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1.
Nat Commun ; 12(1): 5732, 2021 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-34593797

RESUMEN

Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease.

2.
Nat Commun ; 12(1): 5743, 2021 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-34593817

RESUMEN

Machine learning has been increasingly used for protein engineering. However, because the general sequence contexts they capture are not specific to the protein being engineered, the accuracy of existing machine learning algorithms is rather limited. Here, we report ECNet (evolutionary context-integrated neural network), a deep-learning algorithm that exploits evolutionary contexts to predict functional fitness for protein engineering. This algorithm integrates local evolutionary context from homologous sequences that explicitly model residue-residue epistasis for the protein of interest with the global evolutionary context that encodes rich semantic and structural features from the enormous protein sequence universe. As such, it enables accurate mapping from sequence to function and provides generalization from low-order mutants to higher-order mutants. We show that ECNet predicts the sequence-function relationship more accurately as compared to existing machine learning algorithms by using ~50 deep mutational scanning and random mutagenesis datasets. Moreover, we used ECNet to guide the engineering of TEM-1 ß-lactamase and identified variants with improved ampicillin resistance with high success rates.

3.
BMJ Glob Health ; 6(10)2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34615662

RESUMEN

INTRODUCTION: Disease-specific 'vertical' programmes and health system strengthening (HSS) 'horizontal' programmes are not mutually exclusive; programmes may be implemented with the dual objectives of achieving both disease-specific and broader HSS outcomes. However, there remains an ongoing need for research into how dual objective programmes are operationalised for optimum results. METHODS: A qualitative study encompassing four grantee programmes from two partner countries, Tanzania and Sierra Leone, in the Comic Relief and GlaxoSmithKline 'Fighting Malaria, Improving Health' partnership. Purposive sampling maximised variation in terms of geographical location, programme aims and activities, grantee type and operational sector. Data were collected via semi-structured interviews. Data analysis was informed by a general inductive approach. RESULTS: 51 interviews were conducted across the four grantees. Grantee organisations structured and operated their respective projects in a manner generally supportive of HSS objectives. This was revealed through commonalities identified across the four grantee organisations in terms of their respective approach to achieving their HSS objectives, and experienced tensions in pursuit of these objectives. Commonalities included: (1) using short-term funding for long-term initiatives; (2) benefits of being embedded in the local health system; (3) donor flexibility to enable grantee responsiveness; (4) the need for modest expectations; and (5) the importance of micro-innovation. CONCLUSION: Health systems strengthening may be pursued through disease-specific programme grants; however, the respective practice of both the funder and grantee organisation appears to be a key influence on whether HSS will be realised as well as the overall extent of HSS possible.


Asunto(s)
Programas de Gobierno , Malaria , Humanos , Malaria/prevención & control , Investigación Cualitativa , Sierra Leona , Tanzanía
4.
Hum Resour Health ; 19(1): 126, 2021 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-34627282

RESUMEN

BACKGROUND: Many factors contribute to engagement in rural and remote (RR) medical practice, but little is known about the factors associated with rural and remote medical practice in such remote locations as the Maluku Province of Indonesia. This study describes factors associated with actual RR practice, preferred RR practice, and intention to remain practice in Maluku Province. METHODS: An online survey of work-related experience and intentions for future rural work was administered to 410 doctors working in the Maluku province of Indonesia. Participant characteristics were described using descriptive statistics, associations between the independent variables with the location of the workforce, intention to remain practice in Maluku, preference for future RR practice in Maluku were analysed using Chi-square tests and logistic regression. RESULTS: A total of 324 responses (79% response rate) were recorded, comprising 70% females and 30% Pattimura University graduates of doctors employed in Maluku. Doctors working in RR areas were more likely to be a GP (OR 3.49, CI 1.03-11.8), have a monthly salary of more than IDR 6 million (OR 11.5, CI 4.24-31.1), and have no additional practice (OR 2.78, CI 1.34-5.78). Doctors intended to stay practice in Maluku were more likely to be born in Maluku (OR 7.77, CI 3.42-17.7) and have graduated from Pattimura University (OR 3.06, CI 1.09-8.54), and less likely to be a temporary employee (OR 0.24, CI 0.10-0.57). Doctors who prefer future RR practice in Maluku were more likely to experience rural living (OR 2.05 CI 1.05-3.99), have a positive indication of the impact of community exposure during medical schools on their current practice (OR 2.08, CI 1.06-4.09), currently practising in RR Maluku (OR 8.23, CI 3.27-20.8); and less likely to have bigger take-home pay (OR 0.30, CI 0.13-0.70). CONCLUSION: This study indicates that special attention should be given to recruiting doctors with a rural background and ongoing support through attractive opportunities to build a sustainable RR workforce. Since a regional medical school helps supply doctors to the RR areas in its region, a sustained collaboration between medical schools and local government implementing relevant strategies are needed to widen participation and improve the recruitment and retention of RR doctors.

