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The proliferation and dissemination of antimicrobial-resistant bacteria is an increasingly global challenge and is attributed mainly to the excessive or improper use of antibiotics. Currently, the gold-standard phenotypic methodology for detecting resistant strains is agar plating, which is a time-consuming process that involves multiple subculturing steps. Genotypic analysis techniques are fast, but they require pure starting samples and cannot differentiate between viable and non-viable organisms. Thus, there is a need to develop a better method to identify and prevent the spread of antimicrobial resistance. This work presents a novel method for detecting and identifying antibiotic-resistant strains by combining a cell sorter for bacterial detection and an elastic-light-scattering method for bacterial classification. The cell sorter was equipped with safety mechanisms for handling pathogenic organisms and enabled precise placement of individual bacteria onto an agar plate. The patterning was performed on an antibiotic-gradient plate, where the growth of colonies in sections with high antibiotic concentrations confirmed the presence of a resistant strain. The antibiotic-gradient plate was also tested with an elastic-light-scattering device where each colony's unique colony scatter pattern was recorded and classified using machine learning for rapid identification of bacteria. Sorting and patterning bacteria on an antibiotic-gradient plate using a cell sorter reduced the number of subculturing steps and allowed direct qualitative binary detection of resistant strains. Elastic-light-scattering technology is a rapid, label-free, and non-destructive method that permits instantaneous classification of pathogenic strains based on the unique bacterial colony scatter pattern. KEY POINTS: ⢠Individual bacteria cells are placed on gradient agar plates by a cell sorter ⢠Laser-light scatter patterns are used to recognize antibiotic-resistant organisms ⢠Scatter patterns formed by colonies correspond to AMR-associated phenotypes.
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Antibacterianos , Farmacorresistencia Bacteriana , Fenotipo , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Bacterias/genética , Bacterias/clasificación , Citometría de Flujo/métodos , Pruebas de Sensibilidad Microbiana/métodos , LuzRESUMEN
While TGF-ß signaling is essential for microglial function, the cellular source of TGF-ß1 ligand and its spatial regulation remains unclear in the adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-ß1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to the activation of microglia featuring a dyshomeostatic transcriptome that resembles disease-associated, injury-associated, and aged microglia, suggesting microglial self-produced TGF-ß1 ligands are important in the adult CNS. Astrocytes in MG-Tgfb1 inducible (i)KO mice show a transcriptome profile that is closely aligned with an LPS-associated astrocyte profile. Additionally, using sparse mosaic single-cell microglia KO of TGF-ß1 ligand we established an autocrine mechanism for signaling. Here we show that MG-Tgfb1 iKO mice present cognitive deficits, supporting that precise spatial regulation of TGF-ß1 ligand derived from microglia is required for the maintenance of brain homeostasis and normal cognitive function in the adult brain.
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Comunicación Autocrina , Cognición , Homeostasis , Ratones Noqueados , Microglía , Factor de Crecimiento Transformador beta1 , Animales , Microglía/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Ratones , Cognición/fisiología , Astrocitos/metabolismo , Transducción de Señal , Encéfalo/metabolismo , Masculino , Transcriptoma , Ratones Endogámicos C57BL , Neuronas/metabolismoRESUMEN
Bacteria subjected to antiseptic or antibiotic stress often develop tolerance, a trait that can lead to permanent resistance. To determine whether photodynamic agents could be used to counter tolerance, we evaluated three non-iron hemin analogs (M-PpIX; M = Al, Ga, In) as targeted photosensitizers for antimicrobial photodynamic inactivation (aPDI) following exposure to sublethal H2O2. Al-PpIX is an active producer of ROS whereas Ga- and In-PpIX are more efficient at generating singlet oxygen. Al- and Ga-PpIX are highly potent aPDI agents against S. aureus and methicillin-resistant strains (MRSA) with antimicrobial activity (3 log reduction in colony-forming units) at nanomolar concentrations. The aPDI activities of Al- and Ga-PpIX against S. aureus were tested in the presence of 1 mM H2O2 added at different stages of growth. Bacteria exposed to H2O2 during log-phase growth were less susceptible to aPDI but bacteria treated with H2O2 in their postgrowth phase exhibited aPDI hypersensitivity, with no detectable colony growth after treatment with 15 nM Ga-PpIX.
