Correlates of periodontal decline and biologic markers in older adults

BACKGROUND: There is limited information on infectious and host responses distinguishing older people with or without active periodontitis. This study measured bacterial and serum cytokine and high-sensitivity C-reactive protein (hsCRP) levels in older persons. METHODS: Elders (mean age: 67 years), whose periodontal status had declined most or least (20% worst or 20% best) over 5 years, were enrolled. Two years later, they were classified as periodontally declining (active periodontitis [AP]), if they had at least five teeth with probing depth (PD) > or =5 mm, or stable (stable periodontally [SP]), if they did not. Groups were compared with respect to demographics, PD, clinical loss of attachment, subgingival bacteria, serum hsCRP, interleukin (IL)-1beta and -6, and chronic diseases. RESULTS: Ten AP and 24 SP subjects were identified; 13% of women and 44% of men from the original sample were in the AP group (P <0.05). Most Asians were SP; most whites and all African Americans were classified as having AP (P <0.01). More AP elders had osteoporosis (P <0.01), but the AP and SP groups did not differ with respect to IL-1beta and -6 or hsCRP. Bacterial counts were higher in the AP group for Parvimonas micra (previously Peptostreptococcus micros or Micromonas micros) (7.7 x 10(5) cells versus 3.8 x 10(5) cells; P <0.05), Prevotella intermedia (25.7 x 10(5) cells versus 9.8 x 10(5) cells; P <0.01), Tannerella forsythia (previously T. forsythensis) (16.2 x 10(5) cells versus 8.0 x 10(5) cells; P <0.05), and Streptococcus mutans (6.2 x 10(5) cells versus 2.0 x 10(5) cells; P <0.01). Three risk factors were most predictive of periodontal decline: PD, osteoporosis, and being white or African American. CONCLUSION: Periodontal decline was associated with osteoporosis, ethnicity, PD, gender, serum hsCRP, and levels of four bacterial species.

Successful lower extremity angioplasty improves brachial artery flow-mediated dilation in patients with peripheral arterial disease

INTRODUCTION: Peripheral arterial disease (PAD) is associated with systemic impaired flow-mediated dilation (FMD) and increased risk for cardiovascular events. Decreased FMD may be caused by a decrease in arterial shear stress due to claudication and inflammation due to muscle ischemia and reperfusion. We assumed that endovascular revascularization of lower limb arterial obstructions ameliorates FMD and lowers inflammation through improvement of peripheral perfusion. METHODS: The study was a prospective, open, randomized, controlled, single-center follow-up evaluation assessing the effect of endovascular revascularization on brachial artery reactivity (FMD) measured by ultrasound, white blood cell (WBC) count, high-sensitive C-reactive protein (hs-CRP), and fibrinogen. We investigated 33 patients (23 men) with chronic and stable PAD (Rutherford 2 to 3) due to femoropopliteal obstruction. Variables were assessed at baseline and after 4 weeks in 17 patients (group A) who underwent endovascular revascularization and best medical treatment, and in 16 patients (group B) who received best medical treatment only. RESULTS: FMD did not differ between group A and B (4.96% +/- 1.86% vs 4.60% +/- 2.95%; P = .87) at baseline. It significantly improved after revascularization in group A (6.44% +/- 2.88%; P = .02) compared with group B at 4 weeks of follow-up (4.53% +/- 3.17%; P = .92), where it remained unchanged. The baseline ankle-brachial index (ABI) was similar for group A and B (0.63 +/- 0.15 vs 0.66 +/- 0.10; P = .36). At 4 weeks of follow-up, ABI was significantly increased in group A (1.05 +/- 0.15; P = .0004) but remained unchanged in group B (0.62 +/- 0.1). WBC counts of the two groups were comparable at baseline (group A: 7.6 +/- 2.26 x 10(6)/mL and group B: 7.8 +/- 2.02 x 10(6)/mL, P = .81). In group A, the leukocyte count significantly decreased after angioplasty from 7.6 +/- 2.26 to 6.89 +/- 1.35 x 10(6)/mL (P = .03). For group B, WBC count did not differ significantly compared with baseline (7.76 +/- 2.64 x 10(6)/mL; P = .94). No effects were observed on hs-CRP or fibrinogen from endovascular therapy. CONCLUSION: Endovascular revascularization with reestablishment of peripheral arterial perfusion improves FMD and reduces WBC count in patients with claudication. Revascularization may therefore have clinical implications beyond relief of symptoms, for example, reducing oxidative stress caused by repeated muscle ischemia or increased shear stress due to improved ambulatory activity.

