Association of Tumor Necrosis Factor-α Inhibitors with Incident Dementia: Analysis Based on Population-Based Cohort Studies.

BACKGROUND AND OBJECTIVE: Preliminary evidence suggests a possible preventive effect of tumor necrosis factor-α inhibitors (TNFi) on incident dementia. The objective of the analysis was to investigate the association between TNFi and the risk of incident dementia in a population undergoing treatment for rheumatological disorders. METHODS: We followed patients aged ≥ 65 years with dementia and rheumatological conditions in two cohort studies, DANBIO (N = 21,538), a Danish clinical database, and AOK PLUS (N = 7112), a German health insurance database. We defined incident dementia using diagnostic codes and/or medication use and used Cox regression to compare the associations of TNFi with other rheumatological therapies on the risk of dementia. To ensure that the patients were receiving long-term medication, we included patients with rheumatic diseases and systemic therapies. RESULTS: We observed similar trends towards a lower risk of dementia associated with TNFi versus other anti-inflammatory agents in both cohorts (hazard ratios were 0.92 [95% confidence interval 0.76, 1.10] in DANBIO and 0.89 [95% confidence interval 0.63, 1.24] in AOK PLUS, respectively). CONCLUSIONS: Tumor necrosis factor-α inhibitors may decrease the risk of incident dementia although the association did not reach statistical significance in this analysis. Further research, ideally with randomization, is needed to gauge the potential of repurposing TNFi for dementia prevention and/or treatment.

Effects of dietary hydrolysate supplementation on growth, body composition, hematological responses, and liver histology of juvenile giant trevally (Caranx ignobilis Forsskal, 1775).

A feeding study was conducted to investigate how fish protein hydrolysate (FPH) supplementation affected the growth, feed utilization, body composition, and hematology of juvenile giant trevally (Caranx ignobilis Forsskal, 1775). Seven isonitrogenous (52% protein) and isocaloric diets (10% lipid) were formulated, wherein shrimp hydrolysate (SH) and tuna hydrolysate (TH) were used to replace fishmeal at inclusion levels of 0 (control), 30, 60, and 90 g/kg and labeled as control, SH30, SH60, SH90, TH30, TH60, and TH90, respectively. Each diet was fed to triplicate groups of juvenile giant trevally for 8 weeks. The results showed higher final body weight and specific growth rate in fish fed SH30, SH60, TH30, and TH60 than fed control diet. No difference was observed in feed intake, but reduced feed conversion ratio (FCR) was found in fish fed SH30, SH60, TH30, and TH60, demonstrating these diets improved feed utilization. TH90 caused deposition of lipid droplet in the hepatocyte, a sign of liver damage. Total monounsaturated fatty acids, polyunsaturated fatty acids (PUFA), and highly unsaturated fatty acids in fish were not affected by FPH supplementation. Fish fed TH30 showed lower ∑n - 3 PUFA than the fish fed remaining dietary treatments. The elevated serum protein was seen in fish fed control, SH30, SH60, and TH30, demonstrating that these diets were beneficial for the innate immune response in giant trevally. The results indicate that TH and SH could be incorporated into diets of giant trevally at 30-60 g/kg, replacing 7%-13% fishmeal with enhanced growth and health benefits.

Label-Free Single Nanoparticle Identification and Characterization in Demanding Environment, Including Infectious Emergent Virus.

Unknown particle screening-including virus and nanoparticles-are keys in medicine, industry, and also in water pollutant determination. Here, RYtov MIcroscopy for Nanoparticles Identification (RYMINI) is introduced, a staining-free, non-invasive, and non-destructive optical approach that is merging holographic label-free 3D tracking with high-sensitivity quantitative phase imaging into a compact optical setup. Dedicated to the identification and then characterization of single nano-object in solution, it is compatible with highly demanding environments, such as level 3 biological laboratories, with high resilience to external source of mechanical and optical noise. Metrological characterization is performed at the level of each single particle on both absorbing and transparent particles as well as on immature and infectious HIV, SARS-CoV-2 and extracellular vesicles in solution. The capability of RYMINI to determine the nature, concentration, size, complex refractive index and mass of each single particle without knowledge or model of the particles' response is demonstrated. The system surpasses 90% accuracy for automatic identification between dielectric/metallic/biological nanoparticles and ≈80% for intraclass chemical determination of metallic and dielectric. It falls down to 50-70% for type determination inside the biological nanoparticle's class.