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This chapter discusses the problems related to the application of conventional flow cytometers to microbiology. To address some of those limitations, the concept of spectral flow cytometry is introduced and the advantages over conventional flow cytometry for bacterial sorting are presented. We demonstrate by using ThermoFisher's Bigfoot spectral sorter where the spectral signatures of different stains for staining bacteria are demonstrated with an example of performing unmixing on spectral datasets. In addition to the Bigfoot's spectral analysis, the special biosafety features of this instrument are discussed. Utilizing these biosafety features, the sorting and patterning at the single cell level is optimized using non-pathogenic bacteria. Finally, the chapter is concluded by presenting a novel, label free, non-destructive, and rapid phenotypic method called Elastic Light Scattering (ELS) technology for identification of the patterned bacterial cells based on their unique colony scatter patterns.
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Bacterias , Citometría de Flujo , Citometría de Flujo/métodos , Análisis de la Célula Individual/métodos , Dispersión de RadiaciónRESUMEN
Spectral flow cytometry has emerged as a significant player in the cytometry marketplace, with the potential for rapid growth. Despite a slow start, the technology has made significant strides in advancing various areas of single-cell analysis utilized by the scientific community. The integration of spectral cytometry into clinical laboratories and diagnostic processes is currently underway and is expected to garner a significant level of widespread acceptance in the near future. However, incorporating a new methodological approach into existing research programs can lead to misunderstandings or even misuse. This chapter offers an introductory yet comprehensive explanation of the scientific principles that form the foundation of spectral cytometry. Specifically, it delves into the unmixing processes that are utilized for data analysis. This overview is designed for those who are new to the field and seeking an informative guide to this exciting emerging technology.
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Citometría de Flujo , Análisis de la Célula Individual , Citometría de Flujo/métodos , Humanos , Análisis de la Célula Individual/métodos , AnimalesRESUMEN
Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinson's disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVM's potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.
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We transplanted six solid organs from three hepatitis C virus (HCV) polymerase chain reaction (PCR)-positive donors during 2018-2023. Recipients were treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir for 4-12 weeks, with all six achieving sustained virological response without significant adverse events. As occurs in other jurisdictions, solid organ transplants from HCR PCR-positive donors can be safely utilised in Australia.
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Hepatitis C Crónica , Hepatitis C , Humanos , Hepacivirus/genética , Antivirales/uso terapéutico , Australia Occidental/epidemiología , Sofosbuvir/uso terapéutico , Donantes de Tejidos , Reacción en Cadena de la Polimerasa , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológicoRESUMEN
CONTEXT: The study investigates the impact of Hubbard U correction and spin-orbit coupling (SOC) on the structural, mechanical, electronic, and optical properties of Ti[Formula: see text]O[Formula: see text] and SrTiO[Formula: see text] compounds. The research is motivated by the potential applications of these materials in photovoltaics, with a focus on understanding their properties for such use. The ductility, ionicity, and mechanical stability of both compounds at zero pressure are assessed, indicating their potential as resilient materials. Also, the compounds display high refractive indices and absorption coefficients, indicating their suitability for solar harvesting applications. The predicted bandgaps align primarily with the UV-Vis areas of the electromagnetic spectrum, highlighting their potential in this domain. METHODS: Computational techniques employed in this study are density functional theory (DFT) with and without spin-orbit coupling, as well as DFT+U methods, implemented using the Quantum ESPRESSO (QE) package. The study adopts the Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional, while employing a plane-wave basis set with an energy cutoff of 50 Ry for wavefunctions and 500 Ry for charge density.
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The Ecuadorian Amazon is home to a rich biodiversity of woody plant species. Nonetheless, their conservation remains difficult, as some areas remain poorly explored and lack georeferenced records. Therefore, the current study aims predominantly to analyze the collection patterns of timber species in the Amazon lowlands of Ecuador and to evaluate the conservation coverage of these species in protected areas. Furthermore, we try to determine the conservation category of the species according to the criteria of the IUCN Red List. We identified that one third of the timber species in the study area was concentrated in three provinces due to historical botanical expeditions. However, a worrying 22.0% of the species had less than five records of presence, and 29.9% had less than ten records, indicating a possible underestimation of their presence. In addition, almost half of the species evaluated were unprotected, exposing them to deforestation risks and threats. To improve knowledge and conservation of forest biodiversity in the Ecuadorian Amazon, it is recommended to perform new botanical samplings in little-explored areas and digitize data in national herbaria. It is critical to implement automated assessments of the conservation status of species with insufficient data. In addition, it is suggested to use species distribution models to identify optimal areas for forest restoration initiatives. Effective communication of results and collaboration between scientists, governments, and local communities are key to the protection and sustainable management of forest biodiversity in the Amazon region.
