Novel evidence of obesity paradox in esophageal adenocarcinoma: perspective on genes that uncouple adiposity from dismal outcomes.
Background: Obesity is a strong risk factor for esophageal adenocarcinoma (EAC). Nevertheless, not all the patients with EAC are obesity, and a substantial proportion of obesity patients don't suffer from poor prognoses. The mechanisms behind the "obesity paradox" that uncouple obesity from dismal outcomes in EAC are unclear. This study aimed to explore the "obesity-guarding" genes (OGG) profiles and their prognostic values in patients with EAC. Methods: Gene expression data and clinical information of patients with EAC were downloaded from The Cancer Genome Atlas (TCGA) database. Enrichment analysis was used to explore the OGG functions and pathways. Cox regression analysis and nomogram model were performed to investigate the OGG prognostic values for overall survival (OS). In addition, relations between OGG and immune cells were assessed by the "CIBERSORT" algorithm and the Tumor IMmune Estimation Resource (TIMER) tool. Finally, the results were experimentally validated in real-world study. Results: A total of 69 OGG were retrieved, and 17 significantly differentially expressed genes (SDEG) were identified between normal and EAC tissues. Enrichment analysis showed the OGG were enriched in the mitochondrion-related and various receptor pathways. Univariate Cox regression results showed that the MCM6, ATXN2 and CSK were significantly associated with OS (P=0.036, 0.039, 0.046, respectively). Multivariate Cox regression analysis showed MCM6 and CSK were independent prognostic genes for OS (P=0.025, 0.041, respectively). Nomogram demonstrated that the OGG had good predictive abilities for the 1-, 2-, and 3-year OS. Immunity analysis demonstrated that OGG were significantly associated with immune cells (P <0.05). In addition, clinical correlation analysis revealed that the OGG had significant relations with clinical parameters (P <0.05). The experiment results confirmed that the SDEG were significantly different between normal and EAC tissues (P <0.05). Conclusions: We identified the OGG expression profiles that may uncouple obesity from poor survival in patients with EAC. They have prognostic values in predicting patients' OS, and may be exploited for prognostic biomarkers.


Fitness facility staff demonstrate high fidelity when implementing an evidence-based diabetes prevention program.
Translating evidence-based diabetes prevention programs into the community is needed to make promising interventions accessible to individuals at-risk of type 2 diabetes. To increase the likelihood of successful translation, implementation evaluations should be conducted to understand program outcomes and provide feedback for future scale-up sites. The purpose of this research was to examine the delivery of, and engagement with, an evidence-based diet and exercise diabetes prevention program when delivered by fitness facility staff within a community organization. Ten staff from a community organization were trained to deliver the diabetes prevention program. Between August 2019-March 2020, 26 clients enrolled in the program and were assigned to one of the ten staff. Three fidelity components were accessed. First, staff completed session-specific fidelity checklists (n = 156). Second, two audio-recorded counseling sessions from all clients underwent an independent coder fidelity check (n = 49). Third, staff recorded client goals on session-specific fidelity checklists and all goals were independently assessed for (a) staff goal-setting fidelity, (b) client intervention receipt, and (c) client goal enactment by two coders (n = 285). Average self-reported fidelity was 90% for all six sessions. Independent coder scores for both counseling sessions were 83% and 81%. Overall staff helped clients create goals in line with program content and had a goal achievement of 78%. The program was implemented with high fidelity by staff at a community organization and clients engaged with the program. Findings increase confidence that program effects are due to the intervention itself and provide feedback to refine implementation strategies to support future scale-up efforts.


MicroRNA‑448 inhibits the progression of retinoblastoma by directly targeting ROCK1 and regulating PI3K/AKT signalling pathway.
Retinoblastoma (RB) is the most common primary intraocular malignancy during infancy and childhood worldwide. Numerous microRNAs (miRNAs) contribute to RB initiation and progression through the regulation of cell proliferation, cycle, apoptosis, migration, invasion and metastasis. Therefore, further investigation concerning the expression, roles and associated mechanisms of RB‑related miRNAs may be beneficial to develop novel strategies for patients with this malignancy. Recently, miRNA‑448 (miR‑448) has been reported to be aberrantly expressed and to play an important role in several types of human cancer. However, the expression patterns and biological roles of miR‑448 in RB have not been studied. The aim of the present study was to detect the expression levels of miR‑448 and investigate its functions in RB and its associated molecular mechanisms. In the present study, miR‑448 was significantly downregulated in RB tissues and cell lines. Upregulation of miR‑448 decreased cell proliferation and invasion and increased apoptosis in RB cells. Additionally, ρ‑associated coiled‑coil containing protein kinase 1 (ROCK1) was validated as a novel direct target gene of miR‑448 in RB. ROCK1 was overexpressed in RB tissues and inversely correlated with miR‑448 expression. Furthermore, ROCK1 silencing induced effects on the proliferation, invasion and apoptosis of RB cells similar to those observed following miR‑448 overexpression. Moreover, restoration of miR‑448 expression markedly reversed the effects of miR‑448 overexpression on RB cells, further supporting the hypothesis that ROCK1 is a direct functional target of miR‑448 in RB. Importantly, miR‑448 targeted ROCK1 to inhibit the activation of the PI3K/AKT signalling pathway in RB. These results demonstrated that miR‑448 may serve as a tumour suppressor in RB by directly targeting ROCK1 and regulating the PI3K/AKT signalling pathway, thereby suggesting that miR‑448 may be an effective therapeutic target for treating this aggressive cancer.


The mutations associated with dilated cardiomyopathy.
Cardiomyopathy is an important cause of heart failure and a major indication for heart transplantation in children and adults. This paper describes the state of the genetic knowledge of dilated cardiomyopathy (DCM). The identification of the causing mutation is important since presymptomatic interventions of DCM have proven value in preventing morbidity and mortality. Additionally, as in general in genetic studies, the identification of the mutated genes has a direct clinical impact for the families and population involved. Identifying causative mutations immediately amplifies the possibilities for disease prevention through carrier screening and prenatal testing. This often lifts a burden of social isolation from affected families, since healthy family members can be assured of having healthy children. Identification of the mutated genes holds the potential to lead to the understanding of disease etiology, pathophysiology, and therefore potential therapy. This paper presents the genetic variations, or disease-causing mutations, contributing to the pathogenesis of hereditary DCM, and tries to relate these to the functions of the mutated genes.


Factors affecting comparative resistance of naturally occurring and subcultured Pseudomonas aeruginosa to disinfectants.
A strain of Pseudomonas aeruginosa was isolated in pure culture from the reservoir of a hospital mist therapy unit by an extinction-dilution technique; its natural distilled water environment was used as a growth and maintenance medium. After a single subculture on Trypticase soy agar, the strain showed a marked decrease in resistance to inactivation by acetic acid, glutaraldehyde, chlorine dioxide, and a quaternary ammonium compound when compared with naturally occurring cells grown in mist therapy unit water. The following factors were observed to affect the relative resistances of naturally occurring and subcultured cells of the P. aeruginosa strain: (i) temperature at which the cultures were incubated prior to exposure to disinfectants, (ii) growth phase of the cultures at the time of exposure to disinfectants, (iii) nature of the suspending menstruum for disinfectants, and (iv) exposure to fluorescent light during incubation of inocula prior to testing. The applied significance of these findings may alter the present concepts of disinfectant testing as well as routine control procedures in the hospital environment.


The Use of Plasmapheresis in a Severe Case of Amiodarone-Induced Thyrotoxicosis.
Amiodarone-induced thyrotoxicosis (AIT) can be difficult to treat since amiodarone's long half-life leads to a persistent effect on thyroid function. We present a case of a 74-year-old male with severe AIT who presented with altered mentation and ultimately required intubation and intensive care for management of thyroid storm. Standard medical therapy for treatment of thyroid storm was initiated immediately, but the patient remained unresponsive with worsening biochemical parameters with increasing total T3 levels and sustained elevated levels of free T4 after 5 days of medical management. Due to the lack of a clinical and biochemical response to conventional medical therapy, the patient was started on plasmapheresis and underwent a total of 7 cycles of plasmapheresis over a period of 10 days. He significantly improved with plasmapheresis and was successfully bridged to a total thyroidectomy, which was completed without complications.


Regulation of methionine biosynthesis in Escherichia coli: mapping of the metJ locus and properties of a metJ plus-metJ minus diploid.
MetJ(-) mutants of Escherichia coli have elevated nonrepressible levels of the enzymes of methionine biosynthesis and S-adenosylmethionine synthetase (ATP:L-methionine S-adenosyltransferase, EC 22.214.171.124). In E. coli, as in Salmonella typhimurium, the metJ locus is close to metB (95% cotransduction of metB and metJ markers), but in E. coli the order is reversed, with metJ mapping clockwise to metB. A stable merodiploid, heterozygous for metJ, is subject to repression by methionine. Thus, metJ functions via a diffusible product. MetJ could either be a regulatory locus or could code for an enzyme required for the synthesis of a methionine metabolite that functions in the control system.


Evaluation of prognostic indicators for elderly patients admitted in intensive care units.
The elderly constitute a population with their own features and frequent admissions in intensive care units. This study has the objective to evaluate the ability to predict the survival of these patients through the APACHE II, UNICAMP II, SAPS II and SAPS 3 indexes, global and Central America/South equations. Elderly patients admitted from 01/01/2006 to 12/3/2006, defined as age > 60 years, were included in this study. Those who were readmitted were excluded. The rate of lethality standardized, calibration and discrimination for each index in the remaining patients were analysed. The outcome were death or hospital discharge. Three hundred eighty six elderly patients were included in this study, being 36 excluded by readmission, remaining 350 for analysis. The rate of lethality standardized came near to the unit in all indexes, except the SAPS II (TLP=1.5455) which underestimated the lethality. The calibration, via Hosmer-Lemeshow tests was inadequate (p < 0.05), except for the UNICAMP II (p > 0.5). On the calibration curve, the models have distanced themselves from the pattern line. All of them presented an excellent discrimination via receiver operating characteristics curves (> 0.8). In the studied population, the models presented an excellent discrimination and inadequate calibration. SAPS II underestimated the lethality.