Pseudovacuoles--immobilized by high-pressure freezing--are associated with blebbing in walker carcinosarcoma cells

By applying high pressure freezing and freeze-substitution, we observed large inclusions of homogeneous appearance in the front of locomoting Walker carcinosarcoma cells that have not been described earlier. Live cell imaging revealed that these inclusions were poor in lipids and nucleic acids but had a high lysine (and hence protein) content. Usually one such structure 2-5 mum in size was present at the front of motile Walker cells, predominantly in the immediate vicinity of newly forming blebs. By correlating the lysine-rich areas in fixed and embedded cells with electron microscopic pictures, inclusions could be assigned to confined, faintly stained cytoplasmic areas that lacked a surrounding membrane; they were therefore called pseudovacuoles. After high-pressure freezing and freeze substitution, pseudovacuoles appeared to be filled with 20 nm large electron-transparent patches surrounded by 12 and 15 nm large particles. The heat shock protein Hsp90 was identified by peptide sequencing as a major fluorescent band on SDS-PAGE of lysine-labelled Walker cell extracts. By immunofluorescence, Hsp90 was found to be enriched in pseudovacuoles. Colocalization of the lysine with a potassium-specific dye in living cells revealed that pseudovacuoles act as K+ stores in the vicinity of forming blebs. We propose that pseudovacuoles might support blebbing by locally regulating the intracellular hydrostatic pressure.

Tuberculosis in a Swiss army training camp: contact investigation using an Interferon gamma release assay

BACKGROUND: In tuberculosis (TB), the risk of exposure is determined mainly by the proximity to and the hours of direct contact with an infectious patient. We describe the contact investigation after detection of an infectious form of TB in a military camp using an Interferon-g-Release-Assay (IGRA, QuantiFERON-TB Gold In Tube [QTF-GIT]) eight weeks after detection of the index case. INDEX PATIENT: The index patient presented with fever, cough and weight loss in the military hospital six weeks after entering the camp. TB was suspected and anti-tuberculous therapy given immediately. Subsequently, TB was microbiologically confirmed. METHODS: Four exposure groups were formed a priori based on the proximity and the hours of direct contact to the index case. 168 (95.5%) agreed to be investigated: - Group A: sharing the same dormitory (15 persons) - Group B: same platoon, but not sharing the dormitory (20 persons) - Group C: staff and patients of the military hospital (22 persons) - Group D: other three platoons and senior military staff (111 persons). RESULTS: 34 (20.2%) out of 168 contacts tested positive in the QFT-GIT assay. For the exposure groups, the respective QFT-GIT testing results were: group A, 14/15 (93%); group B, 4/20 (20%); group C, 5/22 (22.7%); and group D, 11/111 (9.9%). No secondary TB cases were identified. CONCLUSIONS: In our study, test results show a correlation with the risk of exposure, suggesting that IGRA may be useful for the assessment of TB infection in TB contacts. The high mobility of recruits reduced traceability of contacts. In this context, QFT-GIT allowed for an efficient screening of contacts at a single time point.

Hypertensive nephropathy treatment by heart-protecting musk pill: a study of anti-inflammatory therapy for target organ damage of hypertension.

This study was designed to investigate the protective effect of the heart-protecting musk pill (HMP) on inflammatory injury of kidney from spontaneously hypertensive rat (SHR). Male SHRs aged 4 weeks were divided into SHR model group, HMP low-dosage group (13.5 mg/kg), and HMP high-dosage group (40 mg/kg). Age-matched Wistar-Kyoto rats were used as normal control. All rats were killed at 12 weeks of age. Tail-cuff method and enzyme-linked immunosorbent assay were used to determine rat systolic blood pressure and angiotensin II (Ang II) contents, respectively. Renal inflammatory damage was evaluated by the following parameters: protein expressions of inflammatory cytokines, carbonyl protein contents, nitrite concentration, infiltration of monocytes/macrophages in interstitium and glomeruli, kidney pathological changes, and excretion rate of urinary protein. HMP did not prevent the development of hypertension in SHR. However, this Chinese medicinal compound decreased renal Ang II content. Consistent with the change of renal Ang II, all the parameters of renal inflammatory injury were significantly decreased by HMP. This study indicates that HMP is a potent suppressor of renal inflammatory damage in SHR, which may serve as a basis for the advanced preventive and therapeutic investigation of HMP in hypertensive nephropathy.