Purine containing carbonucleoside phosphonate analogues as novel chemotype for Plasmodium falciparum Inhibition.

The nucleotidase ISN1 is a potential therapeutic target of the purine salvage pathway of the malaria parasite Plasmodium falciparum. We identified PfISN1 ligands by in silico screening of a small library of nucleos(t)ide analogues and by thermal shift assays. Starting from a racemic cyclopentyl carbocyclic phosphonate scaffold, we explored the diversity on the nucleobase moiety and also proposed a convenient synthetic pathway to access the pure enantiomers of our initial hit (compound (±)-2). 2,6-Disubstituted purine containing derivatives such as compounds 1, (±)-7e and ß-L-(+)-2 showed the most potent inhibition of the parasite in vitro, with low micromolar IC50 values. These results are remarkable considering the anionic nature of nucleotide analogues, which are known to lack activity in cell culture experiments due to their scarce capacity to cross cell membranes. For the first time, we report the antimalarial activity of a carbocyclic methylphosphonate nucleoside with an L-like configuration.

Differences and similarities in recognition of co-factors by Taf14.

Taf14 is a subunit of multiple fundamental complexes implicated in transcriptional regulation and DNA damage repair in yeast cells. Here, we investigate the association of Taf14 with the consensus sequence present in other subunits of these complexes and describe the mechanistic features that affect this association. We demonstrate that the precise molecular mechanisms and biological outcomes underlying the Taf14 interactions depend on the accessibility of binding interfaces, the ability to recognize other ligands, and a degree of sensitivity to temperature and chemical and osmotic stresses. Our findings aid in a better understanding of how the distribution of Taf14 among the complexes is mediated.

How Single Amino Acid Substitutions Can Disrupt a Protein Hetero-Dimer Interface: Computational and Experimental Studies of the LigAB Dioxygenase from Sphingobium sp. Strain SYK-6.

Protocatechuate 4,5-dioxygenase (LigAB) is a heterodimeric enzyme that catalyzes the dioxygenation of multiple lignin derived aromatic compounds. The active site of LigAB is at the heterodimeric interface, with specificity conferred by the alpha subunit and catalytic residues contributed by the beta subunit. Previous research has indicated that the phenylalanine at the 103 position of the alpha subunit (F103α) controls selectivity for the C5 position of the aromatic substrates, and mutations of this residue can enhance the rate of catalysis for substrates with larger functional groups at this position. While several of the mutations to this position (Valine, V; Threonine, T; Leucine, L; and Histidine, H) were catalytically active, other mutations (Alanine, A; and Serine, S) were found to have reduced dimer interface affinity, leading to challenges in copurifing the catalytically active enzyme complex under high salt conditions. In this study, we aimed to experimentally and computationally interrogate residues at the dimer interface to discern the importance of position 103α for maintaining the integrity of the heterodimer. Molecular dynamic simulations and electrophoretic mobility assays revealed a preference for nonpolar/aromatic amino acids in this position, suggesting that while substitutions to polar amino acids may produce a dioxygenase with a useful substrate utilization profile, those considerations may be off-set by potential destabilization of the catalytically active oligomer. Understanding the dimerization of LigAB provides insight into the multimeric proteins within the largely uncharacterized superfamily and characteristics to consider when engineering proteins that can degrade lignin efficiently. These results shed light on the challenges associated with engineering proteins for broader substrate specificity.

[Connective tissue diseases and pregnancy]. / Connectivites et grossesse.

Connective tissue diseases are rare usually affecting women of reproductive age. Patients should be informed about the potential obstetrical risks associated with their disease as well as potential exacerbations during pregnancy, while simultaneously being reassured with the prospect of a positive pregnancy outcome. In recent years, significant progress has been made in medical treatments, giving women the opportunity to consider pregnancy. Preconception counseling is critical to pregnancy planning. An effective contraceptive measure should be recommended based on disease activity and teratogenic medications should be modified. Pregnancy monitoring are managed based on specific clinical and serological markers (such as the presence of anti-SSA/SSB or anti-phospholipid antibodies). A multidisciplinary approach is essential for a safe pregnancy.