Palmitoylation and membrane cholesterol stabilize μ-opioid receptor homodimerization and G protein coupling.
A cholesterol-palmitoyl interaction has been reported to occur in the dimeric interface of the β₂-adrenergic receptor crystal structure. We sought to investigate whether a similar phenomenon could be observed with μ-opioid receptor (OPRM1), and if so, to assess the role of cholesterol in this class of G protein-coupled receptor (GPCR) signaling. C3.55(170) was determined to be the palmitoylation site of OPRM1. Mutation of this Cys to Ala did not affect the binding of agonists, but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex. In addition, both attenuation of receptor palmitoylation (by mutation of C3.55[170] to Ala) and inhibition of cholesterol synthesis (by treating the cells with simvastatin, a HMG-CoA reductase inhibitor) impaired receptor signaling, possibly by decreasing receptor homodimerization and Gαi2 coupling; this was demonstrated by co-immunoprecipitation, immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) analyses. A computational model of the OPRM1 homodimer structure indicated that a specific cholesterol-palmitoyl interaction can facilitate OPRM1 homodimerization at the TMH4-TMH4 interface. We demonstrate that C3.55(170) is the palmitoylation site of OPRM1 and identify a cholesterol-palmitoyl interaction in the OPRM1 complex. Our findings suggest that this interaction contributes to OPRM1 signaling by facilitating receptor homodimerization and G protein coupling. This conclusion is supported by computational modeling of the OPRM1 homodimer.


Effects of high-intensity functional training on physical fitness and sport-specific performance among the athletes: A systematic review with meta-analysis.
This study aims to meta-analyze the impact of high-intensity functional training on athletes' physical fitness and sport-specific performance. A systematic search was conducted in five well-known academic databases (PubMed, Scopus, Web of Science, EBSCOhost, and the Cochrane Library) up to July 1, 2023. The literature screening criteria included: (1) studies involving healthy athletes, (2) a HIFT program, (3) an assessment of outcomes related to athletes' physical fitness or sport-specific performance, and (4) the inclusion of randomized controlled trials. The Physical Therapy Evidence Database (PEDro) scale was used to evaluate the quality of studies included in the meta-analysis. 13 medium- and high-quality studies met the inclusion criteria for the systematic review, involving 478 athletes aged between 10 and 24.5 years. The training showed a small to large effect size (ES = 0.414-3.351; all p < 0.05) in improving upper and lower body muscle strength, power, flexibility, and sport-specific performance. High-intensity functional training effectively improves athletes' muscle strength, power, flexibility, and sport-specific performance but has no significant impact on endurance and agility. Future research is needed to explore the impact of high-intensity functional training on athletes' speed, balance, and technical and tactical performance parameters.


Epigallocatechin-3-gallate(-)protects Chang liver cells against ethanol-induced cytotoxicity and apoptosis.
The objective of the study was to investigate the effect of epigallocatechin-3-gallate (EGCG) on ethanol (EtOH)-induced cytotoxicity in human Chang liver cells. Cells were incubated with either 30 mM EtOH alone or together in presence of (25 microM) EGCG for 24 hr. Assays were performed in treated cells to evaluate the ability of EGCG to prevent the toxic effects of EtOH. EtOH exposure suppressed the growth of Chang liver cells and induced lactate dehydrogenase leakage, oxygen radical formation, peroxidation of lipids, mitochondrial dysfunction and apoptosis. Reduced glutathione (GSH) concentration was significantly decreased (P < 0.05) while oxidized glutathione (GSSG) concentration was significantly elevated in EtOH-treated cells as compared to normal cells. Incubation of EGCG along with EtOH significantly prevented EtOH-dependent cell loss and lactate dehydrogenase leakage. This was associated with a reduction in oxidative damage as reflected by a reduction in the generation of reactive oxygen species, and in lipid peroxidation and maintenance of intracellular GSH/GSSG ratio. EGCG decreased the accumulation of sub-G(1) phase cells and reduced apoptosis. The findings suggest that EGCG exerts a protective action during EtOH-induced liver cell damage.


Endotoxin, zymosan, and cytokines decrease the expression of the transcription factor, carbohydrate response element binding protein, and its target genes.
Carbohydrate response element binding protein (ChREBP) is a recently discovered transcription factor whose levels and activity are increased by glucose leading to the activation of target genes, which include acetyl-CoA carboxylase, fatty acid synthase, and liver-type pyruvate kinase. Here, we demonstrate that lipopolysaccharide (LPS) treatment causes a marked decrease in ChREBP mRNA and protein levels in the liver of mice fed a normal chow diet or in mice fasted for 24 h and then re-fed a high carbohydrate diet. This decrease occurs rapidly and is a sensitive response (half-maximal dose 0.1 μg/mouse). The decrease in ChREBP is accompanied by a decrease in the expression of ChREBP target genes. Zymosan and turpentine treatment also decrease hepatic ChREBP levels and the expression of its target genes. Additionally, tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) decrease liver ChREBP expression both in vivo and in Hep3B cells in culture. Finally, LPS decreased ChREBP expression in muscle and adipose tissue. These studies demonstrate that ChREBP is down-regulated during the acute phase response resulting in alterations in the expression of ChREBP regulated target genes. Thus, ChREBP joins a growing list of transcription factors that are regulated during the acute phase response.


T-DNA insertional mutagenesis for functional genomics in rice.
We have produced 22 090 primary transgenic rice plants that carry a T-DNA insertion, which has resulted in 18 358 fertile lines. Genomic DNA gel-blot and PCR analyses have shown that approximately 65% of the population contains more than one copy of the inserted T-DNA. Hygromycin resistance tests revealed that transgenic plants contain an average of 1.4 loci of T-DNA inserts. Therefore, it can be estimated that approximately 25 700 taggings have been generated. The binary vector used in the insertion contained the promoterless beta-glucuronidase (GUS) reporter gene with an intron and multiple splicing donors and acceptors immediately next to the right border. Therefore, this gene trap vector is able to detect a gene fusion between GUS and an endogenous gene, which is tagged by T-DNA. Histochemical GUS assays were carried out in the leaves and roots from 5353 lines, mature flowers from 7026 lines, and developing seeds from 1948 lines. The data revealed that 1.6-2.1% of tested organs were GUS-positive in the tested organs, and that their GUS expression patterns were organ- or tissue-specific or ubiquitous in all parts of the plant. The large population of T-DNA-tagged lines will be useful for identifying insertional mutants in various genes and for discovering new genes in rice.


Increased childhood abuse in patients with premenstrual dysphoric disorder in a Turkish sample: a cross-sectional study.
Abuse is considered to have a place in the etiology of various psychiatric disorders. Premenstrual dysphoric disorder (PMDD) is one of the psychiatric disorders for which abuse could be an etiologic factor; however, few studies have investigated the relationship between abuse and PMDD. In this study, our aim was to investigate childhood abuse in patients with PMDD and compare them with healthy female subjects. This cross-sectional study included 70 women with PMDD (DSM-IV-TR criteria) who were admitted to the outpatient psychiatry clinic of Ankara Yenimahalle State Hospital, Ankara, Turkey, between December 2012 and December 2013. Additionally, 78 healthy controls were included in the study. Sociodemographic, familial, and reproductive period characteristics of the women were recorded. All subjects were administered the Premenstrual Syndrome Scale (PMSS) and the Childhood Trauma Questionnaire (CTQ). Among the sociodemographic characteristics, being a university graduate (76.9%) and being a public servant (70.5%) were significantly higher in the healthy control group (P = .01 and P = .01, respectively). A family history of PMDD (31.4%), a history of postpartum psychiatric disorders (11.4%), and a history of attempted suicide (7.1%) were higher in the PMDD group compared with the healthy control group (P = .001, P = .003, and P = .024, respectively). Significant differences were also found between PMDD and healthy controls in PMSS score (P ≤ .001), CTQ total scores (P = .002), and subscale scores including emotional abuse and emotional neglect (P = .004), physical abuse (P = .009), and sexual abuse (P = .012). To our knowledge, the present study is the first to investigate associations between PMDD and childhood abuse from Turkey. More comprehensive studies on this topic with larger sample sizes are required to enrich the literature and enable practitioners to be more effective in clinical practice.


Effect of maternal asthma on birthweight and neonatal outcome in a British inner-city population.
During pregnancy, asthma-related alterations in placental function and the maternal immune system, and reduced growth affecting female but not male fetuses have been reported in a study of selected Australian women. The objective of this study was to evaluate the effect of asthma management, declared during pregnancy, on birthweight and neonatal outcome at an inner-city hospital in England. Between June 2001 and December 2003, women at antenatal clinics were questioned about asthma (n = 10 983). Women with asthma and singleton uncomplicated pregnancies ending at term were selected (n = 718), with non-asthmatic controls (n = 718). Among asthmatic women using inhaled steroids and bronchodilators (n = 170), 43% of the newborn boys had birthweights <10th centile, compared with 27% of controls (P = 0.011; OR 2.51 [95% CI: 1.52, 4.14]). For girls, the proportions were 28% and 27%. In women using bronchodilators only (n = 178) or those declaring no treatment (n = 370), birthweights were not significantly reduced. Taking account of smoking, ethnicity, gestational age and parity, there was a mean birthweight reduction with inhaled steroids and bronchodilators of 118 g [95% CI 36.0, 199.0 g] compared with the control group. There was no interaction between the effect of asthma treatment and infant gender. Infants of asthmatic women in the three subgroups who required intensive care were more likely to exhibit transient tachypnoea of the newborn than infants of control women (P < 0.005). In our population-based sample, the risk of low birthweight among asthmatic women did not depend on infant gender, while neonatal respiratory morbidity remains a significant health issue in boys and girls.


