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1.
Trends Genet ; 37(5): 406-410, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33518406

RESUMO

The CD225 superfamily regulates vesicular membrane fusion events essential to neurotransmission, immunity, development, and metabolism. Its importance to physiology is reinforced by the identification of polymorphisms associated with disease. This article highlights the shared features that drive the function of CD225 proteins such as interferon-inducible transmembrane proteins 3 (IFITM3) and proline-rich transmembrane protein 2 (PRRT2) and is intended to catalyze efforts towards characterizing the lesser-known family members.


Assuntos
Antígenos de Diferenciação/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Animais , Antígenos de Diferenciação/química , Antígenos de Diferenciação/genética , Exocitose/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fusão de Membrana/fisiologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Família Multigênica , Internalização do Vírus
2.
Small ; 20(7): e2305865, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37798672

RESUMO

2D semiconductors (2SEM) can transform many sectors, from information and communication technology to healthcare. To date, top-down approaches to their fabrication, such as exfoliation of bulk crystals by "scotch-tape," are widely used, but have limited prospects for precise engineering of functionalities and scalability. Here, a bottom-up technique based on epitaxy is used to demonstrate high-quality, wafer-scale 2SEM based on the wide band gap gallium selenide (GaSe) compound. GaSe layers of well-defined thickness are developed using a bespoke facility for the epitaxial growth and in situ studies of 2SEM. The dominant centrosymmetry and stacking of the individual van der Waals layers are verified by theory and experiment; their optical anisotropy and resonant absorption in the UV spectrum are exploited for photon sensing in the technological UV-C spectral range, offering a scalable route to deep-UV optoelectronics.

3.
Small ; 20(40): e2404809, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39169700

RESUMO

2D semiconductors can drive advances in quantum science and technologies. However, they should be free of any contamination; also, the crystallographic ordering and coupling of adjacent layers and their electronic properties should be well-controlled, tunable, and scalable. Here, these challenges are addressed by a new approach, which combines molecular beam epitaxy and in situ band engineering in ultra-high vacuum of semiconducting gallium selenide (GaSe) on graphene. In situ studies by electron diffraction, scanning probe microscopy, and angle-resolved photoelectron spectroscopy reveal that atomically-thin layers of GaSe align in the layer plane with the underlying lattice of graphene. The GaSe/graphene heterostructure, referred to as 2semgraphene, features a centrosymmetric (group symmetry D3d) polymorph of GaSe, a charge dipole at the GaSe/graphene interface, and a band structure tunable by the layer thickness. The newly-developed, scalable 2semgraphene is used in optical sensors that exploit the photoactive GaSe layer and the built-in potential at its interface with the graphene channel. This proof of concept has the potential for further advances and device architectures that exploit 2semgraphene as a functional building block.

4.
Popul Health Metr ; 22(1): 7, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38643138

RESUMO

BACKGROUND: Disability-free life expectancy (DFLE) has been used to gain a better understanding of the population's quality of life. OBJECTIVES: The authors aimed to estimate age and sex-specific disability-free life expectancy (DFLE) for urban and rural areas of Bangladesh, as well as to investigate the differences in DFLE between males and females of urban and rural areas. METHODS: Data from the Bangladesh Sample Vital Statistics-2016 and the Bangladesh Household Income and Expenditure Survey (HIES)-2016 were used to calculate the disability-free life expectancy (DFLE) of urban and rural males and females in Bangladesh in 2016. The DFLE was calculated using the Sullivan method. RESULTS: With only a few exceptions, rural areas have higher mortality and disability rates than urban areas. For both males and females, statistically significant differences in DFLE were reported between urban and rural areas between the ages of birth and 39 years. In comparison to rural males and females, urban males and females had a longer life expectancy (LE), a longer disability-free life expectancy, and a higher share of life without disability. CONCLUSION: This study illuminates stark urban-rural disparities in LE and DFLE, especially among individuals aged < 1-39 years. Gender dynamics reveal longer life expectancy but shorter disability-free life expectancy for Bangladeshi women compared to men, emphasizing the need for targeted interventions to address these pronounced health inequalities.