5.
BMC Health Serv Res ; 21(1): 1043, 2021 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-34600508

RESUMEN

BACKGROUND: Demand for eye care has increased in recent decades in China due to rapid socioeconomic development and demographic shift. Knowledge of output and productivity of ophthalmic services would allow policymakers to optimize resource allocation, and is therefore essential. This study sought to map the landscape of ophthalmic services available in Shanghai, China. METHODS: In 2018, a government-led survey was conducted of all 86 tertiary/secondary hospitals and five major private hospitals providing eye care in Shanghai in the form of electronic questionnaire, which encompassed ophthalmic services (outpatient and emergency room [ER] visit, inpatient admissions, and surgical volume) and service productivity in terms of annual outpatient and ER visits per doctor, inpatient admissions per bed, and surgical volume per doctor. Comparisons were made among different levels of hospitals with categorical variables tested by Chi-square analysis. RESULTS: The response rate was 85.7%. The Eye and Ear, Nose, and Throat (EENT) Hospital was the largest tertiary specialty hospital, and alone contributed to the highest 21.0% of annual ophthalmic outpatient and ER visits (visits per doctor: 5460), compared with other 26 tertiary hospitals, 46 secondary hospitals and five private hospitals (visits per doctor: 3683, 4651 and 1876). The annual inpatient admission was 20,103, 56,992, 14,090, and 52,047 for the EENT Hospital, all the other tertiary hospitals, secondary hospitals and five private hospitals, respectively. Turnover rates were highest for the EENT Hospital and private hospitals. The average surgical volume at the EENT Hospital was 72,666, exceeding that of private (15,874.8) and other tertiary hospitals (3366.7). The EENT Hospital and private hospitals performed 16,982 (14.2%) and 55,538 (46.6%) of all cataract surgeries. Proportions of both complicated cataractous cases and complicated cataract surgeries at the EENT Hospital was the highest, followed by other tertiary and secondary/private hospitals (P < 0.0001). CONCLUSIONS: In Shanghai, public providers dominate ophthalmic services especially for complicated cases, with almost one fifth of services provided by the EENT Hospital alone, while private sectors, though not large in number, still effectively help meet large proportions of eye care demand. Optimization of hierarchical medical system is warranted to improve the efficiency and standardization of ophthalmic services.


Asunto(s)
Catarata , China/epidemiología , Hospitales Privados , Humanos , Gobierno Local , Encuestas y Cuestionarios
6.
Commun Biol ; 4(1): 1152, 2021 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-34611268

RESUMEN

Memory consolidation requires astrocytic microdomains for protein recycling; but whether this lays a mechanistic foundation for long-term information storage remains enigmatic. Here we demonstrate that persistent synaptic strengthening invited astrocytic microdomains to convert initially internalized (pro)-brain-derived neurotrophic factor (proBDNF) into active prodomain (BDNFpro) and mature BDNF (mBDNF) for synaptic re-use. While mBDNF activates TrkB, we uncovered a previously unsuspected function for the cleaved BDNFpro, which increases TrkB/SorCS2 receptor complex at post-synaptic sites. Astrocytic BDNFpro release reinforced TrkB phosphorylation to sustain long-term synaptic potentiation and to retain memory in the novel object recognition behavioral test. Thus, the switch from one inactive state to a multi-functional one of the proBDNF provides post-synaptic changes that survive the initial activation. This molecular asset confines local information storage in astrocytic microdomains to selectively support memory circuits.