Emergency cardiac surgery in patients with acute coronary syndromes: a review of the evidence and perioperative implications of medical and mechanical therapeutics.
Patients with acute coronary syndromes who require emergency cardiac surgery present complex management challenges. The early administration of antiplatelet and antithrombotic drugs has improved overall survival for patients with acute myocardial infarction, but to achieve maximal benefit, these drugs are given before coronary anatomy is known and before the decision to perform percutaneous coronary interventions or surgical revascularization has been made. A major bleeding event secondary to these drugs is associated with a high rate of death in medically treated patients with acute coronary syndrome possibly because of subsequent withholding of antiplatelet and antithrombotic therapies that otherwise reduce the rate of death, stroke, or recurrent myocardial infarction. Whether the added risk of bleeding and blood transfusion in cardiac surgical patients receiving such potent antiplatelet or antithrombotic therapy before surgery specifically for acute coronary syndromes affects long-term mortality has not been clearly established. For patients who do proceed to surgery, strategies to minimize bleeding include stopping the anticoagulation therapy and considering platelet and/or coagulation factor transfusion and possibly recombinant-activated factor VIIa administration for refractory bleeding. Mechanical hemodynamic support has emerged as an important option for patients with acute coronary syndromes in cardiogenic shock. For these patients, perioperative considerations include maintaining appropriate anticoagulation, ensuring suitable device flow, and periodically verifying correct device placement. Data supporting the use of these devices are derived from small trials that did not address long-term postoperative outcomes. Future directions of research will seek to optimize the balance between reducing myocardial ischemic risk with antiplatelet and antithrombotics versus the higher rate perioperative bleeding by better risk stratifying surgical candidates and by assessing the effectiveness of newer reversible drugs. The effects of mechanical hemodynamic support on long-term patient outcomes need more stringent analysis.


Codon conservation in the influenza A virus genome defines RNA packaging signals.
Genome segmentation facilitates reassortment and rapid evolution of influenza A virus. However, segmentation complicates particle assembly as virions must contain all eight vRNA species to be infectious. Specific packaging signals exist that extend into the coding regions of most if not all segments, but these RNA motifs are poorly defined. We measured codon variability in a large dataset of sequences to identify areas of low nucleotide sequence variation independent of amino acid conservation in each segment. Most clusters of codons showing very little synonymous variation were located at segment termini, consistent with previous experimental data mapping packaging signals. Certain internal regions of conservation, most notably in the PA gene, may however signify previously unidentified functions in the virus genome. To experimentally test the bioinformatics analysis, we introduced synonymous mutations into conserved codons within known packaging signals and measured incorporation of the mutant segment into virus particles. Surprisingly, in most cases, single nucleotide changes dramatically reduced segment packaging. Thus our analysis identifies cis-acting sequences in the influenza virus genome at the nucleotide level. Furthermore, we propose that strain-specific differences exist in certain packaging signals, most notably the haemagglutinin gene; this finding has major implications for the evolution of pandemic viruses.


Alcohol-Related Knowledge and Alcohol-Related Norms in 4- to 6-Year-Olds-Evidence from the Dutch Electronic Appropriate Beverage Task.
Limited research is available on children's alcohol-related knowledge and alcohol-related norms, yet a better comprehension of these factors may be crucial in explaining alcohol use later in life. This study provides insights into alcohol-related knowledge and alcohol-related norms in 4- to 6-year-olds. Participating children (N = 329; 48.9% boys) were shown, on a tablet, 18 drawings depicting 72 male and female adults and/or children in various situations, and were asked to indicate what the depicted persons drank by touching 1 of 12 depicted beverages (4 alcoholic; 8 nonalcoholic). Subsequently, the children were asked to name the beverages and indicate whether they contained alcohol. Children identified 30.7% of the alcoholic beverages (i.e., beer, champagne, red wine, and white wine) correctly by name, and they identified 41.6% of the alcoholic beverages correctly as alcohol containing. Children more often correctly identified the name and nonalcoholic content of nonalcoholic beverages compared to the name and alcoholic content of alcoholic beverages. No sex differences emerged in the correct identification of the name and the content of both alcoholic beverages and nonalcoholic beverages. However, alcohol-related knowledge was age graded. Alcoholic beverages were more often assigned to male adults (39.2%) than to female adults (24.8%) or to children (13.2%). Additionally, alcoholic beverages were more often assigned to adults depicted in the presumably more appropriate situations (e.g., "when having an indoor party": 37.0%) than to those depicted in the presumably more inappropriate situations (e.g., "when driving a car": 28.6%). Four- to 6-year-olds already have knowledge about alcohol and its norms in adult culture. Insight into the development of children's alcohol-related knowledge and alcohol-related norms over time is required to investigate the transitions to alcohol expectancies, drinking motives, and alcohol initiation often occurring in adolescence.


Differences in plasma MMPs and TIMPs protein expression and chemotherapy response in patients with tobacco- or wood-smoke-induced lung cancer.
One of the risk factors associated with lung cancer in never-smoker patients is wood smoke exposure (WS). However, information about its clinical and molecular characteristics remains scant. This was to analyze--in plasma from patients with tobacco- or wood-smoke-induced lung cancer--whether the enzymatic activity and concentration of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) differ, and to determine whether there was a correlation between these indicators of the metastatic potential and the first-line chemotherapy response. Patients were classified according to lung cancer associated with: the smoking of tobacco (T), WS and where no association with a known risk factor (N) could be established. The gelatinase activity of plasma MMP was analyzed by radiolabeled substrate degradation and zymography assay. Protein expression of MMPs and TIMPs was evaluated by Western blot densitometry analysis. The 26.9% WS patients had a better response to therapy in comparison with the T group (OR = 4.9, 95% CI = 1.25-20.15; p = 0.019). The lowest gelatinase activity was observed in WS subjects, in comparison with T and N subjects (96.7 ± 15.9, 182.9 ± 31.5 and 163.3 ± 22.7 µg of degraded gelatin/mg of incubated plasma protein, respectively; p < 0.025); this enzymatic activity corresponded to MMP-2. The highest MMP-2, MMP-9, MT1-MMP and TIMP-1 plasma levels were observed in T subjects. Tobacco and wood smoke have different effects on MMP and TIMP synthesis and gelatinase activity, directly influencing lung cancer metastatic potential and chemotherapy response.


Construction of an electrode for intraoperative nerve stimulation.
The electrode described in this paper consist of a barrel or handle with its conducting cable and a detachable stimulating tip. It is constructed of inexpensive and commercially available materials and is disposable. During the course of a stimulation study, electrode tips of different lengths or curvatures may be substituted without the need to replace the electrode barrel and cable.


[Causes and factors of development of drug resistance in pulmonary tuberculosis].
To prevent secondary multidrug resistance and polyresistance of Mycobacterium tuberculosis (MBT), it is necessary to strictly observe the tested chemotherapy regimens during intensive care by using at least four essential antituberculous drugs (ATD) mainly in combination. The rehabilitative phase should be monitored at outpatient units of a day hospital. To prevent cross MBT infection with drug resistance to essential ATD and to efficiently use expensive reserve drugs, it is necessary to set up specialized inpatient units (wards) for treatment and rooms for outpatient receipt of patients who isolate drug-resistant MBT strains.


A theoretical framework for strain-related trabecular bone maintenance and adaptation.
It is assumed that density and morphology of trabecular bone is partially controlled by mechanical forces. How these effects are expressed in the local metabolic functions of osteoclast resorption and osteoblast formation is not known. In order to investigate possible mechano-biological pathways for these mechanisms we have proposed a mathematical theory (Nature 405 (2000) 704). This theory is based on hypothetical osteocyte stimulation of osteoblast bone formation, as an effect of elevated strain in the bone matrix, and a role for microcracks and disuse in promoting osteoclast resorption. Applied in a 2-D Finite Element Analysis model, the theory explained the formation of trabecular patterns. In this article we present a 3-D FEA model based on the same theory and investigated its potential morphological predictability of metabolic reactions to mechanical loads. The computations simulated the development of trabecular morphological details during growth, relative to measurements in growing pigs, reasonably realistic. They confirmed that the proposed mechanisms also inherently lead to optimal stress transfer. Alternative loading directions produced new trabecular orientations. Reduction of load reduced trabecular thickness, connectivity and mass in the simulation, as is seen in disuse osteoporosis. Simulating the effects of estrogen deficiency through increased osteoclast resorption frequencies produced osteoporotic morphologies as well, as seen in post-menopausal osteoporosis. We conclude that the theory provides a suitable computational framework to investigate hypothetical relationships between bone loading and metabolic expressions.


Effect of home telehealth care on blood pressure control: A public healthcare centre model.
This study aimed to evaluate the effectiveness of home telehealth care combined with case management by public health nurses, in improving blood pressure control in patients with hypertension. This cohort study examined the data of patients with hypertension obtained from a telehealth service centre database, between July 2011- June 2012. Eligible patients were adults (≥40 years old) with both prehypertension and hypertension, living alone or in the remote suburbs of metropolitan areas. Demographic data were collected from 12 district public health centre in Taipei, Taiwan. Following enrolment, patients received an appropriate and validated home telehealth device kit for automatic blood pressure monitoring and automated modem via a telephone line or a desktop computer with Internet connection to enable data transmission between the patient's home and telehealth service centre. Patients were instructed to upload the measured data immediately every day. The study outcomes included blood pressure and home telehealth service utilisation. Of the 432 patients recruited, 408 (94%) completed data collection. Linear regression analysis found an average 22.1 mm Hg reduction in systolic blood pressure after one year. The mean slope of systolic blood pressure was classified as decreased or non-decreased. An systolic blood pressure decreasing trend was observed in 52.2% patients, while 47.8% patients showed an increasing systolic blood pressure trend. Patients in the decreased systolic blood pressure group tended to be older ( p = 0. 0001), with a greater proportion of hypertension alarms ( p = 0. 001), improved self-blood pressure monitoring behaviour ( p = 0.009) and higher self-measured blood pressure monitoring frequency ( p = 0. 010). Patients in the decreased systolic blood pressure group had a higher self-measured blood pressure monitoring frequency (odds ratio = 0.95, 95% confidence interval, 0.91-0.99, p = 0. 013) than their counterparts. Home telehealth care combined with care management by public health nurses based in public health care centre was feasible and effective for improving blood pressure control among patients with hypertension. Further studies should conduct a thorough analysis of the cost-effectiveness of this intervention. A randomised controlled trial with a longer follow-up period is required to examine the effects of the improved home telehealth device kit on the care of patients with hypertension.