Protein-protein interaction between phototaxis receptor sensory Rhodopsin I and its transducer HtrI

The molecular complex containing the seven transmembrane helix photoreceptor S&barbelow;ensory R&barbelow;hodopsin I&barbelow; (SRI) and transducer protein HtrI (H&barbelow;alobacterial Transducer for SRI&barbelow;) mediates color-sensitive phototaxis responses in the archaeon Halobacterium salinarum. Orange light causes an attractant response by a one-photon reaction and white light (orange + UV light) a repellent response by a two-photon reaction. Three aspects of SRI-HtrI structure/function and the signal transduction pathway were explored. First, the coupling of HtrI to the photoactive site of SRI was analyzed by mutagenesis and kinetic spectroscopy. Second, SRI-HtrI mutations and suppressors were selected and characterized to elucidate the color-sensing mechanism. Third, the signal relay through the transducer-bound histidine kinase was analyzed using an in vitro reconstitution system with known and newly identified taxis components. ^ Twenty-one mutations on HtrI were introduced by site-directed mutagenesis. Several replacements of charged residues perturbed the photochemical kinetics of SRI which led to the finding of a cluster of residues at the membrane/cytoplasm interface in HtrI electrostatically coupled to the photoactive site of SRI. We found by laser-flash kinetic spectroscopy that the transducer and these residues have specific effects on the light-induced proton transfer between the retinal chromophore and the protein. ^ One of the mutations showed an unusual mutant phenotype we called “inverted” signaling, in which the cell produces a repellent response to normally attractant light. Therefore, this mutant (E56Q of HtrI) had lost the color-discrimination by the SRI-HtrI complex. We used suppressor analysis to better understand the phenotype. Certain suppressors resulted in return of attractant responses to orange light but with inversion of the normally repellent response to white light to an attractant response. To explain this and other results, we formulated the Conformational Shuttling model in which the HtrI-SRI complex is poised in a metastable equilibrium of two conformations shifted in opposite directions by orange and white light. We tested this model by behavioral analysis (computerized cell tracking and motion study) of double mutants of inverting and suppressing mutations and the results confirmed the equilibrium-shift explanation. ^ We developed an in vitro system for measuring the effect of purified transducer on the histidine-kinase CheAH that controls the flagellar motor switch. The rate of kinase autophosphorylation was stimulated >2 fold in the reconstitution of the complete signal transduction system from purified components from H. salinarum. The in vitro assay also showed that the kinase activity was reduced in the absence and in the presence of high levels of linker protein CheWH. (Abstract shortened by UMI.) ^

Variation in precursor lesions of pancreatic cancer among high-risk groups

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups. EXPERIMENTAL DESIGN Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0-127 months) or 36 months (0-110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery. RESULTS Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable. CONCLUSION In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group.

Cloning and characterization of an Actinobacillus pleuropneumoniae outer membrane protein belonging to the family of PAL lipoproteins

A 14-kDa outer membrane protein (OMP) was purified from Actinobacillus pleuro-pneumoniae serotype 2. The protein strongly reacts with sera from pigs experimentally or naturally infected with any of the 12 serotypes of A. pleuropneumoniae. The gene encoding this protein was isolated from a gene library of A. pleuropneumoniae serotype 2 reference strain by immunoscreening. Expression of the cloned gene in Escherichia coli revealed that the protein is also located in the outer membrane fraction of the recombinant host. DNA sequence analysis of the gene reveals high similarity of the protein's amino acid sequence to that of the E. coli peptidoglycan-associated lipoprotein PAL, to the Haemophilus influenzae OMP P6 and to related proteins of several other Gram-negative bacteria. We have therefore named the 14-kDa protein PalA, and its corresponding gene, palA. The 20 amino-terminal amino acid residues of PalA constitute a signal sequence characteristic of membrane lipoproteins of prokaryotes with a recognition site for the signal sequence peptidase II and a sorting signal for the final localization of the mature protein in the outer membrane. The DNA sequence upstream of palA contains an open reading frame which is highly similar to the E. coli tolB gene, indicating a gene cluster in A. pleuropneumoniae which is very similar to the E. coli tol locus. The palA gene is conserved and expressed in all A. pleuropneumoniae serotypes and in A. lignieresii. A very similar palA gene is present in A. suis and A. equuli.

CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis

Binding of CD47 to signal regulatory protein alpha (SIRPα), an inhibitory receptor, negatively regulates phagocytosis. In acute myeloid leukemia (AML), CD47 is overexpressed on peripheral blasts and leukemia stem cells and inversely correlates with survival. Aim of the study was to investigate the correlation between CD47 protein expression by immunohistochemistry (IHC) in a bone marrow (BM) tissue microarray (TMA) and clinical outcome in AML patients. CD47 staining on BM leukemia blasts was scored semi-quantitatively and correlated with clinical parameters and known prognostic factors in AML. Low (scores 0-2) and high (score 3) CD47 protein expression were observed in 75% and 25% of AML patients. CD47 expression significantly correlated with percentage BM blast infiltration and peripheral blood blasts. Moreover, high CD47 expression was associated with nucleophosmin (NPM1) gene mutations. In contrast, CD47 expression did not significantly correlate with overall or progression free survival or response to therapy. In summary, a BM TMA permits rapid and reproducible semi-quantitative analysis of CD47 protein expression by IHC. While CD47 expression on circulating AML blasts has been shown to be a negative prognostic marker for a very defined population of AML patients with NK AML, CD47 expression on AML BM blasts is not.

First-trimester glycosylated hemoglobin in women at high risk for gestational diabetes.

INTRODUCTION Our aim was to investigate the prognostic value of first-trimester glycosylated hemoglobin (HbA1c) in pregnant women with risk factors for developing gestational diabetes mellitus (GDM). MATERIAL AND METHODS This is an observational retrospective cohort study conducted at the Department of Obstetrics and Gynecology, University Hospital Bern, Switzerland. We included pregnant women at high risk for GDM (n = 208), who had an HbA1c measurement in the first trimester. We compared HbA1c values of women who later developed GDM with those who did not develop GDM. Diagnosis of GDM was made on the basis of a 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation. We further examined the prevalence of GDM in relation to the first-trimester HbA1c value. RESULTS The prevalence of GDM in our high-risk group was 14.7%. Women who developed GDM had significantly higher first-trimester HbA1c values [5.43 ± 0.31% (36 ± 3 mmol/mol) vs. 5.23 ± 0.28% (34 ± 3 mmol/mol); p = 0.0026]. Moreover, all pregnant women with HbA1c ≥6.0% (42 mmol/mol) developed GDM, whereas those with <4.5% (26 mmol/mol) did not. CONCLUSIONS Women at risk for GDM have higher first-trimester HbA1c levels and values ≥6.0% (42 mmol/mol) are predictive of GDM. This information may be useful for counseling these women and providing appropriate advice on diet and lifestyle modification early in pregnancy.

The Associations Between Social, Behavioral, and Health Risk Factors on a High School Student’s Decision to Pursue Post High School Plans

Background: Due to the relationship between SES and health, pursuing post high-school plans can lead to better future health outcomes for the student. The current paper assesses how behavioral and health risk factors, and family and social support, effect a student’s decision to pursue post high school plans. Methods: Data from the Youth Behavioral Component of the 2007 Connecticut School Health Survey were analyzed. Composite measures of exposure to/participation in violent behavior, mental and physical health, family/social support and substance abuse were created. The effects of these domains on the decision to pursue post high-school plans were assessed using logistic regression. Data were stratified by socioeconomic status. Results: Low SES students were more likely than high SES students to be doubtful for post high-school plans. Cocaine abuse emerged as the risk factor that put low SES students at the highest odds of not pursuing post high-school plans, followed by involvement in violent/aggressive behavior, and receiving less family/social support than their peers. Similar findings regarding violence and family/social support were found in the high SES group. Findings regarding substance abuse in the high SES group were not statistically significant. Discussion: Prevention programs regarding violence and substance abuse may have the added benefit of increasing the likelihood that high school students will make post high school plans. Preventing cocaine use among low SES students may be of particular importance. Violence prevention measures should be tailored to the target group. Adequate family/social support emerged as an encouraging factor for post high school plans.