Assuntos
Pessoas com Deficiência , Expectativa de Vida Saudável , Masculino , Humanos , Feminino , Adulto , Bangladesh/epidemiologia , Qualidade de Vida , Expectativa de Vida , Renda
5.
Glia ; 71(8): 1804-1829, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37026600

RESUMO

Autoantibodies against the NR1 subunit of NMDA receptors (NMDARs) have been shown to promote crosslinking and internalization of bound receptors in NMDAR encephalitis (NMDARE). This internalization-mediated loss of NMDARs is thought to be the major mechanism leading to pathogenic outcomes in patients. However, the role of bound autoantibody in engaging the resident immune cells, microglia, remains poorly understood. Here, using a patient-derived monoclonal NR1 autoantibody (hNR1-mAb) and a co-culture system of microglia and neurons, we could show that hNR1-mAb bound to hippocampal neurons led to microglia-mediated removal of hNR1-mAb bound NMDARs. These complexes were found to accumulate inside endo-lysosomal compartments of microglia. Utilizing another patient isolated monoclonal autoantibody, against the α1-subunit of GABAA receptors (α1-GABAA -mAb), such removal of receptors was found to be specific to the antibody-bound receptor targets. Interestingly, along with receptor removal, we also observed a reduction in synapse number, more specifically in the numbers of post-synaptic proteins like PSD95 and Homer 1, when microglia were present in the culture. Importantly, mutations in the Fc region of hNR1-mAb, blocking its Fcγ receptor (FcγR) and complement binding, attenuated hNR1-mAb driven loss of NMDARs and synapses, indicating that microglia engagement by bound hNR1-mAb is critical for receptor and synapse loss. Our data argues for an active involvement of microglia in removal of NMDARs and other receptors in individuals with autoimmune encephalitis, thereby contributing to the etiology of these diseases.


Assuntos
Autoanticorpos , Receptores de N-Metil-D-Aspartato , Humanos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Autoanticorpos/metabolismo , Técnicas de Cocultura , Microglia/metabolismo , Neurônios/metabolismo , Ácido gama-Aminobutírico/metabolismo
6.
Bioorg Med Chem Lett ; 92: 129406, 2023 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-37423504

RESUMO

Gamma-glutamyl transferase 1 (GGT1) is a critical enzyme involved in the hydrolysis and/or transfer of gamma-glutamyl groups of glutathione, which helps maintain cysteine levels in plasma. In this study, we synthesized L-ABBA analogs to investigate their inhibitory effect on GGT1 hydrolysis and transpeptidase activity, with the goal of defining the pharmacophore of L-ABBA. Our structure-activity relationship (SAR) study revealed that an α-COO- and α-NH3+ group, as well as a two-CH2 unit distance between α-C and boronic acid, are essential for the activity. The addition of an R (alkyl) group at the α-C reduced the activity of GGT1 inhibition, with L-ABBA being the most potent inhibitor among the analogs. Next, we investigated the impact of L-ABBA on plasma levels of cysteine and GSH species, with the expectation of observing reduced cysteine levels and enhanced GSH levels due to its GGT1 inhibition. We administered L-ABBA intraperitoneally and determined the plasma levels of cysteine, cystine, GSH, and GSSG using LCMS. Our results showed time- and dose-dependent L-ABBA changes in total plasma cysteine and GSH levels. This study is the first to demonstrate the regulation of plasma thiol species upon GGT1 inhibition, with plasma cystine levels reduced by up to âˆ¼ 75 % with L-ABBA (0.3 mg/dose). Cancer cells are highly dependent on the uptake of cysteine from plasma for maintaining high levels of intracellular glutathione. Thus, our findings suggest that GGT1 inhibitors, such as L-ABBA, have the potential to be used in GSH reduction thereby inducing oxidative stress in cancer cells and reducing their resistance to many chemotherapeutic agents.

