Prevalence and associated factors of shisha smoking among students in Senegal: Global Youth Tobacco Survey 2020.

INTRODUCTION: Although shisha smoking is banned in Senegal, it has become increasingly popular, especially among youth. Despite the health risks associated with shisha smoking, there are few studies on shisha smoking in West Africa and none in Senegal. Our study assessed the prevalence and factors associated with shisha smoking among students aged 13-15 years in Senegal. METHODS: We used the 2020 Global Youth Tobacco Survey (GYTS) Senegal data from 2524 students aged 13-15 years. We calculated the weighted prevalence of ever and current (past 30 days) shisha smoking. Multivariable logistic regression analyses identified factors associated with ever and current shisha smoking among students. RESULTS: The prevalences of ever and current shisha smoking were 9.8% (95% CI: 7.7-12.3) and 2.2% (95% CI: 1.5-3.1), respectively. Ever shisha smoking was significantly associated with being male (AOR=1.97; 95% CI: 1.33-2.92), current cigarette smoking (AOR=7.54; 95% CI: 2.95-19.29), higher class grade (AOR=2.27; 95% CI:1.10-4.67), more weekly pocket money (AOR=3.29; 95% CI:1.36-7.95), current use of smokeless tobacco (AOR=11.53; 95% CI: 4.98- 26.72), and exposure to secondhand cigarette smoke in public (AOR=1.55; 95% CI: 1.00-2.41). Current shisha smoking was significantly associated with current cigarette smoking (AOR=21.75; 95% CI: 6.08-77.78), more weekly pocket money (AOR=8.91; 95% CI: 1.75-45.40), current use of smokeless tobacco (AOR=8.26; 95% CI: 2.07-33.04), and fathers' smoking (AOR=3.34; 95% CI: 1.24-8.96). CONCLUSIONS: One in 10 students aged 13-15 years have ever smoked shisha and 2.2% were currently smoking it, suggesting that shisha smoking is a public health concern in Senegal. Senegal might consider offering students more education on the harms of shisha, both in schools and through comprehensive media campaigns that address all tobacco products.

Gender differences in use of cigarette and non-cigarette tobacco products among adolescents aged 13-15 years in 20 African countries.

INTRODUCTION: Examining gender differences in youth tobacco use is important as it aligns tobacco control within the context of broader human development goals seeking to eliminate gender inequalities. In this study, we examined gender differences in adolescent use of cigarettes, smokeless tobacco, shisha, and e-cigarettes in Africa. METHODS: This was a cross-sectional study using data from the Global Youth Tobacco Survey. Our analytical sample comprised 56442 adolescents aged 13-15 years from 20 African countries. Weighted, country-specific prevalence estimates were computed overall and by gender. Adjusted prevalence ratios (APRs) were calculated in a multivariable Poisson regression model to examine whether correlates of tobacco use differed between boys and girls. RESULTS: Ever cigarette smoking prevalence was significantly higher among boys than girls in 16 of the 20 countries, but a significantly higher percentage of girls reported earlier age of cigarette smoking initiation than boys within pooled analysis. Some of the largest gender differences in current cigarette smoking were seen in Algeria (12.2% vs 0.8%, boys and girls, respectively), Mauritius (21.2% vs 6.6%), and Madagascar (15.0% vs 4.1%). Current use of e-cigarettes, shisha, and smokeless tobacco was generally comparable between boys and girls where data existed. Among girls, higher levels of reported exposure to tobacco advertisement were positively associated with shisha smoking whereas perceived tobacco harm was inversely associated with current cigarette and shisha smoking. Among boys, perceived social acceptability of smoking at parties was associated with an increased likelihood of cigarette smoking (APR=2.27; 95% Cl: 1.20-4.30). CONCLUSIONS: The prevalence of cigarette smoking among boys was higher than that of girls in many countries. However, girls who smoke tend to start at an earlier age than boys. Differential gender patterns of cigarette and non-cigarette tobacco product use among youth may have implications for future disease burden. As the tobacco control landscape evolves, tobacco prevention efforts should focus on all tobacco products, not just cigarettes.