7.
Nature ; 598(7879): 49-52, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34616055

RESUMEN

Spacecraft missions have observed regolith blankets of unconsolidated subcentimetre particles on stony asteroids1-3. Telescopic data have suggested the presence of regolith blankets also on carbonaceous asteroids, including (101955) Bennu4 and (162173) Ryugu5. However, despite observations of processes that are capable of comminuting boulders into unconsolidated materials, such as meteoroid bombardment6,7 and thermal cracking8, Bennu and Ryugu lack extensive areas covered in subcentimetre particles7,9. Here we report an inverse correlation between the local abundance of subcentimetre particles and the porosity of rocks on Bennu. We interpret this finding to mean that accumulation of unconsolidated subcentimetre particles is frustrated where the rocks are highly porous, which appears to be most of the surface10. The highly porous rocks are compressed rather than fragmented by meteoroid impacts, consistent with laboratory experiments11,12, and thermal cracking proceeds more slowly than in denser rocks. We infer that regolith blankets are uncommon on carbonaceous asteroids, which are the most numerous type of asteroid13. By contrast, these terrains should be common on stony asteroids, which have less porous rocks and are the second-most populous group by composition13. The higher porosity of carbonaceous asteroid materials may have aided in their compaction and cementation to form breccias, which dominate the carbonaceous chondrite meteorites14.

8.
Front Immunol ; 12: 667875, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34603277

RESUMEN

Translational research on immune checkpoint inhibitors (ICIs) has been underway. However, in the unselected population, only a few patients benefit from ICIs. Therefore, screening predictive markers of ICI efficacy has become the current focus of attention. We collected mutation and clinical data from an ICI-treated non-small cell lung cancer (NSCLC) cohort. Then, a univariate Cox regression model was used to analyze the relationship between tumor necrosis factor α signaling mutated (TNFα-MT) and the prognosis of immunotherapy for NSCLC. We retrospectively collected 36 NSCLC patients (local-cohort) from the Zhujiang Hospital of Southern Medical University and performed whole-exome sequencing (WES). The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to explore the association between TNFα-MT and the immune microenvironment. A local cohort was used to validate the association between TNFα-MT and immunogenicity. TNFα-MT was associated with significantly prolonged overall survival (OS) in NSCLC patients after receiving immunotherapy. Additionally, TNFα-MT is related to high immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations) and enrichment of infiltrating immune cells. These results suggest that TNFα-MT may serve as a potential clinical biomarker for NSCLC patients receiving ICIs.

9.
Cogn Sci ; 45(10): e13042, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34606110

RESUMEN

Previous studies have shown that the human visual system can detect a face and elicit a saccadic eye movement toward it very efficiently compared to other categories of visual stimuli. In the first experiment, we tested the influence of facial expressions on fast face detection using a saccadic choice task. Face-vehicle pairs were simultaneously presented and participants were asked to saccade toward the target (the face or the vehicle). We observed that saccades toward faces were initiated faster, and more often in the correct direction, than saccades toward vehicles, regardless of the facial expressions (happy, fearful, or neutral). We also observed that saccade endpoints on face images were lower when the face was happy and higher when it was neutral. In the second experiment, we explicitly tested the detection of facial expressions. We used a saccadic choice task with emotional-neutral pairs of faces and participants were asked to saccade toward the emotional (happy or fearful) or the neutral face. Participants were faster when they were asked to saccade toward the emotional face. They also made fewer errors, especially when the emotional face was happy. Using computational modeling, we showed that this happy face advantage can, at least partly, be explained by perceptual factors. Also, saccade endpoints were lower when the target was happy than when it was fearful. Overall, we suggest that there is no automatic prioritization of emotional faces, at least for saccades with short latencies, but that salient local face features can automatically attract attention.

10.
Nat Commun ; 12(1): 5812, 2021 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-34608164

RESUMEN

The advantage of locally applied anesthetics is that they are not associated with the many adverse effects, including addiction liability, of systemically administered analgesics. This therapeutic approach has two inherent pitfalls: specificity and a short duration of action. Here, we identified nociceptor endocytosis as a promising target for local, specific, and long-lasting treatment of inflammatory pain. We observed preferential expression of AP2α2, an α-subunit isoform of the AP2 complex, within CGRP+/IB4- nociceptors in rodents and in CGRP+ dorsal root ganglion neurons from a human donor. We utilized genetic and pharmacological approaches to inhibit nociceptor endocytosis demonstrating its role in the development and maintenance of acute and chronic inflammatory pain. One-time injection of an AP2 inhibitor peptide significantly reduced acute and chronic pain-like behaviors and provided prolonged analgesia. We evidenced sexually dimorphic recovery responses to this pharmacological approach highlighting the importance of sex differences in pain development and response to analgesics.