Thiol-targeted introduction of selenocysteine to polypeptides for synthesis of glutathione peroxidase mimics.
Because the seleno-l-cysteine (SeCys or Sec) insertion into selenoproteins occurs by a specific translational control process, it is quite difficult to express the SeCys-containing polypeptides even by the state-of-the-art genetic engineering techniques. In this paper, we describe a convenient synthetic method for the selective introduction of a SeCys derivative to polypeptides under physiological conditions. One SeCys residue in the seleno-l-cystine (SeCys-Se-Se-SeCys) methyl ester was first substituted with the Boc-protected penicillamine (Pen) methyl ester to form selenenylsulfide (SeCys-Se-S-Pen), an intermediate in the cellular glutathione peroxidase (GPx) catalytic cycle. Subsequently, the SeCys-Pen was coupled with the thiol-specific N-carboxymethylmaleimide through the α-amino group of the SeCys {[2-(N-maleimidyl)-1-oxo-ethyl-SeCys-methyl-Se-yl]-S-Pen methyl ester, MOE-SeCys-Pen}. The use of the MOE-SeCys-Pen allowed the selective introduction of the SeCys moiety to human serum albumin by alkylation of the thiol at its cysteine34, which generated the GPx-like activity responsible for the selenium atom in the MOE-SeCys-Pen. Consequently, this synthetic method will allow generating SeCys-containing artificial polypeptides with a GPx-like activity.


[Unconventional Laveran].
Charles Louis Alphonse Laveran - 18 June 1845 - 18 May 1922: first French Nobel Prize in Medicine, "in recognition of his work on the role played by protozoa in causing diseases". One hundred years after his death, only written records remain of his work and life. The witnesses to this period are no more. Alphonse Laveran has become an "object" of history.He was deeply involved in a turbulent historical period, marked by crises of regime change (Monarchy/Empire/Republic), military events (French colonial expansion in North Africa from 1830, the wars of 1870 and 1914-1918) and their consequences (the medical impact of infections in the colonial empire and during armed conflicts, the Dreyfus affair, among others), the advent of Pasteurian "microbiology" and the deciphering of the causes and modes of transmission of infectious diseases. A player on the edge of the military and civilian worlds, with their own, sometimes incompatible, visions of the aims and objectives to be pursued, Alphonse Laveran lived through these upheavals in a society in the throes of change, in his family and scientific environment.Paradoxically, the primary sources available to us for learning about this scientist and man are both abundant and "scarce" for us in the 21st century. His scientific publications and many of his speeches at various academies, committees and meetings are for the most part public and accessible, giving us a vision of a professional in scientific and medical research in action, presenting and convincing people of his ideas and theoretical and practical insights. The writings of his contemporaries, both public and private, shed light on - distort? - the man's many facets. On the other hand, there are few surviving sources on the man and his vision of life, his life and that of his family and friends.We will rely on the archives that have been preserved, in particular by the organisations that welcomed him during his military and civilian career, as well as by his wife Marie Laveran and his colleague Marie Phisalix, one of the first doctors of medicine in France and a renowned herpetologist. These two female figures have preserved and contributed to his memory. Let's take a closer look at the man behind the scientist, as we can imagine him through the traces that remain.


G-protein-coupled receptors, channels, and Na+-H+ exchanger in nuclear membranes of heart, hepatic, vascular endothelial, and smooth muscle cells.
The action of several peptides and drugs is thought to be primarily dependent on their interactions with specific cell surface G-protein-coupled receptors and ionic transporters such as channels and exchangers. Recent development of 3-D confocal microscopy allowed several laboratories, including ours, to identify and study the localization of receptors, channels, and exchangers at the transcellular level of several cell types. Using this technique, we demonstrated in the nuclei of several types of cells the presence of Ca(2+) channels as well as Na(+)-H(+) exchanger and receptors such as endothelin-1 and angiotensin II receptors. Stimulation of these nuclear membrane G-protein-coupled receptors induced an increase of nuclear Ca(2+). Our results suggest that, similar to the plasma membrane, nuclear membranes possess channels, exchangers and receptors such as those for endothelin-1 and angiotensin II, and that the nucleus seems to be a cell within a cell. This article will emphasize these findings.


MooSciTIC: Training of trainers in West African research and higher education.
The MooSciTIC project is a capacity-building initiative targeting West African research scientists and higher education teachers. The project aimed to improve the self-reliance of researchers and upgrade research practices by providing on-site summer schools on trans-disciplinary topics such as scientific writing, communication, and integrity. Here, we explain how this program was designed and implemented and share the positive responses from our trainees, hoping to inspire similar initiatives.


Acquired unilateral condylar hyperplasia and facial asymmetry: report of case.
A clinical report is presented of a 12-year-old female with right mandibular hyperplasia, facial asymmetry, bitemporal headaches and left temporomandibular joint pain. Past medical history was noncontributory with the exception of a bicycle accident at age eight, which resulted in minor facial trauma. The management and treatment of this case illustrates the importance of long-term follow-up by the pedodontist and the necessity of a team approach involving pedodontics, orthodontics and oral surgery.


The Vibrio H-Ring Facilitates the Outer Membrane Penetration of the Polar Sheathed Flagellum.
The bacterial flagellum has evolved as one of the most remarkable nanomachines in nature. It provides swimming and swarming motilities that are often essential for the bacterial life cycle and pathogenesis. Many bacteria such as Salmonella and Vibrio species use flagella as an external propeller to move to favorable environments, whereas spirochetes utilize internal periplasmic flagella to drive a serpentine movement of the cell bodies through tissues. Here, we use cryo-electron tomography to visualize the polar sheathed flagellum of Vibrio alginolyticus with particular focus on a Vibrio-specific feature, the H-ring. We characterized the H-ring by identifying its two components FlgT and FlgO. We found that the majority of flagella are located within the periplasmic space in the absence of the H-ring, which are different from those of external flagella in wild-type cells. Our results not only indicate the H-ring has a novel function in facilitating the penetration of the outer membrane and the assembly of the external sheathed flagella but also are consistent with the notion that the flagella have evolved to adapt highly diverse needs by receiving or removing accessary genes.IMPORTANCE Flagellum is the major organelle for motility in many bacterial species. While most bacteria possess external flagella, such as the multiple peritrichous flagella found in Escherichia coli and Salmonella enterica or the single polar sheathed flagellum in Vibrio spp., spirochetes uniquely assemble periplasmic flagella, which are embedded between their inner and outer membranes. Here, we show for the first time that the external flagella in Vibrio alginolyticus can be changed as periplasmic flagella by deleting two flagellar genes. The discovery here may provide new insights into the molecular basis underlying assembly, diversity, and evolution of flagella.


Morphogenetic effects of 6-azauracil and 6-azauridine.
When 6-azauracil and 6-azauridine are fed to larvae of the tu(w) rc strain of Drosophila melano-gaster which has the normal wing shape, adults hatch with shortened, obliquely truncated wings. This wing shape resembles that of the mutant dumpy. On the other hand, administration of these drugs to the mutant dumpy strain increases wing length, and flies with normal wings are obtained.


Clinical Analysis of the Effects of Frontal Bone Reconstruction and Cranial Suture Reconstruction in the Operation of Simple Premature Closure of Frontal Suture in Infants.
To compare, and to analyze the effects of cranial suture reconstruction and frontal bone reconstruction in the operation of premature closure of the sagittal suture in infants. A total of 35 infants with simple premature closure of frontal suture were divided into the experimental group (n=18) and the control group (n=17). In the experimental group, the skull model was reconstructed by imaging examination and three-dimensional (3D) printing technique before operation, and the frontal bone reconstruction was used to guide the surgical treatment of cranial stenosis. In the control group, the skull model was reconstructed by imaging examination and 3D printing technique before operation, and the cranial suture reconstruction was performed by the same operator. The surgical effects of the two groups were compared. During the 12-month follow-up after operation, the interfrontal angles of scaphoid malformation were 153.67 ± 12.77 and 128.67 ± 7.90 in the experimental and control groups, respectively. The difference between the two groups was statistically significant. Frontal bone reconstruction surgery can guide the operation of cranial stenosis, significantly improve the surgical treatment effect of infants with frontal suture, and esthetically enhance the head type of infants. Moreover, its effect is better than that of traditional operation, which is worth given significant attention in clinical settings.


Substitution of the Bordetella pertussis lipid A phosphate groups with glucosamine is required for robust NF-kappaB activation and release of proinflammatory cytokines in cells expressing human but not murine Toll-like receptor 4-MD-2-CD14.
Bordetella pertussis endotoxin is a key modulator of the host immune response, mainly due to the role of its lipid A moiety in Toll-like receptor 4 (TLR4)-mediated signaling. We have previously demonstrated that the lipid A phosphate groups of B. pertussis BP338 can be substituted with glucosamine in a BvgAS-regulated manner. Here we examined the effect of this lipid A modification on the biological activity of B. pertussis endotoxin. We compared purified endotoxin and heat-killed B. pertussis BP338 whole cells that have modified lipid A phosphate groups to an isogenic mutant lacking this modification with respect to their capacities to induce the release of inflammatory cytokines by human and murine macrophages and to participate in the TLR4-mediated activation of NF-kappaB in transfected HEK-293 cells. We found inactivated B. pertussis cells to be stronger inducers of proinflammatory cytokines in THP-1-derived macrophages when lipid A was modified. Most notably, lack of lipid A modification abolished the ability of purified B. pertussis endotoxin to induce the release of inflammatory cytokines by human THP-1-derived macrophages but led to only slightly reduced inflammatory cytokine levels when stimulating murine (RAW 264.7) macrophages. Accordingly, upon stimulation of HEK-293 cells with inactivated bacteria and purified endotoxin, lack of lipid A modification led to impaired NF-kappaB activation only when human, and not when murine, TLR4-MD-2-CD14 was expressed. We speculate that in B. pertussis, lipid A modification has evolved to benefit the bacteria during human infection by modulating immune defenses rather than to evade innate immune recognition.