Changes in Tobacco Product Use Among Students Aged 13 to 15 Years in 34 Countries, Global Youth Tobacco Survey, 2012-2020.

INTRODUCTION: Most adults who currently use tobacco start before age 21. Comprehensive, cost-effective strategies and interventions to prevent initiation and encourage tobacco use cessation among youth are critical aspects of protecting youth from the harms of commercial tobacco. We describe changes in current tobacco product use among youth in 34 sites using data from the Global Youth Tobacco Survey (GYTS). METHODS: GYTS is a nationally representative school-based survey of students aged 13 to 15 years. The analysis included 34 sites that completed 2 survey waves during 2012-2020. Prevalence of current tobacco use was assessed for each country. Marginal effects in multivariable logistic regression models were used to estimate adjusted prevalence difference (aPD) between waves. RESULTS: The adjusted prevalence of current tobacco product use remained unchanged in more than 60% of the included sites. For any tobacco use, significant decreases were reported for Bhutan (aPD = -8.1; 95% CI, -12.9 to -3.4), Micronesia (aPD = -7.2; 95% CI, -9.7 to -4.7), San Marino (aPD = -7.0; 95% CI, -11.2 to -2.7), Togo (aPD = -2.7; 95% CI, -4.6 to -0.7), and Panama (aPD = -2.2; 95% CI, -4.1 to -0.4); significant increases were reported for Moldova, Albania, and Paraguay. Current e-cigarette use increased significantly in 7 of 10 sites. CONCLUSION: Data show that progress toward reducing tobacco use among youth stalled during 2012-2020, while e-cigarette use increased in a few sites with available data.

Precision Psychiatry: Biomarker-Guided Tailored Therapy for Effective Treatment and Prevention in Major Depression.

Depression contributes greatly to global disability and is a leading cause of suicide. It has multiple etiologies and therefore response to treatment can vary significantly. By applying the concepts of personalized medicine, precision psychiatry attempts to optimize psychiatric patient care by better predicting which individuals will develop an illness, by giving a more accurate biologically based diagnosis, and by utilizing more effective treatments based on an individual's biological characteristics (biomarkers). In this chapter, we discuss the basic principles underlying the role of biomarkers in psychiatric pathology and then explore multiple biomarkers that are specific to depression. These include endophenotypes, gene variants/polymorphisms, epigenetic factors such as methylation, biochemical measures, circadian rhythm dysregulation, and neuroimaging findings. We also examine the role of early childhood trauma in the development of, and treatment response to, depression. In addition, we review how new developments in technology may play a greater role in the determination of new biomarkers for depression.

α7 Nicotinic Acetylcholine Receptor: A Potential Target in Treating Cognitive Decline in Schizophrenia.

PURPOSE: The aim of this article is to review the recent trials of α7 nicotinic acetylcholine receptor (α7 nAChR) agonists and positive allosteric modulators (PAMs) on the treatment of cognitive decline in schizophrenia. α7 Nicotinic acetylcholine receptor abnormalities in schizophrenia and clinical implications of α7 nAChR agonists and PAMs are also discussed. PROCEDURES: Studies were searched on PubMed with keywords "nicotinic," "alpha7," and "schizophrenia" over a 2-year period: January 1, 2016, to December 1, 2017. Cognition was not included in key terms in order to broaden the results. Inclusion criteria included (1) article categorization as a clinical study, review, or journal article; (2) schizophrenia diagnosis based on Diagnostic and Statistical Manual of Mental Disorders criteria; (3) article in English; (4) objective measure of cognition from effects of α7 nAChR agonists/PAMs; and (5) article currently published. FINDINGS: A total of 76 studies were found over the past 2 years. Fifteen of these studies were included in this review. Human studies were limited. Cognitive-related improvements in rodent models were found across the 6 cognitive constructs: perception, executive functioning, social and affective processes, working memory, and long-term memory. IMPLICATIONS: These results support the potential of nAChR agonists and PAMs to improve cognitive decline in patients with schizophrenia as an adjunct treatment to antipsychotics. However, these results were found primarily in rodent models of schizophrenia, and further primate/human studies are necessary to support this conclusion in humans.