7.
Nanotechnology ; 34(24)2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36917852

RESUMO

This article addresses the synthesis of Fe3+doped TiO2nanoparticles with variations of molar concentrations of Fe3+and their adequate use as potential photocatalysts for Photocatalysis applications. Synthesized photocatalysts were characterized thoroughly by different analytical techniques in terms of morphological, chemical, structural, crystalline, optical, electronic structure, surface area etc properties. The occurrence of red shift phenomenon of the energy band gap attributes to the transfer of charges and transition between the d electrons of dopant and conduction band (CB) or valence band (VB) of TiO2. The doping of Fe3+ions generates more trap sites for charge carriers with the surface trap sites. Thorough experimental conclusions revealed that the Fe3+ions necessarily regulate the catalytic property of TiO2nanomaterial. The obtained total degradation efficiency rate of Methylene Blue (MB) was 93.3% in the presence of 0.1 M Fe3+in the host material and for Malachite Green Oxalate the efficiency was 100% in the presence of 0.05 M and 0.1 M Fe3+in the host material. In both the cases the total visible light irradiation time was 90 min. The adsorption properties of the photocatalysts have been also performed in a dark for 90 min in the presence of MB dye. However, till now there are hardly reported photocatalysts which shows complete degradation of these toxic organic dyes by visible light driven photocatalysis. of potential values of valence and conduction band shows the production of active oxidizing species for hydrogen yield and the possible mechanism of the Schottky barrier has been proposed. A schematic diagram of visible light driven Photocatalysis has been pictured showing degradation activity of Fe3+-TiO2catalysts sample.

8.
J Virol ; 95(21): e0068021, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34319781

RESUMO

The interferon-induced transmembrane (IFITM) gene family performs multiple functions in immunity, including inhibition of virus entry into cells. The IFITM repertoire varies widely between species and consists of protein-coding genes and pseudogenes. The selective forces driving pseudogenization within gene families are rarely understood. In this issue, the human pseudogene IFITM4P is characterized as a virus-induced, long noncoding RNA that contributes to restriction of influenza A virus by regulating mRNA levels of IFITM1, IFITM2, and IFITM3.


Assuntos
Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/metabolismo , Influenza Humana/virologia , Proteínas de Membrana/metabolismo , Pseudogenes , RNA Longo não Codificante/genética , RNA Longo não Codificante/farmacologia , Antígenos de Diferenciação/metabolismo , Antivirais/imunologia , Antivirais/farmacologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Vírus da Influenza A/imunologia , Influenza Humana/imunologia , Interferons/imunologia , Proteínas de Membrana/imunologia , RNA Longo não Codificante/imunologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Internalização do Vírus
9.
Occup Ther Health Care ; : 1-11, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35834426

RESUMO

This descriptive study describes the practice and challenges of occupational therapists in Bangladesh during the COVID-19 pandemic using an online survey. Eighty-four participants who are practising in both clinical and community settings anonymously participated in the study between January - March 2021. About a third (38.5%) of participants continued hands-on service, 29.5% started working from home, 19.2% worked in both methods, and 12.8% stopped working and almost 12% commenced telerehabilitation service as a new practice. This paper describes the practice as well as the different challenges. Implications of the results are explored as well as future needs.

10.
J Biol Chem ; 295(27): 9223-9243, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32414843

RESUMO

Skp1, a subunit of E3 Skp1/Cullin-1/F-box protein ubiquitin ligases, is modified by a prolyl hydroxylase that mediates O2 regulation of the social amoeba Dictyostelium and the parasite Toxoplasma gondii The full effect of hydroxylation requires modification of the hydroxyproline by a pentasaccharide that, in Dictyostelium, influences Skp1 structure to favor assembly of Skp1/F-box protein subcomplexes. In Toxoplasma, the presence of a contrasting penultimate sugar assembled by a different glycosyltransferase enables testing of the conformational control model. To define the final sugar and its linkage, here we identified the glycosyltransferase that completes the glycan and found that it is closely related to glycogenin, an enzyme that may prime glycogen synthesis in yeast and animals. However, the Toxoplasma enzyme catalyzes formation of a Galα1,3Glcα linkage rather than the Glcα1,4Glcα linkage formed by glycogenin. Kinetic and crystallographic experiments showed that the glycosyltransferase Gat1 is specific for Skp1 in Toxoplasma and also in another protist, the crop pathogen Pythium ultimum The fifth sugar is important for glycan function as indicated by the slow-growth phenotype of gat1Δ parasites. Computational analyses indicated that, despite the sequence difference, the Toxoplasma glycan still assumes an ordered conformation that controls Skp1 structure and revealed the importance of nonpolar packing interactions of the fifth sugar. The substitution of glycosyltransferases in Toxoplasma and Pythium by an unrelated bifunctional enzyme that assembles a distinct but structurally compatible glycan in Dictyostelium is a remarkable case of convergent evolution, which emphasizes the importance of the terminal α-galactose and establishes the phylogenetic breadth of Skp1 glycoregulation.