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In this study, the structural, electronic, mechanical, optical, and thermoelectric properties of the cubic half-Heusler compound ZrCoY(Y[bond, double bond]Sb and Bi) obtained using first-principles calculations are presented. The following exchange-correlation functionals have been employed: Generalized Gradient Approximation with Perdew-Burke-Ernzerhoff (GGA-PBE), Generalized Gradient Approximation with Perdew-Burke-Enzerhoff for solids (GGA-PBESol) and Local Density Approximation (LDA). Both ZrCoSb and ZrCoBi compounds are mechanically and dynamically stable, based on the elastic and phonon properties analysis. The calculated electronic band gaps for both compounds are about 1 eV, as predicted by all the three functionals. Since it is noted that GGA-PBE functional is most favourable for predicting structural properties and the energetic stability of ZrCoSb and ZrCoBi compounds, it is further used to calculate their thermoelectric properties. Within the energy range of 0-40 eV, the refractive index, dielectric constant, and energy loss function of ZrCoSb and ZrCoBi compounds are calculated. The possibility of electronic transition from the valence band maximum (VBM) to the conduction minimum band (CBM) is confirmed by the occurrence of absorption peaks in the visible range. For the evaluation of thermoelectric properties, the p-type and n-type doping attained Seebeck coefficients of 1800 and -1800 µVK-1 at 300 K, respectively. The maximum peak of 17 × 1011 W/m s K2 is attained in n-type doping, according to the power factor results.
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The issue of food fraud has become a significant global concern as it affects both the quality and safety of food products, ultimately resulting in the loss of customer trust and brand loyalty. To address this problem, we have developed an innovative approach that can tackle various types of food fraud, including adulteration, substitution, and dilution. Our methodology utilizes an integrated system that combines laser-induced breakdown spectroscopy (LIBS) and Raman spectroscopy. Although both techniques emerged as valuable tools for food analysis, they have until now been used separately, and their combined potential in food fraud has not been thoroughly tested. The aim of our study was to demonstrate the potential benefits of integrating Raman and LIBS modalities in a portable system for improved product classification and subsequent authentication. In pursuit of this objective, we designed and tested a compact, hybrid Raman/LIBS system, which exhibited distinct advantages over the individual modalities. Our findings illustrate that the combination of these two modalities can achieve higher accuracy in product classification, leading to more effective and reliable product authentication. Overall, our research highlights the potential of hybrid systems for practical applications in a variety of industries. The integration and design were mainly focused on the detection and characterization of both elemental and molecular elements in various food products. Two different sets of solid food samples (sixteen Alpine-style cheeses and seven brands of Arabica coffee beans) were chosen for the authentication analysis. Class detection and classification were accomplished through the use of multivariate feature selection and machine-learning procedures. The accuracy of classification was observed to improve by approximately 10% when utilizing the hybrid Raman/LIBS spectra, as opposed to the analysis of spectra from the individual methods. This clearly demonstrates that the hybrid system can significantly improve food authentication accuracy while maintaining the portability of the combined system. Thus, the successful implementation of a hybrid Raman-LIBS technique is expected to contribute to the development of novel portable devices for food authentication in food as well as other various industries.
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Queso , Espectrometría Raman , Contaminación de Medicamentos , Fraude , IndustriasRESUMEN
Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI. Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60â mL/minute/1.73 m2). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model. Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88). Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality.
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Unmasking the subtleties of the immune system requires both a comprehensive knowledge base and the ability to interrogate that system with intimate sensitivity. That task, to a considerable extent, has been handled by an iterative expansion in flow cytometry methods, both in technological capability and also in accompanying advances in informatics. As the field of fluorescence-based cytomics matured, it reached a technological barrier at around 30 parameter analyses, which stalled the field until spectral flow cytometry created a fundamental transformation that will likely lead to the potential of 100 simultaneous parameter analyses within a few years. The simultaneous advance in informatics has now become a watershed moment for the field as it competes with mature systematic approaches such as genomics and proteomics, allowing cytomics to take a seat at the multi-omics table. In addition, recent technological advances try to combine the speed of flow systems with other detection methods, in addition to fluorescence alone, which will make flow-based instruments even more indispensable in any biological laboratory. This paper outlines current approaches in cell analysis and detection methods, discusses traditional and microfluidic sorting approaches as well as next-generation instruments, and provides an early look at future opportunities that are likely to arise.