Oxytocin and social functioning.

Social anxiety is a form of anxiety characterized by continuous fear of one or more social or performance situations. Although multiple treatment modalities (cognitive behavioral therapy, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors, benzodiazepines) exist for social anxiety, they are effective for only 60% to 70% of patients. Thus, researchers have looked for other candidates for social anxiety treatment. Our review focuses on the peptide oxytocin as a potential therapeutic option for individuals with social anxiety. Animal research both in nonprimates and primates supports oxytocin's role in facilitation of prosocial behaviors and its anxiolytic effects. Human studies indicate significant associations between social anxiety and oxytocin receptor gene alleles, as well as social anxiety and oxytocin plasma levels. In addition, intranasal administration of oxytocin in humans has favorable effects on social anxiety symptomology. Other disorders, including autism, schizophrenia, and anorexia, have components of social anxiety in their pathophysiology. The therapeutic role of oxytocin for social dysfunction in these disorders is discussed.

La ansiedad social es una forma de ansiedad caracterizada por un temor continuo de una o varias situaciones sociales o de rendimiento. Aunque para la ansiedad social existen diversas modalidades terapéuticas (terapia cognitivo conductual, inhibidores selectivos de la recaptura de serotonina, inhibidores selectivos de la recaptura de serotonina y noradrenalina, y benzodiacepinas), ellas resultan efectivas en no más del 60% a 70% de los pacientes. Debido a esto, los investigadores han buscado otras opciones de terapia para la ansiedad social. Esta revisión se enfoca en el péptido oxitocina como una potencial opción terapéutica para sujetos con ansiedad social. La investigación animal tanto de primates como de no primates da soporte al papel de la oxitocina en la facilitación de las conductas pro-sociales y sus efectos ansiolíticos. Los estudios en humanos muestran asociaciones significativas entre la ansiedad social y los alelos del gen del receptor de oxitocina, como también de la ansiedad social y los niveles plasmáticos de oxitocina. Además, la administración de oxitocina intranasal en humanos tiene efectos favorables para la sintomatología de la ansiedad social. Otras patologías, incluyendo el autismo, la esquizofrenia y la anorexia tienen componentes de la ansiedad social en sus fisiopatologías. En este artículo se discute el papel terapéutico de la oxitocina para la disfunción social en estas patologías.

L'anxiété sociale est une forme d'anxiété caractérisée par la peur permanente d'une ou plusieurs situations sociales ou de performance. De nombreuses modalités de traitement existent pour l'anxiété sociale, (thérapie cognitive comportementale, inhibiteurs sélectifs de la recapture de la sérotonine, inhibiteurs sélectifs de la recapture de la noradrénaline, benzodiazépines), mais elles ne sont efficaces que pour 60 à 70 % des patients. Des chercheurs ont donc examiné d'autres possibilités de traitement de l'anxiété sociale. Cet article s'intéresse au peptide ocytocine comme traitement éventuel des personnes atteintes d'anxiété sociale. La recherche chez les animaux, à la fois chez les primates et les non-primates, confirme que l'ocytocine facilite les comportements pro-sociaux et a des effets anxiolytiques. D'après des études chez l'homme, il existe des associations significatives entre l'anxiété sociale et les allèles du gène du récepteur de l'ocytocine ainsi qu'entre l'anxiété sociale et les concentrations plasmatiques d'ocytocine. De plus, l'administration intranasale d'ocytocine chez l'homme a des effets bénéfiques sur les symptômes de l'anxiété sociale. Nous analysons ensuite le rôle thérapeutique de l'ocytocine sur le dysfonctionnement social dans l'autisme, la schizophrénie et l'anorexie, des troubles dont la physiopathologie présente une composante d'anxiété sociale.