Assuntos
Galactose/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Dictyostelium/metabolismo , Proteínas F-Box/metabolismo , Glucosiltransferases/metabolismo , Glicoproteínas/metabolismo , Glicosilação , Glicosiltransferases/metabolismo , Hidroxilação , Hidroxiprolina/metabolismo , Filogenia , Pró-Colágeno-Prolina Dioxigenase/genética , Prolil Hidroxilases/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Ligases SKP Culina F-Box/fisiologia , Toxoplasma/metabolismo
11.
Sensors (Basel) ; 21(8)2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33917665

RESUMO

In this paper, an integrated thermoelectric (TE) and photovoltaic (PV) hybrid energy harvesting system (HEHS) is proposed for self-powered internet of thing (IoT)-enabled wireless sensor networks (WSNs). The proposed system can run at a minimum of 0.8 V input voltage under indoor light illumination of at least 50 lux and a minimum temperature difference, ∆T = 5 °C. At the lowest illumination and temperature difference, the device can deliver 0.14 W of power. At the highest illumination of 200 lux and ∆T = 13 °C, the device can deliver 2.13 W. The developed HEHS can charge a 0.47 F, 5.5 V supercapacitor (SC) up to 4.12 V at the combined input voltage of 3.2 V within 17 s. In the absence of any energy sources, the designed device can back up the complete system for 92 s. The sensors can successfully send 39 data string to the webserver within this time at a two-second data transmission interval. A message queuing telemetry transport (MQTT) based IoT framework with a customised smartphone application 'MQTT dashboard' is developed and integrated with an ESP32 Wi-Fi module to transmit, store, and monitor the sensors data over time. This research, therefore, opens up new prospects for self-powered autonomous IoT sensor systems under fluctuating environments and energy harvesting regimes, however, utilising available atmospheric light and thermal energy.

12.
Environ Dev Sustain ; 23(6): 8179-8194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33041645

RESUMO

Generation of energy across the world is today reliant majorly on fossil fuels. The burning of these fuels is growing in line with the increase in the demand for energy globally. Consequently, climate change, air contamination, and energy security issues are rising as well. An efficient alternative to this grave hazard is the speedy substitution of fossil fuel-based carbon energy sources with the shift to clean sources of renewable energy that cause zero emissions. This needs to happen in conjunction with the continuing increase in the overall consumption of energy worldwide. Many resources of renewable energy are available. These include thermal, solar photovoltaic, biomass and wind, tidal energy, hydropower, and geothermal. Notably, tidal energy exhibits great potential with regard to its dependability, superior energy density, certainty, and durability. The energy mined from the tides on the basis of steady and anticipated vertical movements of the water, causing tidal currents, could be converted into kinetic energy to produce electricity. Tidal barrages could channel mechanical energy, while tidewater river turbines can seize the energy from tidal currents. This study discusses the present trends, ecological effects, and the prospects for technology related to tidal energy.

13.
Trop Med Int Health ; 25(8): 985-995, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32406965

RESUMO

OBJECTIVE: The Cholera-Hospital-Based Intervention for 7-days (CHoBI7) mobile health (mHealth) program delivers mobile messages to diarrhoea patient households promoting water treatment and handwashing with soap. The randomised controlled trial (RCT) of the CHoBI7 mHealth program demonstrated this intervention was effective in significantly reducing diarrhoea and stunting amoung young children. The objective of this study was to assess the implementation of the CHoBI7 mHealth program in delivering mHealth messages during this RCT. METHODS: 517 diarrhoea patient households with 1777 participants received weekly text, voice and interactive voice response (IVR) messages from the CHoBI7 mHealth program over the 12-month program period. The program process evaluation indicators were the following: the percentage of CHoBI7 mHealth messages received and fully listened to by program households (program fidelity and dose), and household members reporting receiving and sharing an mHealth message from the program in the past two weeks (program reach). RESULTS: Ninety two percent of text messages were received by program households. Eighty three percent of voice and 86% of IVR messages sent were fully listened to by at least one household member. Eighty one percent of IVR quiz responses from households were answered correctly. Program households reported receiving a CHoBI7 mHealth message in the past two weeks at 79% of monthly household visits during the 12-month program. Seventy seven percent of participants reported sharing a program message with a spouse, 55% with a neighbour and 49% with a child during the program period. CONCLUSION: There was high fidelity, dose and reach of mobile messages delivered for the CHoBI7 mHealth program. This study presents an approach for process evaluation that can be implemented to evaluate future mHealth programs.