Sociodemographic characteristics as predictors of successful smoking cessation among a group of Hispanic Spanish speaking smokers

Few studies have examined predictors of smoking abstinence among Hispanic groups. The purpose of this dissertation was to examine the relations of sociodemographic characteristics and smoking related factors with smoking abstinence among a group of Hispanic Spanish speaking smokers. This study utilized previously collected data from Hispanic Spanish-speaking smokers (N = 246) who participated in a study entitled Smoking Cessation Services for Hispanic Smokers in Texas. ^ The first study examined sociodemographic characteristics and smoking related mechanisms that predicted smoking abstinence among this group. Two of the characteristics were related to smoking abstinence, marital status and acculturation level. Being unmarried increased the likelihood of being abstinent at the 12 week assessment (OR = 1.80). Those in the high acculturation group were twice as likely to be abstinent (OR = 2.24). Of the smoking related mechanisms, those with higher positive reinforcement expectancies were less likely to be abstinent (OR = .86), as were those with a higher level of affiliative attachment (OR = .86), a higher level of craving (OR = .78) and a higher tolerance to the effect of smoking (OR = .74). The second study was to examine the relationship of objective measures of socioeconomic status (SES) (income, education, or employment) with smoking abstinence among this group. This study also compared the relationship of a subjective measure of SES (Social Status Ladder) to smoking abstinence. None of the objective measures of SES were related to smoking abstinence at the 12 week assessment. The subjective measure of SES did predict smoking abstinence (OR = 1.9) indicting that those that rated themselves ≤4 on the SES scale were more likely to be abstinent. ^ Although this group was recruited using various methods across the state of Texas, the fact that they preferred to interact with the counselor in Spanish may limit the study findings. The results of this study highlight the need for research to examine specific subgroups of people and understand the special circumstances that influence their health behaviors. Furthering our knowledge of the relations between sociodemographic characteristics and smoking cessation could lead to interventions that reduce disparities in smoking cessation. ^

Identification of genetic variation influencing apolipoprotein E levels: Follow-up of genome-wide linkage scans in the GENOA study

Apolipoprotein E (ApoE) plays a major role in the metabolism of high density and low density lipoproteins (HDL and LDL). Its common protein isoforms (E2, E3, E4) are risk factors for coronary artery disease (CAD) and explain between 16 to 23% of the inter-individual variation in plasma apoE levels. Linkage analysis has been completed for plasma apoE levels in the GENOA study (Genetic Epidemiology Network of Atherosclerosis). After stratification of the population by lipoprotein levels and body mass index (BMI) to create more homogeneity with regard to biological context for apoE levels, Hispanic families showed significant linkage on chromosome 17q for two strata (LOD=2.93 at 104 cM for a low cholesterol group, LOD=3.04 at 111 cM for a low cholesterol, high HDLC group). Replication of 17q linkage was observed for apoB and apoE levels in the unstratified Hispanic and African-American populations, and for apoE levels in African-American families. Replication of this 17q linkage in different populations and strata provides strong support for the presence of gene(s) in this region with significant roles in the determination of inter-individual variation in plasma apoE levels. Through a positional and functional candidate gene approach, ten genes were identified in the 17q linked region, and 62 polymorphisms in these genes were genotyped in the GENOA families. Association analysis was performed with FBAT, GEE, and variance-component based tests followed by conditional linkage analysis. Association studies with partial coverage of TagSNPs in the gene coding for apolipoprotein H (APOH) were performed, and significant results were found for 2 SNPs (APOH_20951 and APOH_05407) in the Hispanic low cholesterol strata accounting for 3.49% of the inter-individual variation in plasma apoE levels. Among the other candidate genes, we identified a haplotype block in the ACE1 gene that contains two major haplotypes associated with apoE levels as well as total cholesterol, apoB and LDLC levels in the unstratified Hispanic population. Identifying genes responsible for the remaining 60% of inter-individual variation in plasma apoE level, will yield new insights into the understanding of genetic interactions involved in the lipid metabolism, and a more precise understanding of the risk factors leading to CAD. ^

Technology and characterization of GaN-HEMTs devices: high temperature and trapping effects