Fetal programming and eating disorder risk.

Fetal programming describes the process by which environmental stimuli impact fetal development to influence disease development later in life. Our analysis summarizes evidence for the role of fetal programming in eating disorder etiology through review of studies demonstrating specific obstetric complications and later eating risk of anorexia or bulimia. Using Pubmed, we found thirteen studies investigating obstetric factors and eating disorder risk published between 1999 and 2016. We then discuss modifiable maternal risk factors, including nutrition and stress, that influence anorexia or bulimia risk of their offspring. Translation of these findings applies to preventative strategies by health organizations and physicians to provide optimal health for mothers and their children to prevent development of medical and psychiatric illnesses.

Surveillance for certain health behaviors among States and selected local areas - United States, 2010.

PROBLEM: Chronic diseases (e.g., heart disease, stroke, cancer, and diabetes) are the leading causes of morbidity and mortality in the United States. Engaging in healthy behaviors (e.g., quitting smoking and tobacco use, being more physically active, and eating a nutritious diet) and accessing preventive health-care services (e.g., routine physical checkups, screening for cancer, checking blood pressure, testing blood cholesterol, and receiving recommended vaccinations) can reduce morbidity and mortality from chronic and infectious disease and lower medical costs. Monitoring and evaluating health-risk behaviors and the use of health services is essential to developing intervention programs, promotion strategies, and health policies that address public health at multiple levels, including state, territory, metropolitan and micropolitan statistical area (MMSA), and county. REPORTING PERIOD: January-December 2010. DESCRIPTION OF THE SYSTEM: The Behavioral Risk Factor Surveillance System (BRFSS) is an ongoing, state-based, random-digit-dialed telephone survey of noninstitutionalized adults aged ≥18 years residing in the United States. BRFSS collects data on health-risk behaviors, chronic diseases and conditions, access to health care, and use of preventive health services and practices related to the leading causes of death and disabilities in the United States. This report presents results for 2010 for all 50 states, the District of Columbia, the Commonwealth of Puerto Rico, Guam, the U.S. Virgin Islands, 192 MMSAs, and 302 counties. RESULTS: In 2010, the estimated prevalence of high-risk health behaviors, chronic diseases and conditions, access to health care, and use of preventive health services varied substantially by state and territory, MMSA, and county. In the following summary of results, each set of proportions refers to the range of estimated prevalence for the disease, condition, or behaviors, as reported by survey respondents. Adults reporting good or better health: 67.9%-89.3% for states and territories, 72.2%-92.1% for MMSAs, and 72.8%-95.8% for counties. Adults with health-care coverage: 69.4%-95.7% for states and territories, 45.7%-97.0% for MMSAs, and 45.7%-97.2% for counties. Adults who had a dental visit in the past year: 57.2%-81.7% for states and territories, 47.1%-83.5% for MMSAs, and 47.1%-88.2% for counties. Adults aged ≥65 years having had all their natural teeth extracted (edentulism): 7.4%-36.0% for states and territories, 4.8%-34.8% for MMSAs, and 2.4%-39.3% for counties. A routine physical checkup during the preceding 12 months: 53.8%-80.0% for states and territories, 49.5%-82.6% for MMSAs, and 49.5%-85.3% for counties. Influenza vaccination received during the preceding 12 months among adults aged ≥65 years: 26.9%-73.4% for states and territories, 51.7%-77.1% for MMSAs, and 49.3%-87.8% for