11.
AIDS Patient Care STDS ; 35(10): 401-410, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34623889

RESUMEN

Racial/ethnic minorities are disproportionately affected by poor HIV care outcomes. Studies have also examined the effects of neighborhood-level factor on an individual's health outcomes. Thus, the objective of this study was to assess the effects of neighborhood factors on the association between race/ethnicity and sustained viral suppression (all viral load tests <200 copies/mL per year). Data for 6491 people with HIV in the 2017 Miami-Dade County Ryan White Program and neighborhood-level data by ZIP code tabulated areas from the American Community Survey were utilized. Multi-level logistic regression models were used to assess the role of neighborhood factors on the association between race/ethnicity and sustained viral suppression. Results show that non-Hispanic Blacks had lower odds of sustained viral suppression in low socioeconomic disadvantage [adjusted odds ratio (aOR): 0.39; 95% confidence interval (CI): 0.20-0.74], moderate residential instability (aOR: 0.31; 95% CI: 0.15-0.65), and low and high racial/language homogeneity neighborhoods (aOR: 0.38; 95% CI: 0.16-0.88) and (aOR: 0.38; 95% CI: 0.19-0.75), respectively, when compared to non-Hispanic Whites (NHWs). Haitians also exhibited poor outcomes in neighborhoods characterized by moderate residential instability (aOR: 0.42; 95% CI: 0.18-0.97) and high racial/language homogeneity (aOR: 0.49; 95% CI: 0.26-0.93), when compared to NHWs. In conclusion, disparities in rates of sustained viral suppression were observed for racial/ethnic minorities within various neighborhood-level factors. These findings indicate the importance of addressing neighborhood characteristics to achieve optimal care for minorities.


Asunto(s)
Grupos Étnicos , Infecciones por VIH , Infecciones por VIH/tratamiento farmacológico , Humanos , Características de la Residencia , Respuesta Virológica Sostenida , Estados Unidos , Carga Viral
12.
Front Immunol ; 12: 740249, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34594343

RESUMEN

Objective: To assess in rheumatoid arthritis (RA) patients, treated with different immunosuppressive therapies, the induction of SARS-CoV-2-specific immune response after vaccination in terms of anti-region-binding-domain (RBD)-antibody- and T-cell-specific responses against spike, and the vaccine safety in terms of clinical impact on disease activity. Methods: Health care workers (HCWs) and RA patients, having completed the BNT162b2-mRNA vaccination in the last 2 weeks, were enrolled. Serological response was evaluated by quantifying anti-RBD antibodies, while the cell-mediated response was evaluated by a whole-blood test quantifying the interferon (IFN)-γ-response to spike peptides. FACS analysis was performed to identify the cells responding to spike stimulation. RA disease activity was evaluated by clinical examination through the DAS28crp, and local and/or systemic clinical adverse events were registered. In RA patients, the ongoing therapeutic regimen was modified during the vaccination period according to the American College of Rheumatology indications. Results: We prospectively enrolled 167 HCWs and 35 RA patients. Anti-RBD-antibodies were detected in almost all patients (34/35, 97%), although the titer was significantly reduced in patients under CTLA-4-inhibitors (median: 465 BAU/mL, IQR: 103-1189, p<0.001) or IL-6-inhibitors (median: 492 BAU/mL, IQR: 161-1007, p<0.001) compared to HCWs (median: 2351 BAU/mL, IQR: 1389-3748). T-cell-specific response scored positive in most of RA patients [24/35, (69%)] with significantly lower IFN-γ levels in patients under biological therapy such as IL-6-inhibitors (median: 33.2 pg/mL, IQR: 6.1-73.9, p<0.001), CTLA-4-inhibitors (median: 10.9 pg/mL, IQR: 3.7-36.7, p<0.001), and TNF-α-inhibitors (median: 89.6 pg/mL, IQR: 17.8-224, p=0.002) compared to HCWs (median: 343 pg/mL, IQR: 188-756). A significant correlation between the anti-RBD-antibody titer and spike-IFN-γ-specific T-cell response was found in RA patients (rho=0.432, p=0.009). IFN-γ T-cell response was mediated by CD4+ and CD8+ T cells. Finally, no significant increase in disease activity was found in RA patients following vaccination. Conclusion: This study showed for the first time that antibody-specific and whole-blood spike-specific T-cell responses induced by the COVID-19 mRNA-vaccine were present in the majority of RA patients, who underwent a strategy of temporary suspension of immunosuppressive treatment during vaccine administration. However, the magnitude of specific responses was dependent on the immunosuppressive therapy administered. In RA patients, BNT162b2 vaccine was safe and disease activity remained stable.