Simple identification of mitochondrial lineages in contact zones based on lineage-selective primers.
A variety of research projects focus on genetic variation among and within maternal lineages as encompassed by mitochondrial DNA (mtDNA). While mtDNA often differs substantially between species, large differences may also be found within species. The evaluation of such divergent lineages, for example in intraspecific contact zones (hybrid zones), commonly involves sequencing numerous individuals. Large-scale sequencing is both expensive and labour-intensive. Based on sequences from 15 individuals, we devised a simple and quick polymerase chain reaction assay for identification of divergent mtDNA lineages in a secondary contact zone of the side-blotched lizard (Uta stansburiana). The application uses lineage-selective primers to amplify a lineage-diagnostic product, and is based on each group of mtDNA haplotypes being a monophyletic assemblage of haplotypes sharing the same maternal ancestry, deeply divergent from the other group. The assay was tested on a larger sample (n = 147) of specimens from the contact zone, confirming its usefulness in quick and reliable identification of mtDNA lineages. This approach can be modified for other species, provided diagnostic lineage variation is available, and may also be performed in simple laboratory settings while conducting fieldwork.


Identification of proopiomelanocortin neurones in rat hypothalamus by in situ cDNA-mRNA hybridization.
Ardrenocorticotropic hormone (ACTH), beta-endorphin and the melanotropins (MSHs) are all derived from a single large precursor molecule, proopiomelanocortin (POMC) by individual processing through a series of co- and post-translational modifications. Although the primary site of synthesis is in the pituitary, POMC-derived peptides have been identified in various tissues, notably the brain (see refs 6, 7 for review). A major question concerning brain POMC is whether it is synthesized within the central nervous system (CNS) itself or whether it is taken up from plasma flowing in a retrograde fashion from the pituitary. POMC peptides have been detected immunohistochemically and biochemically in the medial basal hypothalamus, the amygdala and throughout the brain stem. POMC peptide-containing cell bodies have been identified only in two cell groups, however, principally in the periarcuate region of the hypothalamus and to a lesser extent in the nucleus of the tractus solitarius. These and other observations have suggested that POMC peptides are synthesized locally in the medial basal hypothalamus and reach other regions of the CNS by axonal transport. Civelli et al. identified POMC mRNAs in nucleic acid extracts of rat and bovine hypothalami by solution hybridization as well as Northern gel blot analysis, but because of the close proximity of the hypothalamus to the pituitary and the extremely low amounts of POMC mRNA being measured in the hypothalamus, the possibility of tissue contamination during dissection could not be ruled out. We report here the anatomical co-localization of POMC-related peptides and POMC-specific mRNAs to a single major cell group in the medial basal hypothalamus. The presence of POMC-specific mRNA in a POMC peptide-containing cell in the brain is strong support for POMC biosynthesis within brain tissue.


Microtubules: greater than the sum of the parts.
The post-genomic era has produced a variety of new investigation technologies, techniques and approaches that may offer exciting insights into many long-standing questions of scientific research. The microtubule cytoskeleton is a highly conserved system that shows a high degree of internal complexity, is known to be integral to many cell systems and functions on a fundamental level. After decades of study, much is still unknown about microtubules in vivo from the control of dynamics in living cells to their responses to environmental changes and responses to other cellular processes. In the present article, we examine some outstanding questions in the microtubule field and propose a combination of emerging interdisciplinary approaches, i.e. high-throughput functional genomics techniques, quantitative and super-resolution microscopy, and in silico modelling, that could shed light on the systemic regulation of microtubules in cells by networks of regulatory factors. We propose that such an integrative approach is key to elucidate the function of the microtubule cytoskeleton as a complete responsive integral biological system.


Steroid-responsive nephrotic syndrome and allergy: immunological studies.
Immunological studies were performed on 84 children with steroid-sensitive nephrotic syndrome as part of an investigation of the relationship between steroid-responsive nephrotic syndrome and allergy. Serum total IgE levels tended to be raised, particularly in children who had frequent relapses of nephrotic syndrome. Ten children had extremely high levels (greater than 1500 IU/ml) and several of them had neither a history of atopy nor any other identifiable cause. 25% of the children had at least one positive test for specific IgE antibody. IgE was not detected by immunofluorescence in renal biopsy tissue from 25 children, regardless of whether the child was in remission or relapse at the time of biopsy. Serum IgG and IgA levels were depressed particularly at the time of a relapse. Serum IgM tended to be raised and to remain so, even in children who had been in remission for more than a year. No clinically useful relationship was found between the frequency of HLA antigens and the occurrence or course of the syndrome, whether or not accompanied by atopy. Clinical and immunological features of atopy are more common in children with idiopathic nephrotic syndrome. This may be a causal or non-causal association. Pollen sensitivity is a rare cause of nephrotic syndrome; careful search for provocative agents may show other causes.


Gliotransmission: focus on exocytotic release of L-glutamate and D-serine from astrocytes.
The release of neuromodulators, called gliotransmitters, by astrocytes is proposed to modulate neurotransmission and synaptic plasticity, and thereby cognitive functions; but they are also proposed to have a role in diverse neurological disorders. Two main routes have been proposed to ensure gliotransmitter release: non-exocytotic release from cytosolic pools through plasma membrane proteins, and Ca2+-regulated exocytosis through the fusion of gliotransmitter-storing secretory organelles. Regulated Ca2+-dependent glial exocytosis has received much attention and is appealing since its existence endows astrocytes with some of the basic properties thought to be exclusive to neurons and neuroendocrine cells. The present review summarizes recent findings regarding the exocytotic mechanisms underlying the release of two excitatory amino acids, L-glutamate and D-serine.


Salivary Oral Microbiome of Children With Juvenile Idiopathic Arthritis: A Norwegian Cross-Sectional Study.
The oral microbiota has been connected to the pathogenesis of rheumatoid arthritis through activation of mucosal immunity. The objective of this study was to characterize the salivary oral microbiome associated with juvenile idiopathic arthritis (JIA), and correlate it with the disease activity including gingival inflammation. Fifty-nine patients with JIA (mean age, 12.6 ± 2.7 years) and 34 healthy controls (HC; mean age 12.3 ± 3.0 years) were consecutively recruited in this Norwegian cross-sectional study. Information about demographics, disease activity, medication history, frequency of tooth brushing and a modified version of the gingival bleeding index (GBI) and the simplified oral hygiene index (OHI-S) was obtained. Microbiome profiling of saliva samples was performed by sequencing of the V1-V3 region of the 16S rRNA gene, coupled with a species-level taxonomy assignment algorithm; QIIME, LEfSe and R-package for Spearman correlation matrix were used for downstream analysis. There were no significant differences between JIA and HC in alpha- and beta-diversity. However, differential abundance analysis revealed several taxa to be associated with JIA: TM7-G1, Solobacterium and Mogibacterium at the genus level; and Leptotrichia oral taxon 417, TM7-G1 oral taxon 352 and Capnocytophaga oral taxon 864 among others, at the species level. Haemophilus species, Leptotrichia oral taxon 223, and Bacillus subtilis, were associated with healthy controls. Gemella morbillorum, Leptotrichia sp. oral taxon 498 and Alloprevotella oral taxon 914 correlated positively with the composite juvenile arthritis 10-joint disease activity score (JADAS10), while Campylobacter oral taxon 44 among others, correlated with the number of active joints. Of all microbial markers identified, only Bacillus subtilis and Campylobacter oral taxon 44 maintained false discovery rate (FDR) < 0.1. In this exploratory study of salivary oral microbiome we found similar alpha- and beta-diversity among children with JIA and healthy. Several taxa associated with chronic inflammation were found to be associated with JIA and disease activity, which warrants further investigation.


Cyanobacteria drive community composition and functionality in rock-soil interface communities.
Most ecological research on hypoliths, significant primary producers in hyperarid deserts, has focused on the diversity of individual groups of microbes (i.e. bacteria). However, microbial communities are inherently complex, and the interactions between cyanobacteria, heterotrophic bacteria, protista and metazoa are likely to be very important for ecosystem functioning. Cyanobacterial and heterotrophic bacterial communities were analysed by pyrosequencing, while metazoan and protistan communities were assessed by T-RFLP analysis. Microbial functionality was estimated using carbon substrate utilization. Cyanobacterial community composition was significant in shaping community structure and function in hypoliths. Ecological network analysis showed that most significant co-occurrences were positive, representing potential synergistic interactions. There were several highly interconnected associations (modules), and specific cyanobacteria were important in driving the modular structure of hypolithic networks. Together, our results suggest that hypolithic cyanobacteria have strong effects on higher trophic levels and ecosystem functioning.


The genome of the deep-sea anemone Actinernus sp. contains a mega-array of ANTP-class homeobox genes.
Members of the phylum Cnidaria include sea anemones, corals and jellyfish, and have successfully colonized both marine and freshwater habitats throughout the world. The understanding of how cnidarians adapt to extreme environments such as the dark, high-pressure deep-sea habitat has been hindered by the lack of genomic information. Here, we report the first chromosome-level deep-sea cnidarian genome, of the anemone Actinernus sp., which was 1.39 Gbp in length and contained 44 970 gene models including 14 806 tRNA genes and 30 164 protein-coding genes. Analyses of homeobox genes revealed the longest chromosome hosts a mega-array of Hox cluster, HoxL, NK cluster and NKL homeobox genes; until now, such an array has only been hypothesized to have existed in ancient ancestral genomes. In addition to this striking arrangement of homeobox genes, analyses of microRNAs revealed cnidarian-specific complements that are distinctive for nested clades of these animals, presumably reflecting the progressive evolution of the gene regulatory networks in which they are embedded. Also, compared with other sea anemones, circadian rhythm genes were lost in Actinernus sp., which likely reflects adaptation to living in the dark. This high-quality genome of a deep-sea cnidarian thus reveals some of the likely molecular adaptations of this ecologically important group of metazoans to the extreme deep-sea environment. It also deepens our understanding of the evolution of genome content and organization of animals in general and cnidarians in particular, specifically from the viewpoint of key developmental control genes like the homeobox-encoding genes, where we find an array of genes that until now has only been hypothesized to have existed in the ancient ancestor that pre-dated both the cnidarians and bilaterians.