OBJECTIF: Le programme CHoBI7 (Cholera-Hospital-Based-Intervention-for-7-days) de santé mobile (mHealth) délivre des messages mobiles aux ménages avec patients atteints de diarrhée pour promouvoir le traitement de l'eau et le lavage des mains au savon. L'essai contrôlé randomisé (ECR) du programme mHealth CHoBI7 a démontré que cette intervention était efficace pour réduire de manière significative la diarrhée et le retard de croissance chez les jeunes enfants. L'objectif de cette étude était d'évaluer la mise en œuvre du programme CHoBI7 mHealth dans la diffusion des messages mHealth au cours de cet ECR. MÉTHODES: 517 ménages avec des patients atteints de diarrhée ont reçu chaque semaine des messages SMS, vocaux et de réponse vocale interactive (RVI) du programme mHealth de CHoBI7 pendant les 12 mois du programme. Les indicateurs d'évaluation du processus du programme étaient les suivants: le pourcentage de messages mHealth du programme CHoBI7 reçus (fidélité au programme et dose) et entièrement écoutés par les ménages participant au programme (fidélité au programme et dose) et les bénéficiaires déclarant avoir reçu et partagé un message mHealth du programme (portée du programme) au cours des deux dernières semaines. RÉSULTATS: 92% des SMS ont été reçus par les ménages participant au programme. 83% des messages vocaux et 86% des messages RVI envoyés ont été entièrement écoutés par au moins un membre du ménage. 81% des réponses aux quiz RVI des ménages ont été correctement répondues. Les ménages du programme ont déclaré avoir reçu un message CHoBI7 mHealth au cours des deux dernières semaines dans 79% des visites mensuelles des ménages pendant les 12 mois du programme. 77% des participants ont déclaré avoir partagé un message du programme avec un conjoint, 55% avec un voisin et 49% avec un enfant pendant la durée du programme. CONCLUSION: La dose et les messages délivrés dans le cadre du programme mHealth de CHoBI7 l'ont été avec une fidélité élevée. Cette étude présente une approche d'évaluation des processus qui peut être mise en œuvre pour évaluer les futurs programmes mHealth.


Assuntos
Diarreia/prevenção & controle , Promoção da Saúde/métodos , Higiene , Saneamento/métodos , Telemedicina/métodos , Envio de Mensagens de Texto , Purificação da Água/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Cólera/prevenção & controle , Feminino , Transtornos do Crescimento/prevenção & controle , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
BMC Infect Dis ; 20(1): 607, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807087

RESUMO

BACKGROUND: During an evolving outbreak or pandemic, non-pharmaceutical interventions (NPIs) including physical distancing, isolation, and mask use may flatten the peak in communities. However, these strategies rely on community understanding and motivation to engage to ensure appropriate compliance and impact. To support current activities for COVID-19, the objectives of this narrative review was to identify the key determinants impacting on engagement. METHODS: An integrative narrative literature review focused on NPIs. We aimed to identify published peer-reviewed articles that focused on the general community (excluding healthcare workers), NPIs (including school closure, quarantine, isolation, physical distancing and hygiene behaviours), and factors/characteristics (including social, physical, psychological, capacity, motivation, economic and demographic) that impact on engagement. RESULTS: The results revealed that there are a range of demographic, social and psychological factors underpinning engagement with quarantine, school closures, and personal protective behaviours. Aside from the factors impacting on acceptance and compliance, there are several key community concerns about their use that need to be addressed including the potential for economic consequences. CONCLUSION: It is important that we acknowledge that these strategies will have an impact on an individual and the community. By understanding the barriers, we can identify what strategies need to be adopted to motivate individuals and improve community compliance. Using a behavioural framework to plan interventions based on these key barriers, will also ensure countries implement appropriate and targeted responses.