counties. Pneumococcal vaccination ever received among adults aged ≥65 years: 24.7%-74.0% for states and territories, 48.6%-79.9% for MMSAs, and 47.6%-83.1% for counties. Sigmoidoscopy or colonoscopy ever received among adults aged ≥50 years: 37.8%-75.7% for states and territories, 37.3%-79.9% for MMSAs, and 37.3%-82.5% for counties. Blood stool test received during the preceding 2 years among adults aged ≥50 years: 8.5%-27.0% for states and territories, 6.7%-51.3% for MMSAs, and 6.8%-57.2% for counties. Women who reported having had a Papanicolaou test during the preceding 3 years: 67.8%-88.9% for states and territories, 63.3%-91.2% for MMSAs, and 63.2%-95.7% for counties. Women aged ≥40 years who had a mammogram during the preceding 2 years: 63.8%-83.6% for states and territories, 60.3%-86.2% for MMSAs, and 59.3%-89.7% for counties. Current cigarette smokers: 5.8%-26.8% for states and territories, 5.8%-28.5% for MMSAs, and 5.9%-29.8% for counties. Binge drinking during the preceding month: 6.6%-21.6% for states and territories, 3.6%-23.0% for MMSAs, and 3.8%-24.0% for counties. Heavy drinking during the preceding month: 2.0%-7.2% for states and territories, 1.0%-10.0% for MMSAs, and 1.0%-14.2% for counties. Adults reporting no leisure-time physical activity: 17.5%-42.3% for states and territories, 13.1%-37.6% for MMSAs, and 8.5%-39.0% for counties. Adults who were overweight: 32.6%-40.7% for states and territories, 28.5%-42.5% for MMSAs, and 27.2%-46.4% for counties. Adults aged ≥20 years who were obese: 22.1%-35.0% for states and territories, 17.1%-42.1% for MMSAs, and 13.3%-42.1% for counties. Adults with current asthma: 5.2%-11.1% for states and territories, 3.4%-14.5% for MMSAs, and 3.3%-14.6% for counties. Adults with diagnosed diabetes: 5.3%-13.2% for states and territories, 4.6%-15.4% for MMSAs, and 2.6%-18.8% for counties. Adults with limited activities because of physical, mental or emotional problems: 10.8%-28.2% for states and territories, 13.5%-38.3% for MMSAs, and 11.7%-32.0% for counties. Adults using special equipment because of any health problem: 2.8%-10.6% for states and territories, 4.5%-15.5% for MMSAs, and 1.3%-15.5% for counties. Adults aged ≥45 years who have had coronary heart disease: 5.3%-16.7% for states and territories, 6.5%-19.6% for MMSAs, and 4.9%-19.6% for counties. Adults aged ≥45 years who have had a stroke: 2.4%-7.1% for states and territories, 2.3%-8.8% for MSMAs, and 1.7%-8.8% for counties. INTERPRETATION: The findings in this report indicate substantial variations in the health-risk behaviors, chronic diseases and conditions, access to health-care services, and the use of the preventive health services among U.S. adults at the state and territory, MMSA, and county levels. Healthy People 2010 (HP 2010) objectives were established to monitor health behaviors, conditions, and the use of preventive health services for the first decade of the 2000s. The findings in this report indicate that many of the HP 2010 objectives were not achieved by 2010. The findings underscore the continued need for surveillance of health-risk behaviors, chronic diseases, and conditions and of the use of preventive health-care services. PUBLIC HEALTH ACTION: Local and state health departments and federal agencies use BRFSS data to identify populations at high risk for certain health-risk behaviors, chronic diseases, and conditions and to evaluate the use of preventive health-care services. BRFSS data also are used to direct, implement, monitor, and evaluate public health programs and policies that can lead to a reduction in morbidity and mortality from chronic conditions and corresponding health-risk behaviors.

Protein phosphatase 2a (PP2A) binds within the oligomerization domain of striatin and regulates the phosphorylation and activation of the mammalian Ste20-Like kinase Mst3.