Integration of QTL Mapping and Gene Fishing Techniques to Dissect the Multi-Main Stem Trait in Rapeseed (Brassica napus L.).
Rapeseed is one of the most important oilseed crops in the world. Improving the production of rapeseed is beneficial to relieve the shortage of edible vegetable oil. As the organ of support and transport, the main stem of rapeseed controls the plant architecture, transports the water and nutrients, and determines the number of inflorescence. Increasing the number of main stems would be helpful for the yield improvement in Brassica napus (B. napus). This attractive multi-main stem (MMS) trait was observed in the KN DH population. We investigated not only the frequency of MMS traits but also dissected the genetic basis with QTL mapping analysis and Gene-Fishing technique. A total of 43 QTLs were identified for MMS based on high-density linkage map, which explained 2.95-14.9% of the phenotypic variation, among which two environmental stable QTLs (cqMMS.A3-2 and cqMMS.C3-5) were identified in winter and semi-winter environments. Epistatic interaction analysis indicated cqMMS.C3-5 was an important loci for MMS. According to the functional annotation, 159 candidate genes within QTL confidence intervals, corresponding to 148 Arabidopsis thaliana (A. thaliana) homologous genes, were identified, which regulated lateral bud development and tiller of stem, such as shoot meristemless (STM), WUSCHEL-regulated-related genes, cytokinin response factors (CRF5), cytokinin oxidase (CKX4), gibberellin-regulated (RDK1), auxin-regulated gene (ARL, IAR4), and auxin-mediated signaling gene (STV1). Based on Gene-Fishing analysis between the natural plants and the double-main stem (DMS) plant, 31 differentially expressed genes (DEGs) were also obtained, which were related to differentiation and formation of lateral buds, biotic stimulus, defense response, drought and salt-stress responses, as well as cold-response functional genes. In addition, by combining the candidate genes in QTL regions with the DEGs that were obtained by Gene-Fishing technique, six common candidate genes (RPT2A, HLR, CRK, LRR-RLK, AGL79, and TCTP) were identified, which might probably be related to the formation of MMS phenotype. The present results not only would give a new insight into the genetic basis underlying the regulation of MMS but also would provide clues for plant architecture breeding in rapeseed.


The prognostic value of TP53 mutations in chronic lymphocytic leukemia is independent of Del17p13: implications for overall survival and chemorefractoriness.
Del17p13 predicts poor outcome and chemorefractoriness in chronic lymphocytic leukemia (CLL). Conversely, it is unknown whether TP53 mutations carry any prognostic value independent of del17p13. We tested the independent prognostic value of TP53 mutations in CLL. The study was based on a consecutive series of 308 CLL. DNA sequencing of TP53 exons 2 to 10 and del17p13 interphase fluorescence in situ hybridization were done at CLL diagnosis. Study end points were survival and chemorefractoriness. At diagnosis, TP53 mutations (n = 32) occurred in 31 of 308 (10.0%) patients. Of all CLL showing TP53 disruption by either mutation and/or deletion (n = 44), 10 cases (22.7%) showed TP53 mutations in the absence of del17p13. Multivariate analysis selected TP53 mutations (hazard ratio, 3.20; P = 0.002) as an independent predictor of overall survival after adjustment for del17p13. Also, multivariate analysis selected TP53 mutations (hazard ratio, 3.97; P < 0.001) as an independent predictor of chemorefractoriness after adjustment for del17p13. Compared with cases without TP53 alterations, CLL harboring any type of TP53 disruption (mutation only, del17p13 only, or both mutation and del17p13) uniformly displayed a high prevalence of unfavorable prognosticators and poor outcome. Analysis of sequential CLL samples showed the acquisition of new or additional TP53 alterations at the time of chemorefractoriness. These data show that (a) TP53 mutations are an independent predictor of short survival and chemorefractoriness, and (b) that CLL presenting with TP53 mutations without del17p13 fare as poorly as CLL carrying del17p13. Because CLL harboring TP53 mutations without del17p13 are currently not recognized by conventional diagnostic strategies, these results may be relevant for a comprehensive prognostic characterization of CLL.


[How to plan glucocorticoid withdrawal: diagnostic and therapeutic strategies].
Glucocorticoïds are widely used in medicine and associated with numerous complications. Whenever possible, dosage reduction or treatment withdrawal should be considered as soon as possible depending on the underlying disease being treated. Administration of glucocorticoids induces a physiologic negative feed-back on the hypothalamic-pituitary-adrenal (HPA) axis and three clinical situations can be distinguished during treatment withdrawal: reactivation of the disease for which the glucocorticoids were prescribed, acute adrenal insufficiency and steroid withdrawal syndrome. Acute adrenal insufficiency is a feared complication but probably rare. It is usually seen during stress situations and can be observed long after steroid withdrawal. There is no good predictive marker to anticipate acute adrenal insufficiency and clinical evaluation of the patient remains a key element in its diagnosis. If adrenal insufficiency is suspected, HPA suppression can be assessed with dynamic tests. During stress situation, steroid administration is then recommended depending on the severity of the stress.


Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.
Blood myeloid cells are known to be dysregulated in coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2. It is unknown whether the innate myeloid response differs with disease severity and whether markers of innate immunity discriminate high-risk patients. Thus, we performed high-dimensional flow cytometry and single-cell RNA sequencing of COVID-19 patient peripheral blood cells and detected disappearance of non-classical CD14LowCD16High monocytes, accumulation of HLA-DRLow classical monocytes (Human Leukocyte Antigen - DR isotype), and release of massive amounts of calprotectin (S100A8/S100A9) in severe cases. Immature CD10LowCD101-CXCR4+/- neutrophils with an immunosuppressive profile accumulated in the blood and lungs, suggesting emergency myelopoiesis. Finally, we show that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe form of COVID-19, suggesting a predictive value that deserves prospective evaluation.


Chronic thromboembolic pulmonary hypertension from the perspective of patients with pulmonary embolism.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but feared long-term complication of acute pulmonary embolism (PE), although CTEPH may occur in patients with no history of symptomatic venous thromboembolism. It represents the most severe presentation of the so-called 'post-PE syndrome', a phenomenon of permanent functional limitations after PE caused by deconditioning after PE or ventilatory or circulatory impairment as a result of unresolved pulmonary artery thrombi. Because the post-PE syndrome may occur in up to 50% of PE survivors, and CTEPH tends to have an insidious and non-specific clinical presentation, CTEPH is often not diagnosed or diagnosed after a very long delay. Once the diagnosis is confirmed, the treatment of choice is pulmonary endarterectomy which effectively lowers the pulmonary vascular resistance and normalizes resting pulmonary artery pressures, leading to recovery of the right ventricle. When pulmonary endarterectomy is not technically feasible, balloon pulmonary angioplasty may be a potential acceptable alternative. Also, medical treatment may help to improve patient's symptoms and hemodynamics. Current studies are focusing on strategies for earlier CTEPH diagnosis after acute PE, as well as the most optimal treatment of inoperable patients. This review will focus on the epidemiology, risk factors, diagnosis and treatment of CTEPH from the perspective of the PE patient.


Clinical characteristics and treatment outcomes in a cohort of patients with pyogenic and amoebic liver abscess.
We describe the clinical features of a cohort of patients with liver abscesses and investigate relationships between clinical, radiological and microbiological findings and mortality. Retrospective review of pyogenic (PLA) or amoebic liver abscesses (ALA) diagnosed and treated at a major infectious diseases department in London over 9 years. One hundred forty-one patient records were identified; 132 (93.6%) had PLA and 9 (6.4%) ALA. No organism was identified in 38.6% (51/132); a single bacterial species was isolated in 47.0% (62/132) of PLA, ≥ 2 in 14.4% (19/132). There was weak evidence of variation in abscess size by type of microorganism, with streptococcal PLA typically larger (p = 0.03 for Streptococcus milleri group, p = 0.05 for non-milleri streptococci). Patients with ALA were younger (median 41, IQR 37-51 years) than those with PLA (median 68, IQR 50.5-78 years) (p = 0.003) and all were male (9/9, 100%, (p = 0.03)), with a history of recent travel in the majority (6/9, 66.7% (p = 0.003)). C-reactive protein was higher in ALA than in PLA (p = 0.06). In the entire cohort, loculation (HR = 2.51 (95% CI 1.00-6.32), p = 0.04) and baseline ALP (HR = 4.78 (95% CI 1.19-19.2) per log10 increase, p = 0.03) were associated with mortality. 16S ribosomal RNA (rRNA) analysis was used in a subset of culture-negative cases and increased the diagnostic yield by 13%. Clinical or radiological features cannot be used to distinguish between PLA and ALA, or help identify the bacterial cause of PLA. However, ALA is more common in young, male patients with a history of travel. 16S rRNA analysis of abscess fluid has a role in improving microbiological diagnosis in culture-negative cases.


Diffraction on periodic surface microrelief grating with positive or negative optical anisotropy.
Diffraction optical elements (DOE) are important elements of systems for images displaying and processing. The DOE materials with both positive and negative birefringence enhance performances and functionality of such systems. We have calculated the diffraction of rays passing through optically anisotropic grating with surface microrelief by using our original Exedeep software. At the first time the diffraction parameters for both transmitted and reflected TE- and TM-waves are calculated for materials with both positive and negative optical anisotropy. The simulation results are to be used to create DOE for the visible, UV, IR and THz ranges.


Brevetoxin versus Brevenal Modulation of Human Nav1 Channels.
Brevetoxins (PbTx) and brevenal are marine ladder-frame polyethers. PbTx binds to and activates voltage-gated sodium (Nav) channels in native tissues, whereas brevenal antagonizes these actions. However, the effects of PbTx and brevenal on recombinant Nav channel function have not been systematically analyzed. In this study, the PbTx-3 and brevenal modulation of tissue-representative Nav channel subtypes Nav1.2, Nav1.4, Nav1.5, and Nav1.7 were examined using automated patch-clamp. While PbTx-3 and brevenal elicit concentration-dependent and subtype-specific modulatory effects, PbTx-3 is >1000-fold more potent than brevenal. Consistent with effects observed in native tissues, Nav1.2 and Nav1.4 channels were PbTx-3- and brevenal-sensitive, whereas Nav1.5 and Nav1.7 appeared resistant. Interestingly, the incorporation of brevenal in the intracellular solution caused Nav channels to become less sensitive to PbTx-3 actions. Furthermore, we generated a computational model of PbTx-2 bound to the lipid-exposed side of the interface between domains I and IV of Nav1.2. Our results are consistent with competitive antagonism between brevetoxins and brevenal, setting a basis for future mutational analyses of Nav channels' interaction with brevetoxins and brevenal. Our findings provide valuable insights into the functional modulation of Nav channels by brevetoxins and brevenal, which may have implications for the development of new Nav channel modulators with potential therapeutic applications.