Les connectivites touchent souvent des femmes en âge de procréer. Les patientes doivent être informées des risques obstétricaux ou d'aggravation potentiels de leur maladie, mais également être rassurées quant à leur chance de succès de grossesse. En effet, grâce aux progrès de la médecine, il est possible de mener à bien une grossesse chez ces patientes en prenant certaines précautions. Une contraception efficace doit être mise en place en cas de maladie active, de prise de médicaments tératogènes ou fœto-toxiques. Une adaptation des traitements est donc souvent nécessaire avant la grossesse. Le suivi durant celle-ci, l'accouchement et le postpartum est conditionné par le type de maladie, son activité, ainsi que les profils sérologiques à risques (anti-SSA/SSB, anticorps antiphospholipides). Une approche multidisciplinaire est donc essentielle.

Engaging with benzoyllysine through a π-π-π mechanism.

Epigenetic modifications have been gaining in prominence as fundamental components of the chromatin regulatory machinery. In this review, we summarize the molecular and structural mechanisms of reading, writing, and erasing of lysine benzoylation, a recently discovered posttranslational modification (PTM) in histones. We highlight a unique nature of the conjugated π system of benzoyllysine that may aid in the development of benzoyllysine-specific effectors indifferent to the saturated acyllysine modifications. We also discuss transcriptional and metabolic functions associated with benzoylation of histones and implications of ingesting of sodium benzoate for human health.

Spectroscopy of individual Brownian nanoparticles in real-time using holographic localization.

Individual nanoparticle spectroscopic characterization is fundamental, but challenging in liquids. While confocal selectivity is necessary to isolate a particle in a crowd, Brownian motion constantly offsets the particle from the light collection volume. Here, we present a system able to acquire holograms and reconstruct them to precisely determine the 3D position of a particle in real time. These coordinates drive an adaptive system comprising two galvanometric mirrors (x,y, transverse directions) and a tunable lens (z, longitudinal) which redirect light scattered from the corresponding region of space towards the confocal entrance of a spectrometer, thus allowing long spectral investigations on individual, freely-moving particles. A study of the movements and spectra of individual 100 nm Au nanoparticles undergoing two types of aggregations illustrates the possibilities of the method.

3D Spectroscopic Tracking of Individual Brownian Nanoparticles during Galvanic Exchange.

Monitoring chemical reactions in solutions at the scale of individual entities is challenging: single-particle detection requires small confocal volumes, which are hardly compatible with Brownian motion, particularly when long integration times are necessary. Here, we propose a real-time (10 Hz) holography-based nm-precision 3D tracking of single moving nanoparticles. Using this localization, the confocal collection volume is dynamically adjusted to follow the moving nanoparticle and allow continuous spectroscopic monitoring. This concept is applied to study galvanic exchange in freely moving colloidal silver nanoparticles with gold ions generated in situ. While the Brownian trajectory reveals particle size, spectral shifts dynamically reveal composition changes and transformation kinetics at the single-object level, pointing at different transformation kinetics for free and tethered particles.

Phosphopantetheinyl transferase binding and inhibition by amidino-urea and hydroxypyrimidinethione compounds.

Owing to their role in activating enzymes essential for bacterial viability and pathogenicity, phosphopantetheinyl transferases represent novel and attractive drug targets. In this work, we examined the inhibitory effect of the aminido-urea 8918 compound against the phosphopantetheinyl transferases PptAb from Mycobacterium abscessus and PcpS from Pseudomonas aeruginosa, two pathogenic bacteria associated with cystic fibrosis and bronchiectasis, respectively. Compound 8918 exhibits inhibitory activity against PptAb but displays no activity against PcpS in vitro, while no antimicrobial activity against Mycobacterium abscessus or Pseudomonas aeruginosa could be detected. X-ray crystallographic analysis of 8918 bound to PptAb-CoA alone and in complex with an acyl carrier protein domain in addition to the crystal structure of PcpS in complex with CoA revealed the structural basis for the inhibition mechanism of PptAb by 8918 and its ineffectiveness against PcpS. Finally, in crystallo screening of potent inhibitors from the National Cancer Institute library identified a hydroxypyrimidinethione derivative that binds PptAb. Both compounds could serve as scaffolds for the future development of phosphopantetheinyl transferases inhibitors.