Asunto(s)
Anticuerpos Antivirales/inmunología , Artritis Reumatoide/terapia , Vacunas contra la COVID-19/inmunología , Inmunoterapia/efectos adversos , Linfocitos T/inmunología , Anciano , Artritis Reumatoide/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , COVID-19/prevención & control , Femenino , Humanos , Interferón gamma/inmunología , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/citología , Vacunas Sintéticas/inmunología
13.
BMJ Open ; 11(10): e049134, 2021 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-34607860

RESUMEN

OBJECTIVE: Early in the COVID-19 pandemic, US Veterans Health Administration (VHA) employee occupational health (EOH) providers were tasked with assuming a central role in coordinating employee COVID-19 screening and clearance for duty, representing entirely novel EOH responsibilities. In a rapid qualitative needs assessment, we aimed to identify learnings from the field to support the vastly expanding role of EOH providers in a national healthcare system. METHODS: We employed rapid qualitative analysis of key informant interviews in a maximal variation sample on the parameters of job type, rural versus urban and provider gender. We interviewed 21 VHA EOH providers between July and December 2020. This sample represents 15 facilities from diverse regions of the USA (large, medium and small facilities in the Mid-Atlantic; medium sites in the South; large facilities in the West and Pacific Northwest). RESULTS: Five interdependent needs included: (1) infrastructure to support employee population management, including tools that facilitate infection control measures such as contact tracing (eg, employee-facing electronic health records and coordinated databases); (2) mechanisms for information sharing across settings (eg, VHA listserv), especially for changing policy and protocols; (3) sufficiently resourced staffing using detailing to align EOH needs with human resource capital; (4) connected and resourced local and national leaders; and (5) strategies to support healthcare worker mental health.Our identified facilitators for EOH assuming new challenging and dynamically changing roles during COVID-19 included: (A) training or access to expertise; (B) existing mechanisms for information sharing; (C) flexible and responsive staffing; and (D) leveraging other institutional expertise not previously affiliated with EOH (eg, chaplains to support bereavement). CONCLUSIONS: Our needs assessment highlights local and system level barriers and facilitators of EOH assuming expanded roles during COVID-19. Integrating changes both within and across systems and with alignment of human capital will enable EOH preparedness for future challenges.


Asunto(s)
COVID-19 , Salud Laboral , Personal de Salud , Humanos , Evaluación de Necesidades , Pandemias , SARS-CoV-2 , Salud de los Veteranos , Recursos Humanos
14.
Front Cell Infect Microbiol ; 11: 718350, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34595131