A novel strategy for genetic dissection of complex traits: the population of specific chromosome substitution strains from laboratory and wild mice.
The mouse is an irreplaceable model for understanding the precise genetic mechanisms of mammalian physiological pathways. Thousands of quantitative trait loci (QTLs) have been mapped onto the mouse genome during the last two decades. However, only a few genes' underlying complex traits have been successfully identified, and rapid fine mapping of QTL genes still remains a challenge for mouse geneticists. Currently, the Collaborative Cross (CC) has proceeded to the goal of establishing more than 1,000 recombinant inbred strains for the sub-centimorgan mapping resolution of QTL loci. In this article, a novel complementary strategy, designated as population of specific chromosome substitution strains or PSCSS, is proposed for rapid fine mapping of QTLs on the substituted chromosome. One specific chromosome (Chr 1) of recipient mouse strain C57BL/6 J has been substituted by homologous counterparts from five different inbred strains (C3H/He, FVB/N, AKR, NOD/LtJ, NZW/LacJ), an outbred line Kunmin mouse in China, and 23 wild mice captured in different localities. The primary genetic studies on the structure of these wild donor chromosomes (Chr 1) show that these donor chromosomes harbor extensive genetic polymorphisms, with a high density of SNP distribution, abundant variations of STR alleles, and a high level of historical recombination accumulation. These specific chromosome substitution strains eventually form a special population that has the identical genetic background of the recipient strain and differs only in the donor chromosomes. With simple association studies, known QTLs on the donor chromosome can be rapidly mapped in high resolution without requirement of further crosses. This approach, taking advantage of the extensive genetic polymorphisms of wild resources and chromosome substitution strategy, brings a new outlook for genetic dissection of complex traits.


[Sources of lipids in parenteral and enteral nutrition].
The review is devoted to sources of lipids in enteral and parenteral nutrition. The role of omega-3 and omega polyunsaturated fatty acids in metabolism of some lipid mediators is examined.


[Observation on short and long-term effects of Tuina for treatment of infants eczema].
To access the therapeutic effect of Tuina for treatment of infants eczema. Two hundred and forty children with eczema were randomly divided into a Tuina group and a medication group, 120 cases in each group. The Tuina group was treated with Tuina on ten points using the thumb and middle finger, and the medication group was treated with oral administration of Chlorpheniramine and topical application of zinc oxide ointment or Youzhuoer ointment, etc. The therapeutic effects were evaluated after 3 weeks. The cured-markedly effective rate and total effective rate were 94.2% and 99.2% in the Tuina group and 98.0% and 100.0% in the medication group, respectively, the therapeutic effects were similar in the two groups (both P>0.05); 6 months after treatment, the recurrence rate of 3.8% in the Tuina group was significantly lower than 42.9% in the medication group (P<0.01), and there were no adverse reactions in the whole research process. Tuina on ten points for treatment of infants eczema has unequivocal short-term effect, a stable long-term effect, and low recurrence rate.


Contributions of CTCF and DNA methyltransferases DNMT1 and DNMT3B to Epstein-Barr virus restricted latency.
Establishment of persistent Epstein-Barr virus (EBV) infection requires transition from a program of full viral latency gene expression (latency III) to one that is highly restricted (latency I and 0) within memory B lymphocytes. It is well established that DNA methylation plays a critical role in EBV gene silencing, and recently the chromatin boundary protein CTCF has been implicated as a pivotal regulator of latency via its binding to several loci within the EBV genome. One notable site is upstream of the common EBNA gene promoter Cp, at which CTCF may act as an enhancer-blocking factor to initiate and maintain silencing of EBNA gene transcription. It was previously suggested that increased expression of CTCF may underlie its potential to promote restricted latency, and here we also noted elevated levels of DNA methyltransferase 1 (DNMT1) and DNMT3B associated with latency I. Within B-cell lines that maintain latency I, however, stable knockdown of CTCF, DNMT1, or DNMT3B or of DNMT1 and DNMT3B in combination did not result in activation of latency III protein expression or EBNA gene transcription, nor did knockdown of DNMTs significantly alter CpG methylation within Cp. Thus, differential expression of CTCF and DNMT1 and -3B is not critical for maintenance of restricted latency. Finally, mutant EBV lacking the Cp CTCF binding site exhibited sustained Cp activity relative to wild-type EBV in a recently developed B-cell superinfection model but ultimately was able to transition to latency I, suggesting that CTCF contributes to but is not necessarily essential for the establishment of restricted latency.


A simple COSMO-based method for calculation of hydration energies of neutral molecules.
A simple, non-iterative method to estimate hydration free energies of neutral molecules, ESE, is developed. It requires only atomic charges computed for isolated species. To obtain the solvation free energy, the COSMO electrostatic term is supplemented by an extra correction that describes the cavitation energy, van der Waals and specific interactions. This term depends on atomic parameters that are adjusted using a reference dataset. Despite its simplicity, the ESE method provides accurate hydration energies with a mean absolute error below 1 kcal mol-1, superseding most accurate existing polarization continuum methods. We show that the proposed scheme can be directly extended to non-aqueous solutions.


Therapeutic potential of the endocannabinoid system in the brain.
Cannabinoids have been predominantly considered as the substances responsible of the psychoactive properties of marijuana and other derivatives of Cannabis sativa. However, these compounds are now being also considered for their therapeutic potential, since the term "cannabinoid" includes much more compounds than those present in Cannabis sativa derivatives. Among them, there are numerous synthetic cannabinoids obtained by modifications from plant-derived cannabinoids, but also from the compounds that behave as endogenous ligands for the different cannabinoid receptor subtypes. Within the family of "cannabinoid-related compounds", one should also include some prototypes of selective antagonists for these receptors, and also the recently developed inhibitors of the mechanism of finalization of the biological action of endocannabinoids (transporter + FAAH). All this boom of the cannabinoid pharmacology has, therefore, an explanation in the recent discovery and characterization of the endocannabinoid signaling system, which plays a modulatory role mainly in the brain but also in the periphery. The objective of the present article will be to review, from pharmacological and biochemical points of view, the more recent advances in the study of the endocannabinoid system and their functions in the brain, as well as their alterations in a variety of pathologies and the proposed therapeutic benefits of novel cannabinoid-related compounds that improve the pharmacokinetic and pharmacodynamic properties of classic cannabinoids.


Volume of exercise and fitness nonresponse in sedentary, postmenopausal women.
There is a wide individual heterogeneity in the maximal aerobic fitness (V x O 2max) response to exercise training. To examine predictors of V x O 2max nonresponse after aerobic exercise training in postmenopausal women. The Dose Response to Exercise in Women (DREW) study was a randomized, controlled trial examining the effects of incremental training doses on sedentary postmenopausal women (45-75 yr). Participants were randomized to one of three exercise treatment groups (4, 8, or 12 kcal x kg(-1) x wk(-1)) for 6 months. Participants exercised 3-4 d x wk(-1) at 50% V x O 2max. Predictors of baseline V x O 2max were determined by ANOVA. We used a logistic regression analyses with categorical (ethnicity and treatment group) and standardized continuous variables (age, body mass index [BMI], and baseline V x O 2max) to determine predictors of nonresponse (Delta <or= 0 L x min(-1)). Our analysis included 310 women because the control group was excluded. A total of 44.9%, 23.8%, and 19.3% of the 4-, the 8-, and the 12-kcal x kg(-1) x wk(-1) treatment groups (P < 0.0001), respectively, were nonresponders. Maximal effort, BMI, age, and race significantly predicted baseline V x O 2max. Treatment group (8 and 12 kcal x kg(-1) x wk(-1) vs 4 kcal x kg(-1) x wk(-1); P = 0.0003), baseline V x O 2max (P < 0.0001), and age (P < 0.05) were significant predictors of nonresponse. Odds ratios and 95% confidence intervals were 2.13 (1.53-2.95) for baseline V x O 2max; 1.35 (1.00-1.83) for age; 0.45 (0.24-0.85) for the 8- versus the 4-kcal x kg(-1) x wk(-1) group; and 0.27 (0.13-0.53) for the 12- versus the 4-kcal x kg(-1) x wk(-1) group. Women that were younger, less fit, or exercised more during the DREW trial had greater odds of improving their fitness with training. The most important finding of this study was that greater volumes of exercise were associated with a lower probability of being a nonresponder.


Radiographic evaluation of brachial plexopathy.
Neurologic signs and symptoms of brachial plexopathy may be subtle or confusing, making clinical localization of disease along the length of the brachial plexus difficult. To determine the most direct radiographic approach to diagnosing and anatomically delineating the cause of brachial plexopathy, we reviewed the clinical and radiographic records of 43 patients presenting with signs and symptoms referable to the brachial plexus who received CT and/or myelography as part of their radiographic evaluation. The study population was divided into two groups, those with and those without trauma. Significant deficiencies were detected in the radiographic evaluation of the nontraumatic group, with 35% of these patients having an incomplete or inappropriate CT examination that failed to visualize the full extent of the brachial plexus. In four patients, this led to a significant (greater than 6 months) delay in diagnosis. It was concluded that trauma patients presenting with brachial plexus symptoms should have cervical myelography first, rather than CT. Patients without a history of trauma should be classified on the basis of clinical findings as having central (cord, epidural space, neural foramen) or peripheral (retroclavicular space, axillary apex) disease. If the abnormality is central, myelography should be the first technique used; if peripheral disease is present, CT should be the first study. If the disease extends beyond the confines of the anatomic compartment suggested clinically, the other technique should be used for further evaluation. CT scan protocols for brachial plexus evaluation should employ bolus/drip contrast enhancement to distinguish vascular structures from masses.(ABSTRACT TRUNCATED AT 250 WORDS)


Passive Sensors for Long Duration Internet of Things Networks.
In this work, three different concepts are used to develop a fully passive sensor that is capable of measuring different types of data. The sensor was supplied by Wireless Power Transmission (WPT). Communication between the sensor and reader is established by a backscatter, and to ensure minimum energy consumption, low power techniques are used. In a simplistic way, the process starts by the transmission of two different waves by the reader to the sensor, one of which is used in power transmission and the other of which is used to communicate. Once the sensor is powered, the monitoring process starts. From the monitoring state, results from after processing are used to modulate the incoming wave, which is the information that is sent back from the reader to the tag. This new combination of technologies enables the possibility of using sensors without any cables or batteries to operate 340 cm from the reader. The developed prototype measures acceleration and temperature. However, it is scalable. This system enables a new generation of passive Internet of Things (IoT) devices.