Modified compact fluorescent lamps improve light-induced off-season floral stimulation in dragon fruit farming.

Efficient light-induced floral stimulation plays a key role in energy conservation and maintaining stable productivity during off-season periods of dragon fruit plants. In this study, we first reported on results of a survey on dragon fruit farmers regarding use of lamps in performing artificially induced flowering process in Vietnam. It was found that the use of incandescent lamp was prevalent in dragon fruit cultivation practices, resulting in heavy electricity consumption, and that low-power compact fluorescent light (CFL) bulbs were not extensively utilized, possibly due to low floral induction performance of domestic CFL bulbs. Arguing that emission spectra of currently used lamps were not consistent with adsorption spectra of phytochromes, whose transformation is responsible for flowering process of dragon fruit, we then proposed three improved CFL lamps (power capacity of 20 W) having emission spectra focused on red and far-red regions. New lamp prototypes were tested in 7 field experiments in three different provinces in Vietnam. One improved CFL bulb (treatment 2) performed relatively well in comparison with the incandescent control lamp (60 W) in six out of seven experiments with regard to some growth indicators (e.g., number of floral stems, number of bubs, number of fruits per plant) and fruit yield. Recent success on commercialization of the improved CFL lamp demonstrates the potential of CFL lamps in floral stimulating irradiation of other crops and plants and in alleviating electricity burden in dragon fruit growing areas.

Quantitative Temperature Measurements in Gold Nanorods Using Digital Holography.

Temperature characterization and quantification at the nanoscale remain core challenges in applications based on photoinduced heating of nanoparticles. Here, we propose a new approach to obtain quantitative temperature measurements on individual nanoparticles by combining modulated photothermal stimulation and heterodyne digital holography. From full-field reconstructed holograms, the temperature is determined with a precision of 0.3 K via a simple approach without requiring any calibration or fitting parameters. As an application, the dependence of temperature on the aspect ratio of gold nanoparticles is investigated. A good agreement with numerical simulation is observed.

Lifestyle and psychosocial correlates of oral hygiene practice among Indonesian adolescents.

Poor oral hygiene leads to poor oral health, which in turn has negative impacts on overall health and quality of life. This study aimed to evaluate the prevalence and associated factors of oral hygiene practice among school-going adolescents in Indonesia. Secondary analysis of cross-sectional, nationally representative data from the 2015 Indonesia Global School-based Health Survey, covering 11,142 students aged 11-18 years, was performed. Multiple logistic regression was employed to explore associations between lifestyle, psychosocial factors, and tooth-brushing frequency. Around 10.8% of the students brushed their teeth less frequently than the recommended twice-daily regimen. Male gender, lower socio-economic status, poor dietary practice, longer sedentary time, drug use, psychological distress, less peer support, and no parental support were associated with infrequent tooth brushing. The findings support the need to integrate oral health promotion into general health actions that target families, schools, and social environments of adolescents to develop healthier habits.

Factors Affecting Dental Service Utilisation in Indonesia: A Population-Based Multilevel Analysis.

This study aimed to examine the prevalence of dental service utilisation in Indonesia and its association with social determinants at individual and community levels. Cross-sectional data from the 2014 Indonesian Family Life Survey (IFLS-5) was analysed. Individual independent variables included age, sex, marital status, educational attainment, economic status, health insurance, dental pain, self-reported mouth ulcers, self-rated health status, unmet healthcare needs and smoking status, while community independent variables included cognitive, structural social capital and residential area. Multilevel logistic regressions were performed to explore the associations between independent variables at different levels and the outcome of dental service utilisation. Of the total sample of 16,860 adults aged 15 years or older in our study, around 86.4% never visited a dentist. Dental service utilisation was associated with older age, female, currently not married, higher education level and economic status, health insurance, dental pain, self-reported mouth ulcers, met healthcare needs, never smoking, living in urban areas and communities with high structural social capital. Both individual and broader social determinants influenced dental service utilisation in Indonesia. These factors should be considered in the formulation of oral health policies and programmes aiming to improve dental service utilisation in the country.