BACKGROUND: Striatin, a putative protein phosphatase 2A (PP2A) B-type regulatory subunit, is a multi-domain scaffolding protein that has recently been linked to several diseases including cerebral cavernous malformation (CCM), which causes symptoms ranging from headaches to stroke. Striatin association with the PP2A A/C (structural subunit/catalytic subunit) heterodimer alters PP2A substrate specificity, but targets and roles of striatin-associated PP2A are not known. In addition to binding the PP2A A/C heterodimer to form a PP2A holoenzyme, striatin associates with cerebral cavernous malformation 3 (CCM3) protein, the mammalian Mps one binder (MOB) homolog, Mob3/phocein, the mammalian sterile 20-like (Mst) kinases, Mst3, Mst4 and STK25, and several other proteins to form a large signaling complex. Little is known about the molecular architecture of the striatin complex and the regulation of these sterile 20-like kinases. RESULTS: To help define the molecular organization of striatin complexes and to determine whether Mst3 might be negatively regulated by striatin-associated PP2A, a structure-function analysis of striatin was performed. Two distinct regions of striatin are capable of stably binding directly or indirectly to Mob3--one N-terminal, including the coiled-coil domain, and another more C-terminal, including the WD-repeat domain. In addition, striatin residues 191-344 contain determinants necessary for efficient association of Mst3, Mst4, and CCM3. PP2A associates with the coiled-coil domain of striatin, but unlike Mob3 and Mst3, its binding appears to require striatin oligomerization. Deletion of the caveolin-binding domain on striatin abolishes striatin family oligomerization and PP2A binding. Point mutations in striatin that disrupt PP2A association cause hyperphosphorylation and activation of striatin-associated Mst3. CONCLUSIONS: Striatin orchestrates the regulation of Mst3 by PP2A. It binds Mst3 likely as a dimer with CCM3 via residues lying between striatin's calmodulin-binding and WD-domains and recruits the PP2A A/C heterodimer to its coiled-coil/oligomerization domain. Residues outside the previously reported coiled-coil domain of striatin are necessary for its oligomerization. Striatin-associated PP2A is critical for Mst3 dephosphorylation and inactivation. Upon inhibition of PP2A, Mst3 activation appears to involve autophosphorylation of multiple activation loop phosphorylation sites. Mob3 can associate with striatin sequences C-terminal to the Mst3 binding site but also with sequences proximal to striatin-associated PP2A, consistent with a possible role for Mob 3 in the regulation of Mst3 by PP2A.

Eating disorders and obstetric-gynecologic care.

OBJECTIVE: Disordered eating can have consequences for gynecologic and obstetric patients and fetuses. Amenorrhea, infertility, hyperemesis gravidarum, and preterm birth have been linked to eating disorders (EDs). This study aimed to evaluate obstetrician-gynecologists' ED-related knowledge, attitudes, and practices. METHODS: Questionnaires were sent to 968 Fellows of the American College of Obstetricians and Gynecologists between November 2007 and March 2008. Data were analyzed separately for generalists (provide obstetric and gynecologic care) and gynecologists only (treat only gynecologic patients). RESULTS: A majority of obstetrician-gynecologists assess body weight, exercise, body mass index, and dieting habits. Less than half assess ED history, body image concerns, weight-related cosmetic surgery, binging, and purging. Over half (54%) of generalists believed ED assessment falls within their purview. Most (90.8%) generalists agreed or strongly agreed that EDs can negatively impact pregnancy outcome. A majority rated residency training in diagnosing (88.5%) and treating (96.2%) EDs as barely adequate or less. Most knew low birth weight (91%) and postpartum depression (90%) are associated with maternal EDs, though over a third was unsure about several consequences. Some gender differences emerged; females screen for more ED indicators and are more likely to view ED assessment as within their role. CONCLUSIONS: Despite the consequences of EDs and the fact that most physicians agree EDs can negatively impact pregnancy, only about half view ED assessment as their responsibility. Only some weight- and diet-related topics are assessed, and there are gaps in knowledge of ED consequences. Obstetrician-gynecologists are not confident in their training regarding EDs. Improvement in knowledge and altering obstetrician-gynecologists' view of their responsibilities may improve ED screening rates.

A program evaluation of postpartum/newborn home visitation services in aiken county, South Carolina.