Independent data monitoring committees: preparing a path for the future.
Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.


Depression Treatment by Non-Mental-Health Providers: Incremental Evidence for the Effectiveness of Listening Visits.
Maternal depression is a prevalent public health problem, particularly for low-income mothers of young children. Intervention development efforts, which often focus on surmounting instrumental barriers to care, have not successfully engaged and retained women in treatment. Task-sharing approaches like Listening Visits (LV) could overcome key instrumental and psychological barriers by leveraging the access of trusted, community caregivers to deliver treatment. A recent randomized controlled trial (RCT) demonstrated the efficacy of LV delivered by non-mental-health providers as compared to usual care. The present report presents results from a follow-up phase of that RCT during which participants who had completed LV were followed for an additional 8 weeks and completed measures of depression and quality of life. In addition, participants who were initially randomized to the wait-list control group received LV and were assessed. Treatment gains previously observed in participants completing LV were enhanced during the 8-week follow-up period. Participants receiving LV during the follow-up period experienced significant improvement in depressive symptoms. Results demonstrate the sustainability of LV delivered by non-mental-health providers, and provide preliminary evidence for the replicability of this approach in a sample of predominately low-income pregnant women and mothers of young children.


Indoor fungal composition is geographically patterned and more diverse in temperate zones than in the tropics.
Fungi are ubiquitous components of indoor human environments, where most contact between humans and microbes occurs. The majority of these organisms apparently play a neutral role, but some are detrimental to human lifestyles and health. Recent studies that used culture-independent sampling methods demonstrated a high diversity of indoor fungi distinct from that of outdoor environments. Others have shown temporal fluctuations of fungal assemblages in human environments and modest correlations with human activity, but global-scale patterns have not been examined, despite the manifest significance of biogeography in other microbial systems. Here we present a global survey of fungi from indoor environments (n = 72), using both taxonomic and phylogeny-informative molecular markers to determine whether global or local indoor factors determine indoor fungal composition. Contrary to common ecological patterns, we show that fungal diversity is significantly higher in temperate zones than in the tropics, with distance from the equator being the best predictor of phylogenetic community similarity. Fungal composition is significantly auto-correlated at the national and hemispheric spatial scales. Remarkably, building function has no significant effect on indoor fungal composition, despite stark contrasts between architecture and materials of some buildings in close proximity. Distribution of individual taxa is significantly range- and latitude-limited compared with a null model of randomized distribution. Our results suggest that factors driving fungal composition are primarily global rather than mediated by building design or function.


Lost in Space? Unmasking the T Cell Reaction to Simulated Space Stressors.
The space environment will expose astronauts to stressors like ionizing radiation, altered gravity fields and elevated cortisol levels, which pose a health risk. Understanding how the interplay between these stressors changes T cells' response is important to better characterize space-related immune dysfunction. We have exposed stimulated Jurkat cells to simulated space stressors (1 Gy, carbon ions/1 Gy photons, 1 µM hydrocortisone (HC), Mars, moon, and microgravity) in a single or combined manner. Pro-inflammatory cytokine IL-2 was measured in the supernatant of Jurkat cells and at the mRNA level. Results show that alone, HC, Mars gravity and microgravity significantly decrease IL-2 presence in the supernatant. 1 Gy carbon ion irradiation showed a smaller impact on IL-2 levels than photon irradiation. Combining exposure to different simulated space stressors seems to have less immunosuppressive effects. Gene expression was less impacted at the time-point collected. These findings showcase a complex T cell response to different conditions and suggest the importance of elevated cortisol levels in the context of space flight, also highlighting the need to use simulated partial gravity technologies to better understand the immune system's response to the space environment.


Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline.
In chronic myeloid leukemia (CML) patients, a breakpoint cluster region-Abelson (BCR-ABL1) value >10% at 3 months of therapy is statistically associated with poorer outcome, yet many of these patients still achieve satisfactory outcomes. We investigated 528 first-line imatinib-treated patients to determine whether patients with the poorest outcome can be better discriminated at 3 months. All outcomes were significantly superior for the 410 patients with BCR-ABL1 ≤10% at 3 months (P < .001). However, the poorest outcomes among the 95 evaluable patients with BCR-ABL1 >10% at 3 months were identified by the rate of BCR-ABL1 decline from baseline, assessed by estimating the number of days over which BCR-ABL1 halved. Patients with BCR-ABL1 halving time <76 days (n = 74) had significantly superior outcomes compared with patients whose BCR-ABL1 values did not halve by 76 days (n = 21; 4-year overall survival, 95% vs 58%, P = .0002; progression-free survival, 92% vs 63%, P = .008; failure-free survival, 59% vs 6%, P < .0001; and major molecular response, 54% vs 5%, P = .008). By multivariate analysis, the halving time was an independent predictor of outcome in this poor risk group. Our study highlighted that the rate of BCR-ABL1 decline may be a critical prognostic discriminator of the patients with very poor outcome among those >10% at 3 months. The International Randomized IFN vs STI571 (IRIS) trial was registered at http://www.clinicaltrials.gov as #NCT00006343. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) trial was registered at http://www.clinicaltrials.gov as #NCT00124748. The Therapeutic Intensification in DE-novo Leukaemia (TIDEL) I trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000614493. The TIDEL II trial was registered at http://www.ANZCTR.org.au as #ACTRN12607000325404.


Mate pair sequencing for the detection of chromosomal aberrations in patients with intellectual disability and congenital malformations.
Recently, microarrays have replaced karyotyping as a first tier test in patients with idiopathic intellectual disability and/or multiple congenital abnormalities (ID/MCA) in many laboratories. Although in about 14-18% of such patients, DNA copy-number variants (CNVs) with clinical significance can be detected, microarrays have the disadvantage of missing balanced rearrangements, as well as providing no information about the genomic architecture of structural variants (SVs) like duplications and complex rearrangements. Such information could possibly lead to a better interpretation of the clinical significance of the SV. In this study, the clinical use of mate pair next-generation sequencing was evaluated for the detection and further characterization of structural variants within the genomes of 50 ID/MCA patients. Thirty of these patients carried a chromosomal aberration that was previously detected by array CGH or karyotyping and suspected to be pathogenic. In the remaining 20 patients no causal SVs were found and only benign aberrations were detected by conventional techniques. Combined cluster and coverage analysis of the mate pair data allowed precise breakpoint detection and further refinement of previously identified balanced and (complex) unbalanced aberrations, pinpointing the causal gene for some patients. We conclude that mate pair sequencing is a powerful technology that can provide rapid and unequivocal characterization of unbalanced and balanced SVs in patient genomes and can be essential for the clinical interpretation of some SVs.


Adolescent erythrocytes: influence of high density lipoproteins-cholesterol (HDL-c) plasmatic levels on Na+/Li+ exchange kinetics.
An inverse relationship between HDL-c plasmatic levels and Li+ flux (Na+-Li+ exchange mediated) has been reported in normotensive individuals with hypertensive ancestors as well as in essential hypertensive subjects. This lipoprotein reaction with plasmatic membrane components induces modifications in membrane transport mechanisms as well as in cellular enzymes. In this paper we present data on Li+ flux (Na+-Li+ exchange mediated) in red blood cells from normotensive individuals without hypertensive ancestors. Kinetic analysis of Li+ efflux as a function of Na+(extracell) concentration was carried out. Vmax and Km values were determined. HDL-c plasmatic levels were also determined. Vmax showed a significant inverse correlation with HDL-c levels. No significant correlation of Km values with HDL-c levels was observed. The data presented support previous data showing that variable Vmax is sensitive to cellular environmental factors. Otherwise the Km variable not influenced by these factors is sensitive to hereditary influences.


Light-induced engagement of microglia to focally remodel synapses in the adult brain.
Microglia continuously monitor synapses, but active synaptic remodeling by microglia in mature healthy brains is rarely directly observed. We performed targeted photoablation of single synapses in mature transgenic mice expressing fluorescent labels in neurons and microglia. The photodamage focally increased the duration of microglia-neuron contacts, and dramatically exacerbated both the turnover of dendritic spines and presynaptic boutons as well as the generation of new filopodia originating from spine heads or boutons. The results of microglia depletion confirmed that elevated spine turnover and the generation of presynaptic filopodia are microglia-dependent processes.


The Wellcome Foundation lecture, 1984. Nuclear magnetic resonance imaging in medicine: medical and biological applications and problems.
From early biological work and the first T1 nuclear magnetic resonance (n.m.r.) animal image in 1974, whole-body patient images, by using a two-dimensional Fourier transform method were achieved in Aberdeen in 1980 with a 0.04 T vertical resistive magnet. Different pulse sequences produce images dependent by different amounts on proton density, T1 and T2, and for clinical work it is advantageous to use more than one pulse sequence to image pathology. The slow improvement of spatial resolution with increasing standing magnetic field strength is discussed and information on the T1 and T2 contrast dependence is reviewed: it suggests that the gains from high fields may be less than believed hitherto. Electrocardiogram gating can be used to produce moving images of the beating heart; blood flow can be imaged and surface radiofrequency coils are used for improved detail. N.m.r. imaging has considerable potential for studying response to therapy; mental states and dementia; tissue generation; discriminating body fat and body fluids. Other nuclei such as 23Na can be imaged and the potential to image fluorine-labelled pharmaceuticals could be very exciting; n.m.r. contrast agents are now being developed. Images formed from T1 values measured for each pixel are very useful for diagnosis, but the numerical values themselves are less valuable for distinctive pathological identification. With 15 companies manufacturing n.m.r. imagers and over 200 in use in hospitals, the technique is rapidly becoming established in diagnostic clinical practice and some typical uses are presented.