Los transistores de alta movilidad electrónica basados en GaN han sido objeto de una extensa investigación ya que tanto el GaN como sus aleaciones presentan unas excelentes propiedades eléctricas (alta movilidad, elevada concentración de portadores y campo eléctrico crítico alto). Aunque recientemente se han incluido en algunas aplicaciones comerciales, su expansión en el mercado está condicionada a la mejora de varios asuntos relacionados con su rendimiento y habilidad. Durante esta tesis se han abordado algunos de estos aspectos relevantes; por ejemplo, la fabricación de enhancement mode HEMTs, su funcionamiento a alta temperatura, el auto calentamiento y el atrapamiento de carga. Los HEMTs normalmente apagado o enhancement mode han atraído la atención de la comunidad científica dedicada al desarrollo de circuitos amplificadores y conmutadores de potencia, ya que su utilización disminuiría significativamente el consumo de potencia; además de requerir solamente una tensión de alimentación negativa, y reducir la complejidad del circuito y su coste. Durante esta tesis se han evaluado varias técnicas utilizadas para la fabricación de estos dispositivos: el ataque húmedo para conseguir el gate-recess en heterostructuras de InAl(Ga)N/GaN; y tratamientos basados en flúor (plasma CF4 e implantación de F) de la zona debajo de la puerta. Se han llevado a cabo ataques húmedos en heteroestructuras de InAl(Ga)N crecidas sobre sustratos de Si, SiC y zafiro. El ataque completo de la barrera se consiguió únicamente en las muestras con sustrato de Si. Por lo tanto, se puede deducir que la velocidad de ataque depende de la densidad de dislocaciones presentes en la estructura, ya que el Si presenta un peor ajuste del parámetro de red con el GaN. En relación a los tratamientos basados en flúor, se ha comprobado que es necesario realizar un recocido térmico después de la fabricación de la puerta para recuperar la heteroestructura de los daños causados durante dichos tratamientos. Además, el estudio de la evolución de la tensión umbral con el tiempo de recocido ha demostrado que en los HEMTs tratados con plasma ésta tiende a valores más negativos al aumentar el tiempo de recocido. Por el contrario, la tensión umbral de los HEMTs implantados se desplaza hacia valores más positivos, lo cual se atribuye a la introducción de iones de flúor a niveles más profundos de la heterostructura. Los transistores fabricados con plasma presentaron mejor funcionamiento en DC a temperatura ambiente que los implantados. Su estudio a alta temperatura ha revelado una reducción del funcionamiento de todos los dispositivos con la temperatura. Los valores iniciales de corriente de drenador y de transconductancia medidos a temperatura ambiente se recuperaron después del ciclo térmico, por lo que se deduce que dichos efectos térmicos son reversibles. Se han estudiado varios aspectos relacionados con el funcionamiento de los HEMTs a diferentes temperaturas. En primer lugar, se han evaluado las prestaciones de dispositivos de AlGaN/GaN sobre sustrato de Si con diferentes caps: GaN, in situ SiN e in situ SiN/GaN, desde 25 K hasta 550 K. Los transistores con in situ SiN presentaron los valores más altos de corriente drenador, transconductancia, y los valores más bajos de resistencia-ON, así como las mejores características en corte. Además, se ha confirmado que dichos dispositivos presentan gran robustez frente al estrés térmico. En segundo lugar, se ha estudiado el funcionamiento de transistores de InAlN/GaN con diferentes diseños y geometrías. Dichos dispositivos presentaron una reducción casi lineal de los parámetros en DC en el rango de temperaturas de 25°C hasta 225°C. Esto se debe principalmente a la dependencia térmica de la movilidad electrónica, y también a la reducción de la drift velocity con la temperatura. Además, los transistores con mayores longitudes de puerta mostraron una mayor reducción de su funcionamiento, lo cual se atribuye a que la drift velocity disminuye más considerablemente con la temperatura cuando el campo eléctrico es pequeño. De manera similar, al aumentar la distancia entre la puerta y el drenador, el funcionamiento del HEMT presentó una mayor reducción con la temperatura. Por lo tanto, se puede deducir que la degradación del funcionamiento de los HEMTs causada por el aumento de la temperatura depende tanto de la longitud de la puerta como de la distancia entre la puerta y el drenador. Por otra parte, la alta densidad de potencia generada en la región activa de estos transistores conlleva el auto calentamiento de los mismos por efecto Joule, lo cual puede degradar su funcionamiento y Habilidad. Durante esta tesis se ha desarrollado un simple método para la determinación de la temperatura del canal basado en medidas eléctricas. La aplicación de dicha técnica junto con la realización de simulaciones electrotérmicas han posibilitado el estudio de varios aspectos relacionados con el autocalentamiento. Por ejemplo, se han evaluado sus efectos en dispositivos sobre Si, SiC, y zafiro. Los transistores sobre SiC han mostrado menores efectos gracias a la mayor conductividad térmica del SiC, lo cual confirma el papel clave que desempeña el sustrato en el autocalentamiento. Se ha observado que la geometría del dispositivo tiene cierta influencia en dichos efectos, destacando que la distribución del calor generado en la zona del canal depende de la distancia entre la puerta y el drenador. Además, se ha demostrado que la temperatura ambiente tiene un considerable impacto en el autocalentamiento, lo que se atribuye principalmente a la dependencia térmica de la conductividad térmica de las capas y sustrato que forman la heterostructura. Por último, se han realizado numerosas medidas en pulsado para estudiar el atrapamiento de carga en HEMTs sobre sustratos de SiC con barreras de AlGaN y de InAlN. Los resultados obtenidos en los transistores con barrera de AlGaN han presentado una disminución de la corriente de drenador y de la transconductancia sin mostrar un cambio en la tensión umbral. Por lo tanto, se puede deducir que la posible localización de las trampas es la región de acceso entre la puerta y el drenador. Por el contrario, la reducción de la corriente de drenador observada en los dispositivos con barrera de InAlN llevaba asociado un cambio significativo en la tensión umbral, lo que implica la existencia de trampas situadas en la zona debajo de la puerta. Además, el significativo aumento del valor de la resistencia-ON y la degradación de la transconductancia revelan la presencia de trampas en la zona de acceso entre la puerta y el drenador. La evaluación de los efectos del atrapamiento de carga en dispositivos con diferentes geometrías ha demostrado que dichos efectos son menos notables en aquellos transistores con mayor longitud de puerta o mayor distancia entre puerta y drenador. Esta dependencia con la geometría se puede explicar considerando