RESUMEN

Innate (-like) T lymphocytes such as natural killer T (NKT) cells play a pivotal role in the recognition of microbial infections and their subsequent elimination. They frequently localize to potential sites of pathogen entry at which they survey extracellular and intracellular tissue spaces for microbial antigens. Engagement of their T cell receptors (TCRs) induces an explosive release of different cytokines and chemokines, which often pre-exist as constitutively expressed gene transcripts in NKT cells and underlie their poised effector state. Thus, NKT cells regulate immune cell migration and activation and subsequently, bridge innate and adaptive immune responses. In contrast to conventional T cells, which react to peptide antigens, NKT cells recognize lipids presented by the MHC class I like CD1d molecule on antigen presenting cells (APCs). Furthermore, each NKT cell TCR can recognize various antigen specificities, whereas a conventional T lymphocyte TCR reacts mostly only to one single antigen. These lipid antigens are either intermediates of the intracellular APC`s-own metabolism or originate from the cell wall of different bacteria, fungi or protozoan parasites. The best-characterized subset, the type 1 NKT cell subset expresses a semi-invariant TCR. In contrast, the TCR repertoire of type 2 NKT cells is diverse. Furthermore, NKT cells express a panoply of inhibitory and activating NK cell receptors (NKRs) that contribute to their primarily TCR-mediated rapid, innate like immune activation and even allow an adaption of their immune response in an adoptive like manner. Dueto their primary localization at host-environment interfaces, NKT cells are one of the first immune cells that interact with signals from different microbial pathogens. Vice versa, the mutual exchange with local commensal microbiota shapes also the biology of NKT cells, predominantly in the gastrointestinal tract. Following infection, two main signals drive the activation of NKT cells: first, cognate activation upon TCR ligation by microbial or endogenous lipid antigens; and second, bystander activation due to cytokines. Here we will discuss the role of NKT cells in the control of different microbial infections comparing pathogens expressing lipid ligands in their cell walls to infectious agents inducing endogenous lipid antigen presentation by APCs.


Asunto(s)
Células T Asesinas Naturales , Presentación de Antígeno , Antígenos CD1d , Hongos , Receptores de Antígenos de Linfocitos T
15.
Front Cell Infect Microbiol ; 11: 725859, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34595134

RESUMEN

Imported malaria and recurrent infections are becoming an emerging issue in many malaria non-endemic countries. This study aimed to determine the molecular patterns of the imported malaria infections and recurrence. Blood samples were collected from patients with imported malaria infections during 2016-2018 in Guangxi Zhuang Autonomous Region, China. Next-generation amplicon deep-sequencing approaches were used to assess parasite genetic diversity, multiplexity of infection, relapse, recrudescence, and antimalarial drug resistance. A total of 44 imported malaria cases were examined during the study, of which 35 (79.5%) had recurrent malaria infections within 1 year. The majority (91.4%) had one recurrent malaria episode, whereas two patients had two recurrences and one patient had three recurrences. A total of 19 recurrence patterns (the species responsible for primary and successive clinical episodes) were found in patients returning from malaria epidemic countries. Four parasite species were detected with a higher than usual proportion (46.2%) of non-falciparum infections or mixed-species infections. An increasing trend of recurrence infections and reduced drug treatment efficacy were observed among the cases of imported malaria. The high recurrence rate and complex patterns of imported malaria from Africa to non-endemic countries have the potential to initiate local transmission, thereby undermining efforts to eliminate locally acquired malaria. Our findings highlight the power of amplicon deep-sequencing applications in molecular epidemiological studies of the imported malaria recurrences.


Asunto(s)
Antimaláricos , Enfermedades Transmisibles Importadas , Malaria Falciparum , Malaria , Antimaláricos/uso terapéutico , China/epidemiología , Enfermedades Transmisibles Importadas/epidemiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Malaria/tratamiento farmacológico , Malaria/epidemiología , Malaria Falciparum/epidemiología
16.
Langmuir ; 37(40): 11676-11687, 2021 10 12.
Artículo en Inglés | MEDLINE | ID: mdl-34601878

RESUMEN

Self-assembled wormlike micelles (WLMs) are widely studied in small-molecule surfactants due to their unique ability to break and recombine; however, less is known about the structure and dynamics of nonionic polymer WLMs. Here, solutions of seven triblock poloxamers, composed of poly(propylene oxide) (PPO) midblocks and poly(ethylene oxide) (PEO) end blocks, are comprehensively examined to determine the role of poloxamer composition, temperature, and inorganic salt type and concentration on rod formation and subsequent elongation into WLMs. Phase separation and sphere-to-rod transition temperatures were quantified via cloud point measurements and shear rheology, respectively, and corroborated with small-angle neutron scattering (SANS). The local microstructure of resulting rodlike micelles is remarkably similar across poloxamer type and sodium fluoride (NaF) or sodium chloride (NaCl) content. Salt addition reduces transition temperatures, with the most pronounced effects for poloxamers with high PEO molecular weights and PEO fractions. Between these two temperatures, several poloxamers elongate into WLMs, where shear rheology detects increases in viscosity up to 6 orders of magnitude. Despite similar local microstructures, poloxamer identity and salt content impact micelle growth substantially, where large poloxamers with lower PEO fractions exhibit the highest viscosities and longest relaxation times. While sodium fluoride has little impact on micelle growth, increasing NaCl concentration dramatically increases the WLM viscosity and relaxation time. This result is explained by different interactions of each salt with the micelle: whereas NaF interacts primarily with PEO chains, NaCl may also partition to the PPO/PEO interface in low levels, increasing micelle surface tension, scission energy, and contour length.

