical thoughts. The risk of suicide becomes high when compulsive acts cannot control anxiety. Behavior and cognitive therapy is the most frequent type of psychological help: the principal target is the change of emotional reactions.

The prevalence and risk factors associated with dyslipidemia in type 2 diabetic patients in the autonomous Region of Cantabria. / Prevalencia y factores de riesgo asociados a la dislipidemia en pacientes diabéticos tipo 2 de la Comunidad de Cantabria.

BACKGROUND AND OBJECTIVE: Dyslipidemia is one of the main risk factors in cardiovascular disease in patients with diabetes mellitus type 2 (DM2). The aim of this study is to evaluate the prevalence and risk factors associated with dyslipidemia in the population with diabetes mellitus type 2 in the region of Cantabria. MATERIAL AND METHODS: This is a transversal study carried out at Cantabrian primary health care centres (n=680). A representative, random sample of the population with DM2, ranging from 18-85, was selected using a multistage procedure. The medical records were obtained, and by means of interviews the data of the risk factors to be studied was secured. The correlation with dyslipidemia was analysed by means of logistic regression. RESULTS: There were 52.1% of males, the average age was 69.8, the evolution of diabetes was 9.99 years, 84.3% had arterial hypertension, 76.6% were overweight or obese and the average HbA1c was 6.96%. The prevalence of dyslipidemia was 85.3%, and in the bivariate analysis this is associated with a history of peripheral artery disease, controlled diabetes, antihypertensive treatment, glomerular filtration, HbA1c>7%, body fat estimated as being either overweight or obese, a history of cardiovascular disease, age and HbA1c. In the multivariate analysis the independent factors were being female and a history of cardiovascular disease. CONCLUSION: The prevalence of dyslipidemia in our study was 85.3%, and is consistent with figures found in previous published studies. The independent associated risk factors were being female and a past medical history of cardiovascular disease.

23S rRNA nucleotides in the peptidyl transferase center are essential for tryptophanase operon induction.

Distinct features of the ribosomal peptide exit tunnel are known to be essential for recognition of specific amino acids of a nascent peptidyl-tRNA. Thus, a tryptophan residue at position 12 of the peptidyl-tRNA TnaC-tRNA(Pro) leads to the creation of a free tryptophan binding site within the ribosome at which bound tryptophan inhibits normal ribosome functions. The ribosomal processes that are inhibited are hydrolysis of TnaC-tRNA(Pro) by release factor 2 and peptidyl transfer of TnaC of TnaC-tRNA(Pro) to puromycin. These events are normally performed in the ribosomal peptidyl transferase center. In the present study, changes of 23S rRNA nucleotides in the 2585 region of the peptidyl transferase center, G2583A and U2584C, were observed to reduce maximum induction of tna operon expression by tryptophan in vivo without affecting the concentration of tryptophan necessary to obtain 50% induction. The growth rate of strains with ribosomes with either of these changes was not altered appreciably. In vitro analyses with mutant ribosomes with these changes showed that tryptophan was not as efficient in protecting TnaC-tRNA(Pro) from puromycin action as wild-type ribosomes. However, added tryptophan did prevent sparsomycin action as it normally does with wild-type ribosomes. These findings suggest that these two mutational changes act by reducing the ability of ribosome-bound tryptophan to inhibit peptidyl transferase activity rather than by reducing the ability of the ribosome to bind tryptophan. Thus, the present study identifies specific nucleotides within the ribosomal peptidyl transferase center that appear to be essential for effective tryptophan induction of tna operon expression.