que la longitud y densidad de trampas de la puerta virtual son independientes de las dimensiones del dispositivo. Finalmente se puede deducir que para conseguir el diseño óptimo durante la fase de diseño no sólo hay que tener en cuenta la aplicación final sino también la influencia que tiene la geometría en los diferentes aspectos estudiados (funcionamiento a alta temperatura, autocalentamiento, y atrapamiento de carga). ABSTRACT GaN-based high electron mobility transistors have been under extensive research due to the excellent electrical properties of GaN and its related alloys (high carrier concentration, high mobility, and high critical electric field). Although these devices have been recently included in commercial applications, some performance and reliability issues need to be addressed for their expansion in the market. Some of these relevant aspects have been studied during this thesis; for instance, the fabrication of enhancement mode HEMTs, the device performance at high temperature, the self-heating and the charge trapping. Enhancement mode HEMTs have become more attractive mainly because their use leads to a significant reduction of the power consumption during the stand-by state. Moreover, they enable the fabrication of simpler power amplifier circuits and high-power switches because they allow the elimination of negativepolarity voltage supply, reducing significantly the circuit complexity and system cost. In this thesis, different techniques for the fabrication of these devices have been assessed: wet-etching for achieving the gate-recess in InAl(Ga)N/GaN devices and two different fluorine-based treatments (CF4 plasma and F implantation). Regarding the wet-etching, experiments have been carried out in InAl(Ga)N/GaN grown on different substrates: Si, sapphire, and SiC. The total recess of the barrier was achieved after 3 min of etching in devices grown on Si substrate. This suggests that the etch rate can critically depend on the dislocations present in the structure, since the Si exhibits the highest mismatch to GaN. Concerning the fluorine-based treatments, a post-gate thermal annealing was required to recover the damages caused to the structure during the fluorine-treatments. The study of the threshold voltage as a function of this annealing time has revealed that in the case of the plasma-treated devices it become more negative with the time increase. On the contrary, the threshold voltage of implanted HEMTs showed a positive shift when the annealing time was increased, which is attributed to the deep F implantation profile. Plasma-treated HEMTs have exhibited better DC performance at room temperature than the implanted devices. Their study at high temperature has revealed that their performance decreases with temperature. The initial performance measured at room temperature was recovered after the thermal cycle regardless of the fluorine treatment; therefore, the thermal effects were reversible. Thermal issues related to the device performance at different temperature have been addressed. Firstly, AlGaN/GaN HEMTs grown on Si substrate with different cap layers: GaN, in situ SiN, or in situ SiN/GaN, have been assessed from 25 K to 550 K. In situ SiN cap layer has been demonstrated to improve the device performance since HEMTs with this cap layer have exhibited the highest drain current and transconductance values, the lowest on-resistance, as well as the best off-state characteristics. Moreover, the evaluation of thermal stress impact on the device performance has confirmed the robustness of devices with in situ cap. Secondly, the high temperature performance of InAlN/GaN HEMTs with different layouts and geometries have been assessed. The devices under study have exhibited an almost linear reduction of the main DC parameters operating in a temperature range from room temperature to 225°C. This was mainly due to the thermal dependence of the electron mobility, and secondly to the drift velocity decrease with temperature. Moreover, HEMTs with large gate length values have exhibited a great reduction of the device performance. This was attributed to the greater decrease of the drift velocity for low electric fields. Similarly, the increase of the gate-to-drain distance led to a greater reduction of drain current and transconductance values. Therefore, this thermal performance degradation has been found to be dependent on both the gate length and the gate-to-drain distance. It was observed that the very high power density in the active region of these transistors leads to Joule self-heating, resulting in an increase of the device temperature, which can degrade the device performance and reliability. A simple electrical method have been developed during this work to determine the channel temperature. Furthermore, the application of this technique together with the performance of electro-thermal simulations have enabled the evaluation of different aspects related to the self-heating. For instance, the influence of the substrate have been confirmed by the study of devices grown on Si, SiC, and Sapphire. HEMTs grown on SiC substrate have been confirmed to exhibit the lowest self-heating effects thanks to its highest thermal conductivity. In addition to this, the distribution of the generated heat in the channel has been demonstrated to be dependent on the gate-to-drain distance. Besides the substrate and the geometry of the device, the ambient temperature has also been found to be relevant for the self-heating effects, mainly due to the temperature-dependent thermal conductivity of the layers and the substrate. Trapping effects have been evaluated by means of pulsed measurements in AlGaN and InAIN barrier devices. AlGaN barrier HEMTs have exhibited a de crease in drain current and transconductance without measurable threshold voltage change, suggesting the location of the traps in the gate-to-drain access region. On the contrary, InAIN barrier devices have showed a drain current associated with a positive shift of threshold voltage, which indicated that the traps were possibly located under the gate region. Moreover, a significant increase of the ON-resistance as well as a transconductance reduction were observed, revealing the presence of traps on the gate-drain access region. On the other hand, the assessment of devices with different geometries have demonstrated that the trapping effects are more noticeable in devices with either short gate length or the gate-to-drain distance. This can be attributed to the fact that the length and the trap density of the virtual gate are independent on the device geometry. Finally, it can be deduced that besides the final application requirements, the influence of the device geometry on the performance at high temperature, on the self-heating, as well as on the trapping effects need to be taken into account during the device design stage to achieve the optimal layout.