Assuntos
Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Higiene , Pandemias/prevenção & controle , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Quarentena/métodos , Isolamento Social , COVID-19 , Surtos de Doenças , Humanos , Instituições Acadêmicas
15.
Bioorg Med Chem Lett ; 29(12): 1537-1540, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987891

RESUMO

Systemic side effects and high hydrophobicity are major disadvantages of paclitaxel (PTX), one of the most popular anticancer drugs. Here, we present singlet oxygen (SO)-activatable and mitochondria-targeted PTX prodrugs to overcome these problems and boost the cytotoxic effect of photodynamic therapy (PDT). Three PTX prodrugs were prepared by conjugating PTX with various cationic groups. Hydrophobicity was determined in LogD7.4 value. Mitochondrial localization was confirmed by fluorescence confocal microscopy and uptake of mitochondria-specific fluorescence probe. Dark- and photo-toxicity were measured in AY-27 cells with MTT assay. All three prodrugs showed better hydrophilicity than PTX and improved phototoxicity when combined with protoporphyrin IX (PpIX) PDT. In conclusion, SO-activatable and higher hydrophilic PTX prodrugs were successfully prepared. This approach could be used to improve the antitumor efficacy of PDT without the systemic side effects of PTX.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Paclitaxel/uso terapêutico , Fotoquimioterapia/métodos , Pró-Fármacos/uso terapêutico , Antineoplásicos Fitogênicos/farmacologia , Humanos , Paclitaxel/farmacologia , Pró-Fármacos/farmacologia , Oxigênio Singlete
16.
J Infect Dis ; 218(suppl_4): S222-S226, 2018 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-30304448

RESUMO

With impending rollout of new conjugate typhoid vaccines, better estimates of typhoid case-fatality ratio are needed for countries to set priorities for public health programs. We enrolled 1425 patients of all ages with blood culture-confirmed Salmonella Typhi from laboratory networks serving inpatients and outpatients in Dhaka, Bangladesh. Participants were asked about symptoms and complications including death experienced over a median 3-month period following blood culture diagnosis. Four fatal cases were identified (case-fatality ratio of 0.3% [95% confidence interval, .05%-.55%]). Applying this case-fatality ratio to global typhoid burden estimates would reduce deaths by 70%.


Assuntos
Antibacterianos/farmacologia , Salmonella typhi/isolamento & purificação , Febre Tifoide/sangue , Febre Tifoide/mortalidade , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Bangladesh/epidemiologia , Hemocultura , Criança , Pré-Escolar , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Salmonella typhi/efeitos dos fármacos , Febre Tifoide/microbiologia , Adulto Jovem
17.
J Biol Chem ; 292(45): 18644-18659, 2017 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-28928220

RESUMO

Skp1 is a subunit of the SCF (Skp1/Cullin 1/F-box protein) class of E3 ubiquitin ligases that are important for eukaryotic protein degradation. Unlike its animal counterparts, Skp1 from Toxoplasma gondii is hydroxylated by an O2-dependent prolyl-4-hydroxylase (PhyA), and the resulting hydroxyproline can subsequently be modified by a five-sugar chain. A similar modification is found in the social amoeba Dictyostelium, where it regulates SCF assembly and O2-dependent development. Homologous glycosyltransferases assemble a similar core trisaccharide in both organisms, and a bifunctional α-galactosyltransferase from CAZy family GT77 mediates the addition of the final two sugars in Dictyostelium, generating Galα1, 3Galα1,3Fucα1,2Galß1,3GlcNAcα1-. Here, we found that Toxoplasma utilizes a cytoplasmic glycosyltransferase from an ancient clade of CAZy family GT32 to catalyze transfer of the fourth sugar. Catalytically active Glt1 was required for the addition of the terminal disaccharide in cells, and cytosolic extracts catalyzed transfer of [3H]glucose from UDP-[3H]glucose to the trisaccharide form of Skp1 in a glt1-dependent fashion. Recombinant Glt1 catalyzed the same reaction, confirming that it directly mediates Skp1 glucosylation, and NMR demonstrated formation of a Glcα1,3Fuc linkage. Recombinant Glt1 strongly preferred the full core trisaccharide attached to Skp1 and labeled only Skp1 in glt1Δ extracts, suggesting specificity for Skp1. glt1-knock-out parasites exhibited a growth defect not rescued by catalytically inactive Glt1, indicating that the glycan acts in concert with the first enzyme in the pathway, PhyA, in cells. A genomic bioinformatics survey suggested that Glt1 belongs to the ancestral Skp1 glycosylation pathway in protists and evolved separately from related Golgi-resident GT32 glycosyltransferases.