OBJECTIVE: Home visiting programs for very young children seek to promote their health and development. We conducted a process and outcome evaluation of the Postpartum/Newborn Home Visit (PPNBHV) service in 1 county. DESIGN: A retrospective study of Aiken County Health records of live infant births in 2004 was conducted. SAMPLE: A random sample of 176 infants who were born in 2004 and enrolled in the women, infants, and children's (WIC) program in the same year was selected. MEASURES: Process measures include timeliness of the home visit, and appropriateness of revisits. Outcome measures include age at WIC enrollment and immunization status at 6/9 months. RESULTS: Of the 176 infants, 76 (43%) received a home visit. Of these, 13 (17%) received the visit within the stipulated time frame. After controlling for potential confounders, infants who received a home visit were 4 times (95% CI 1.92-8.36) as likely to enroll early in the WIC program compared with those who did not. CONCLUSION: The PPNBHV service may contribute to early enrollment in the WIC program. Improvement in the timeliness of the visits is needed. Program monitoring and evaluation are necessary to ensure adherence, measure outcomes, and provide feedback for continuous quality improvement.

Comparison of Semiempirical ZILSH and DFT Calculations of Exchange Constants in Fe4 Butterfly Complexes.

Magnetic interactions in a series of tetranuclear Fe(3+) complexes with the butterfly core structure have been studied with semiempirical ZILSH and density functional theory (DFT) calculations (B3LYP functional). A theoretical analysis of a previously used method of estimating exchange constants from a restricted number of spin configurations reveals systematic errors arising from asymmetry in the complexes, which cause large variations in results with different choices of spin configurations. Correction factors are derived that yield the correct results obtained from full configuration space (FCS) calculations. Exchange constants obtained from DFT FCS calculations for the "body-body" interaction were large and ferromagnetic, in disagreement with values obtained from empirical fits of magnetic susceptibility data for the complexes, established magnetostructural correlations in polynuclear Fe(3+) complexes, and ZILSH calculations. DFT calculations also gave unreasonably large antiferromagnetic exchange constants for interaction between "wingtip" ions that are not directly bridged, again in disagreement with ZILSH calculations. Estimates of exchange constants for interaction of body and wingtip ions obtained with ZILSH and DFT were similar, with the ZILSH values in slightly better agreement with empirical fits. Considering all interactions, the ZILSH method provides results in better accord with experiment than DFT for these complexes. Additional comparisons of exchange constants obtained with different spin coupling schemes showed that values appropriate for two-center spin eigenfunctions gave consistently better results than values calculated with the local spin operator. The effect of basis set was found to be very small. A brief analysis of these findings is given.

New Fe4, Fe6, and Fe8 clusters of iron(III) from the use of 2-pyridyl alcohols: structural, magnetic, and computational characterization.