17.
Theor Biol Med Model ; 18(1): 17, 2021 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-34602095

RESUMEN

Travelers play a role in triggering epidemics of imported dengue fever because they can carry the virus to other countries during the incubation period. If a traveler carrying dengue virus visits open green space and is bitten by mosquitoes, a local outbreak can ensue. In the present study, we aimed to understand the movement patterns of international travelers in Tokyo using mobile phone data, with the goal of identifying geographical foci of dengue transmission. We analyzed datasets based on mobile phone access to WiFi systems and measured the spatial distribution of international visitors in Tokyo on two specific dates (one weekday in July 2017 and another weekday in August 2017). Mobile phone users were classified by nationality into three groups according to risk of dengue transmission. Sixteen national parks were selected based on their involvement in a 2014 dengue outbreak and abundance of Aedes mosquitoes. We found that not all national parks were visited by international travelers and that visits to cemeteries were very infrequent. We also found that travelers from countries with high dengue prevalence were less likely to visit national parks compared with travelers from dengue-free countries. Travelers from countries with sporadic dengue cases and countries with regional transmission tended to visit common destinations. By contrast, the travel footprints of visitors from countries with continuous dengue transmission were focused on non-green spaces. Entomological surveillance in Tokyo has been restricted to national parks since the 2014 dengue outbreak. However, our results indicate that areas subject to surveillance should include both public and private green spaces near tourist sites.

18.
J Neural Eng ; 18(5)2021 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-34607322

RESUMEN

Objective.Electroencephalography (EEG) is a key tool for non-invasive recording of brain activity and the diagnosis of epilepsy. EEG monitoring is also widely employed in rodent models to track epilepsy development and evaluate experimental therapies and interventions. Whereas automated seizure detection algorithms have been developed for clinical EEG, preclinical versions face challenges of inter-model differences and lack of EEG standardization, leaving researchers relying on time-consuming visual annotation of signals.Approach.In this study, a machine learning-based seizure detection approach, 'Epi-AI', which can semi-automate EEG analysis in multiple mouse models of epilepsy was developed. Twenty-six mice with a total EEG recording duration of 6451 h were used to develop and test the Epi-AI approach. EEG recordings were obtained from two mouse models of kainic acid-induced epilepsy (Models I and III), a genetic model of Dravet syndrome (Model II) and a pilocarpine mouse model of epilepsy (Model IV). The Epi-AI algorithm was compared against two threshold-based approaches for seizure detection, a local Teager-Kaiser energy operator (TKEO) approach and a global Teager-Kaiser energy operator-discrete wavelet transform (TKEO-DWT) combination approach.Main results.Epi-AI demonstrated a superior sensitivity, 91.4%-98.8%, and specificity, 93.1%-98.8%, in Models I-III, to both of the threshold-based approaches which performed well on individual mouse models but did not generalise well across models. The performance of the TKEO approach in Models I-III ranged from 66.9%-91.3% sensitivity and 60.8%-97.5% specificity to detect spontaneous seizures when compared with expert annotations. The sensitivity and specificity of the TKEO-DWT approach were marginally better than the TKEO approach in Models I-III at 73.2%-80.1% and 75.8%-98.1%, respectively. When tested on EEG from Model IV which was not used in developing the Epi-AI approach, Epi-AI was able to identify seizures with 76.3% sensitivity and 98.1% specificity.Significance.Epi-AI has the potential to provide fast, objective and reproducible semi-automated analysis of multiple types of seizure in long-duration EEG recordings in rodents.