Assuntos
Citoplasma/enzimologia , Glucosiltransferases/metabolismo , Proteínas de Protozoários/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Toxoplasma/metabolismo , Substituição de Aminoácidos , Proliferação de Células , Biologia Computacional , Citoplasma/metabolismo , Deleção de Genes , Técnicas de Inativação de Genes , Glucosiltransferases/química , Glucosiltransferases/genética , Glicosilação , Mutação , Ressonância Magnética Nuclear Biomolecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Filogenia , Multimerização Proteica , Processamento de Proteína Pós-Traducional , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Quinases Associadas a Fase S/química , Proteínas Quinases Associadas a Fase S/genética , Proteínas Ligases SKP Culina F-Box/química , Proteínas Ligases SKP Culina F-Box/genética , Estereoisomerismo , Especificidade por Substrato , Toxoplasma/citologia , Toxoplasma/genética , Toxoplasma/crescimento & desenvolvimento
19.
J Biol Chem ; 291(9): 4268-80, 2016 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-26719340

RESUMO

Toxoplasma gondii is a protist parasite of warm-blooded animals that causes disease by proliferating intracellularly in muscle and the central nervous system. Previous studies showed that a prolyl 4-hydroxylase related to animal HIFα prolyl hydroxylases is required for optimal parasite proliferation, especially at low O2. We also observed that Pro-154 of Skp1, a subunit of the Skp1/Cullin-1/F-box protein (SCF)-class of E3-ubiquitin ligases, is a natural substrate of this enzyme. In an unrelated protist, Dictyostelium discoideum, Skp1 hydroxyproline is modified by five sugars via the action of three glycosyltransferases, Gnt1, PgtA, and AgtA, which are required for optimal O2-dependent development. We show here that TgSkp1 hydroxyproline is modified by a similar pentasaccharide, based on mass spectrometry, and that assembly of the first three sugars is dependent on Toxoplasma homologs of Gnt1 and PgtA. Reconstitution of the glycosyltransferase reactions in extracts with radioactive sugar nucleotide substrates and appropriate Skp1 glycoforms, followed by chromatographic analysis of acid hydrolysates of the reaction products, confirmed the predicted sugar identities as GlcNAc, Gal, and Fuc. Disruptions of gnt1 or pgtA resulted in decreased parasite growth. Off target effects were excluded based on restoration of the normal glycan chain and growth upon genetic complementation. By analogy to Dictyostelium Skp1, the mechanism may involve regulation of assembly of the SCF complex. Understanding the mechanism of Toxoplasma Skp1 glycosylation is expected to help develop it as a drug target for control of the pathogen, as the glycosyltransferases are absent from mammalian hosts.


Assuntos
Glicosiltransferases/metabolismo , Modelos Moleculares , Processamento de Proteína Pós-Traducional , Proteínas de Protozoários/metabolismo , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Ligases SKP Culina F-Box/metabolismo , Toxoplasma/fisiologia , Sequência de Aminoácidos , Células Cultivadas , Sequência Conservada , Evolução Molecular , Deleção de Genes , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Glicosilação , Humanos , Hidroxiprolina/metabolismo , Dados de Sequência Molecular , Oligossacarídeos/química , Oligossacarídeos/metabolismo , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas Quinases Associadas a Fase S/química , Proteínas Quinases Associadas a Fase S/genética , Alinhamento de Sequência , Espectrometria de Massas em Tandem , Toxoplasma/enzimologia , Toxoplasma/crescimento & desenvolvimento
20.
Bull Math Biol ; 77(11): 2086-124, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26582360

RESUMO

We propose a deterministic continuum model for mixed-culture biofilms. A crucial aspect is that movement of one species is affected by the presence of the other. This leads to a degenerate cross-diffusion system that generalizes an earlier single-species biofilm model. Two derivations of this new model are given. One, like cellular automata biofilm models, starts from a discrete in space lattice differential equation where the spatial interaction is described by microscopic rules. The other one starts from the same continuous mass balances that are the basis of other deterministic biofilm models, but it gives up a simplifying assumption of these models that has recently been criticized as being too restrictive in terms of ecological structure. We show that both model derivations lead to the same PDE model, if corresponding closure assumptions are introduced. To investigate the role of cross-diffusion, we conduct numerical simulations of three biofilm systems: competition, allelopathy and a mixed system formed by an aerobic and an anaerobic species. In all cases, we find that accounting for cross-diffusion affects local distribution of biomass, but it does not affect overall lumped quantities such as the total amount of biomass in the system.


Assuntos
Biofilmes/crescimento & desenvolvimento , Modelos Biológicos , Biomassa , Simulação por Computador , Difusão , Conceitos Matemáticos , Dinâmica não Linear
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