Single prenyl-binding site on protein prenyl transferases

Three distinct protein prenyl transferases, one protein farnesyl transferase (FTase) and two protein geranylgeranyl transferases (GGTase), catalyze prenylation of many cellular proteins. One group of protein substrates contains a C-terminal CAAX motif (C is Cys, A is aliphatic, and X is a variety of amino acids) in which the single cysteine residue is modified with either farnesyl or geranylgeranyl (GG) by FTase or GGTase type-I (GGTase-I), respectively. Rab proteins constitute a second group of substrates that contain a C-terminal double-cysteine motif (such as XXCC in Rab1a) in which both cysteines are geranylgeranylated by Rab GG transferase (RabGGTase). Previous characterization of CAAX prenyl transferases showed that the enzymes form stable complexes with their prenyl pyrophosphate substrates, acting as prenyl carriers. We developed a prenyl-binding assay and show that RabGGTase has a prenyl carrier function similar to the CAAX prenyl transferases. Stable RabGGTase:GG pyrophosphate (GGPP), FTase:GGPP, and GGTase-I:GGPP complexes show 1:1 (enzyme:GGPP) stoichiometry. Chromatographic analysis of prenylated products after single turnover reactions by using isolated RabGGTase:GGPP complex revealed that Rab is mono-geranylgeranylated. This study establishes that all three protein prenyl transferases contain a single prenyl-binding site and suggests that RabGGTase transfers two GG groups to Rabs in independent and consecutive reactions.