The syntheses, crystal structures, magnetochemical characterization, and theoretical calculations are reported for three new iron clusters [Fe 6O 2(NO3) 4(hmp) 8(H 2O) 2](NO3)2 (1), [Fe4(N3)6(hmp)6] (2), and [Fe8O3(OMe)(pdm)4(pdmH) 4(MeOH)2](ClO4)5 (3) (hmpH=2-(hydroxymethyl)pyridine; pdmH2=2,6-pyridinedimethanol). The reaction of hmpH with iron(III) sources such as Fe(NO3) 3.9H2O in the presence of NEt 3 gave 1, whereas 2 was obtained from a similar reaction by adding an excess of NaN3. Complex 3 was obtained in good yield from the reaction of pdmH 2 with Fe(ClO4)3.6H2O in MeOH in the presence of an organic base. The complexes all possess extremely rare or novel core topologies. The core of 1 comprises two oxide-centered [Fe3(mu3-O)](7+) triangular units linked together at two of their apexes by two sets of alkoxide arms of hmp(-) ligands. Complex 2 contains a zigzag array of four Fe (III) atoms within an [Fe4(mu-OR) 6](6+) core, with the azide groups all bound terminally. Finally, complex 3 contains a central [Fe 4(mu4-O)](10+) tetrahedron linked to two oxide-centered [Fe3(mu3-O)](7+) triangular units. Variable-temperature, solid-state dc and ac magnetization studies were carried out on complexes 1-3 in the 5.0-300 K range. Fitting of the obtained magnetization versus field (H) and temperature (T) data by matrix diagonalization and including only axial anisotropy (zero-field splitting, ZFS) established that 1 possesses an S=3 ground-state spin, with g=2.08, and D=-0.44 cm(-1). The magnetic susceptibility data for 2 up to 300 K were fit by matrix diagonalization and gave J1=-9.2 cm(-1), J2=-12.5 cm(-1), and g=2.079, where J 1 and J 2 are the outer and middle nearest-neighbor exchange interactions, respectively. Thus, the interactions between the Fe(III) centers are all antiferromagnetic, giving an S=0 ground state for 2. Similarly, complex 3 was found to have an S=0 ground state. Theoretically computed values of the exchange constants in 2 were obtained with DFT calculations and the ZILSH method and were in good agreement with the values obtained from the experimental data. Exchange constants obtained with ZILSH for 3 successfully rationalized the experimental S = 0 ground state. The combined work demonstrates the ligating flexibility of pyridyl-alcohol chelates and their usefulness in the synthesis of new polynuclear Fex clusters without requiring the copresence of carboxylate ligands.

Protein phosphatase 5 is required for Hsp90 function during proteotoxic stresses in Trypanosoma brucei.

Trypanosoma brucei, a parasitic protozoan that causes African trypanosomiasis in human and domestic animals, adapt in various environments during their digenetic life cycle. In this study, we found that Hsp90 is crucial for the survival of this parasite. Inhibition of Hsp90 activity by geldanamycin (GA) reduced cell growth and increased the level of Hsp90. Both the bloodstream and procyclic forms of T. brucei showed a several-fold greater sensitivity than the mammalian cells to GA and also to 17-AAG, a less toxic derivative of GA, suggesting that Hsp90 could be a potential chemotherapeuric target for African trypanosomiasis. T. brucei Hsp90 interacts with the protein phosphatase 5 (PP5) in vivo. Under normal growth conditions, T. brucei PP5 (TbPP5) and Hsp90 are primarily localized in the cytosol. However, with increase in growth temperature and GA treatment, these proteins translocate to the nucleus. Overproduction of TbPP5 by genetic manipulation reduced the growth inhibitory effect of GA, while knockdown of TbPP5 reduced cell growth more in the presence of GA, as compared to parental control. Depletion of TbPP5, however, did not prevent the induction of Hsp90 protein level during GA treatment. Together, these results suggest that TbPP5 positively regulates the function of Hsp90 to maintain cellular homeostasis during proteotoxic stresses in T. brucei.

Functional characterization of the serine/threonine protein phosphatase 5 from Trypanosoma brucei.

PP5 is a member of the PPP family of serine/threonine protein phosphatases and is present in all eukaryotes. We previously cloned and characterized a PP5 homologue from Trypanosoma brucei. Here, we synchronized the T. brucei procyclic form by hydroxyurea treatment and showed that TbPP5 expression is regulated during cell cycle progression. TbPP5 transcript and protein levels were maximal in the G1 phase of the cell cycle, and reduced about 3-fold in the G2/M phase. To further evaluate its function, TbPP5 expression was depleted in both procyclic and bloodstream forms of T. brucei by RNA interference. In the procyclic form, TbPP5 knockdown resulted in a moderate reduction in cell growth. However, in the bloodstream form, ablation of TbPP5 caused an 8-fold decrease in cell growth. Furthermore, TbPP5 overexpression conferred the ability of procyclic cells to grow in serum-deprived conditions suggesting that TbPP5 acts downstream of serum factor-induced growth in T. brucei. Taken together; these findings suggest that a serum factor (or factors) induces up-regulation of TbPP5 expression during the G1 phase, which is required for proper cell growth.