19.
Front Immunol ; 12: 728896, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34616396

RESUMEN

A purified spike (S) glycoprotein of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) coronavirus was used to study its effects on THP-1 macrophages, peripheral blood mononuclear cells (PBMCs), and HUVEC cells. The S protein mediates the entry of SARS-CoV-2 into cells through binding to the angiotensin-converting enzyme 2 (ACE2) receptors. We measured the viability, intracellular cytokine release, oxidative stress, proinflammatory markers, and THP-1-like macrophage polarization. We observed an increase in apoptosis, ROS generation, MCP-1, and intracellular calcium expression in the THP-1 macrophages. Stimulation with the S protein polarizes the THP-1 macrophages towards proinflammatory futures with an increase in the TNFα and MHC-II M1-like phenotype markers. Treating the cells with an ACE inhibitor, perindopril, at 100 µM reduced apoptosis, ROS, and MHC-II expression induced by S protein. We analyzed the sensitivity of the HUVEC cells after the exposure to a conditioned media (CM) of THP-1 macrophages stimulated with the S protein. The CM induced endothelial cell apoptosis and MCP-1 expression. Treatment with perindopril reduced these effects. However, the direct stimulation of the HUVEC cells with the S protein, slightly increased HIF1α and MCP-1 expression, which was significantly increased by the ACE inhibitor treatment. The S protein stimulation induced ROS generation and changed the mitogenic responses of the PBMCs through the upregulation of TNFα and interleukin (IL)-17 cytokine expression. These effects were reduced by the perindopril (100 µM) treatment. Proteomic analysis of the S protein stimulated THP-1 macrophages with or without perindopril (100 µM) exposed more than 400 differentially regulated proteins. Our results provide a mechanistic analysis suggesting that the blood and vascular components could be activated directly through S protein systemically present in the circulation and that the activation of the local renin angiotensin system may be partially involved in this process. Graphical: Suggested pathways that might be involved at least in part in S protein inducing activation of inflammatory markers (red narrow) and angiotensin-converting enzyme inhibitor (ACEi) modulation of this process (green narrow).


Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Apoptosis/efectos de los fármacos , COVID-19/inmunología , Macrófagos/inmunología , Estrés Oxidativo/efectos de los fármacos , Perindopril/farmacología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , COVID-19/tratamiento farmacológico , COVID-19/fisiopatología , COVID-19/virología , Línea Celular , Humanos , Macrófagos/efectos de los fármacos , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/inmunología , Piroptosis/efectos de los fármacos , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética
20.
Sci Rep ; 11(1): 20121, 2021 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-34635707

RESUMEN

The Brazilian strategy to overcome the spread of COVID-19 has been particularly criticized due to the lack of a national coordinating effort and an appropriate testing program. Here, a successful approach to control the spread of COVID-19 transmission is described by the engagement of public (university and governance) and private sectors (hospitals and oil companies) in Macaé, state of Rio de Janeiro, Brazil, a city known as the National Oil Capital. In 2020 between the 17th and 38th epidemiological week, over two percent of the 206,728 citizens were subjected to symptom analysis and RT-qPCR testing by the Federal University of Rio de Janeiro, with positive individuals being notified up to 48 h after swab collection. Geocodification and spatial cluster analysis were used to limit COVID-19 spreading in Macaé. Within the first semester after the outbreak of COVID-19 in Brazil, Macaé recorded 1.8% of fatalities associated with COVID-19 up to the 38th epidemiological week, which was at least five times lower than the state capital (10.6%). Overall, considering the successful experience of this joint effort of private and public engagement in Macaé, our data suggest that the development of a similar strategy countrywise could have contributed to a better control of the COVID-19 spread in Brazil. Quarantine decree by the local administration, comprehensive molecular testing coupled to scientific analysis of COVID-19 spreading, prevented the catastrophic consequences of the pandemic as seen in other populous cities within the state of Rio de Janeiro and elsewhere in Brazil.


Asunto(s)
Prueba de Ácido Nucleico para COVID-19/estadística & datos numéricos , COVID-19/epidemiología , Pandemias/estadística & datos numéricos , SARS-CoV-2/aislamiento & purificación , Adolescente , Adulto , Anciano , Brasil/epidemiología , COVID-19/diagnóstico , COVID-19/transmisión , COVID-19/virología , Ciudades/epidemiología , Ciudades/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Viral/aislamiento & purificación , SARS-CoV-2/genética , Adulto Joven
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