Conformational flexibility of coenzyme A and its impact on the post-translational modification of acyl carrier proteins by 4'-phosphopantetheinyl transferases.

One central question surrounding the biosynthesis of fatty acids and polyketide-derived natural products is how the 4'-phosphopantetheinyl transferase (PPTase) interrogates the essential acyl carrier protein (ACP) domain to fulfill the initial activation step. The triggering factor of this study was the lack of structural information on PPTases at physiological pH, which could bias our comprehension of the mechanism of action of these important enzymes. Structural and functional studies on the family II PPTase PptAb of Mycobacterium abscessus show that pH has a profound effect on the coordination of metal ions and on the conformation of endogenously bound coenzyme A (CoA). The observed conformational flexibility of CoA at physiological pH is accompanied by a disordered 4'-phosphopantetheine (Ppant) moiety. Finally, structural and dynamical information on an isolated mycobacterial ACP domain, in its apo form and in complex with the activator PptAb, suggests an alternate mechanism for the post-translational modification of modular megasynthases.

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus.

CONTEXT: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion. OBJECTIVE: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase. MATERIALS AND METHODS: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays. RESULTS: A new (2RS,3SR)-3,4',5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity. DISCUSSION: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents. CONCLUSION: The isolated compounds may contribute to the antidiabetic property of C. rotundus.

Escherichia coli as reservoir for macrolide resistance genes.

The plasmid-borne mph(A) gene that confers resistance to azithromycin and has recently emerged in Shigella sonnei is present in multidrug- and non-multidrug-resistant Escherichia coli isolates from 4 continents. Further spread of mph(A) to Shigella and Salmonella spp. may be expected.

Seasonal changes in sleep duration in African American and African college students living in Washington, D.C.

Duration of nocturnal melatonin secretion, a marker of "biological night" that relates to sleep duration, is longer in winter than in summer in patients with seasonal affective disorder (SAD), but not in healthy controls. In this study of African and African American college students, we hypothesized that students who met criteria for winter SAD or subsyndromal SAD (S-SAD) would report sleeping longer in winter than in summer. In addition, based on our previous observation that Africans report more "problems" with change in seasons than African Americans, we expected that the seasonal changes in sleep duration would be greater in African students than in African American students. Based on Seasonal Pattern Assessment Questionnaire (SPAQ) responses, African American and African college students in Washington, D.C. (N = 575) were grouped into a winter SAD/S-SAD group or a no winter diagnosis group, and winter and summer sleep length were determined. We conducted a 2 (season) x 2 (sex) x 2 (ethnicity) x 2 (winter diagnosis group) ANCOVA on reported sleep duration, controlling for age. Contrary to our hypothesis, we found that African and African American students with winter SAD/S-SAD report sleeping longer in the summer than in the winter. No differences in seasonality of sleep were found between African and African American students. Students with winter SAD or S-SAD may need to sacrifice sleep duration in the winter, when their academic functioning/efficiency may be impaired by syndromal or subsyndromal depression, in order to meet seasonally increased academic demands.

Mood sensitivity to seasonal changes in African college students living in the greater Washington D.C. metropolitan area.

The purpose of this study was to estimate the degree of seasonality and prevalence of winter- and summer-type seasonal affective disorder (SAD) in African immigrant college students in comparison with African American peers. A convenience sample of 246 African immigrants and 599 African Americans studying in Washington, D.C. completed the Seasonal Pattern Assessment Questionnaire (SPAQ), which was used to calculate a global seasonality score (GSS) and to estimate the prevalence of winter- and summer-type SAD. Degree of seasonality was related to a complex interaction between having general awareness of SAD, ethnicity, and gender. A greater percentage of African students reported experiencing a problem with seasonal changes relative to African American students, and had summer SAD, but the groups did not differ on GSS and winter SAD. African students reported more difficulties with seasonal changes than their African American peers, which could represent a manifestation of incomplete acclimatization to a higher latitude and temperate climate. As Africans also had a greater rate of summer SAD, this argues against acclimatization to heat.