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Genómica , Proteómica , Citometría de Flujo/métodos , Tecnología , MicrofluídicaRESUMEN
With high success rates of autologous breast reconstruction, the focus has shifted from flap survival to improved patient outcomes. Historically, a criticism of autologous breast reconstruction has been the length of hospital stay. Our institution has progressively shortened the length of stay after deep inferior epigastric artery perforator (DIEP) flap reconstruction and began discharging select patients on postoperative day 1 (POD1). The purpose of this study was to document our experience with POD1 discharges and to identify preoperative and intraoperative factors that may identify patients as candidates for earlier discharge. Methods: An institutional review board-approved, retrospective chart review of patients undergoing DIEP flap breast reconstruction from January 2019 to March 2022 at Atrium Health was completed, consisting of 510 patients and 846 DIEP flaps. Patient demographics, medical history, operative course, and postoperative complications were collected. Results: Twenty-three patients totaling 33 DIEP flaps were discharged on POD1. The POD1 group and the group of all other patients (POD2+) had no difference in age, ASA score, or comorbidities. BMI was significantly lower in the POD1 group (P = 0.039). Overall operative time was significantly lower in the POD1 group, and this remained true when differentiating into unilateral operations (P = 0.023) and bilateral operations (P = 0.01). No major complications occurred in those discharged on POD1. Conclusions: POD1 discharge after DIEP flap breast reconstruction is safe for select patients. Lower BMI and shorter operative times may be predictive in identifying patients as candidates for earlier discharge.
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Immune checkpoint blockade therapy, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types. Despite the recent success of immune checkpoint blockade therapy, however, the response rates in patients with cancer are limited (â¼20%-40%). To improve the success of immune checkpoint blockade therapy, relevant preclinical animal models are essential for the development and testing of multiple combination approaches and strategies. Companion dogs naturally develop several types of cancer that in many respects resemble clinical cancer in human patients. Therefore, the canine studies of immuno-oncology drugs can generate knowledge that informs and prioritizes new immuno-oncology therapy in humans. The challenge has been, however, that immunotherapeutic antibodies targeting canine immune checkpoint molecules such as canine PD-L1 (cPD-L1) have not been commercially available. Here, we developed a new cPD-L1 antibody as an immuno-oncology drug and characterized its functional and biological properties in multiple assays. We also evaluated the therapeutic efficacy of cPD-L1 antibodies in our unique caninized PD-L1 mice. Together, these in vitro and in vivo data, which include an initial safety profile in laboratory dogs, support development of this cPD-L1 antibody as an immune checkpoint inhibitor for studies in dogs with naturally occurring cancer for translational research. Our new therapeutic antibody and caninized PD-L1 mouse model will be essential translational research tools in raising the success rate of immunotherapy in both dogs and humans. Significance: Our cPD-L1 antibody and unique caninized mouse model will be critical research tools to improve the efficacy of immune checkpoint blockade therapy in both dogs and humans. Furthermore, these tools will open new perspectives for immunotherapy applications in cancer as well as other autoimmune diseases that could benefit a diverse and broader patient population.
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Neoplasias , Investigación Biomédica Traslacional , Humanos , Perros , Animales , Ratones , Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias/tratamiento farmacológico , Inmunoterapia , AnticuerposRESUMEN
INTRODUCTION: As chest imaging is a tool for detecting coronavirus disease 2019 (COVID-19), diagnostic radiographers are a key component of the frontline workforce. Due to its unforeseen nature, COVID-19 has challenged radiographers' preparedness in combating its effects. Despite its importance, literature specifically investigating radiographers' readiness is limited. However, the documented experiences are prognostic of pandemic preparedness. Hence, this study aimed to map this literature by addressing the question: 'what does the existing literature reveal about the pandemic preparedness of diagnostic radiographers during COVID-19?'. METHODS: Using Arksey and O'Malley's framework, this scoping review searched for empirical studies in MEDLINE, Embase, Scopus, and CINAHL. Consequently, 970 studies were yielded and underwent processes of deduplication, title and abstract screening, full-text screening, and backward citation searching. Forty-three articles were deemed eligible for data extraction and analysis. RESULTS: Four themes that reflected pandemic preparedness were extrapolated: infection control and prevention, knowledge and education, clinical workflow, and mental health. Notably, the findings highlighted pronounced trends in adaptation of infection protocols, adequate infection knowledge, and pandemic-related fears. However, inconsistencies in the provision of personal protective equipment, training, and psychological support were revealed. CONCLUSION: Literature suggests that radiographers are equipped with infection knowledge, but the changing work arrangements and varied availability of training and protective equipment weakens their preparedness. The disparate access to resources facilitated uncertainty, affecting radiographers' mental health. IMPLICATIONS FOR PRACTICE: By reiterating the current strengths and weaknesses in pandemic preparedness, the findings can guide clinical practice and future research to correct inadequacies in infrastructure, education, and mental health support for radiographers in the current and future disease outbreaks.
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COVID-19 , Humanos , COVID-19/epidemiología , Pandemias , Técnicos Medios en Salud , Control de Infecciones , Equipo de Protección Personal , Prueba de COVID-19RESUMEN
OBJECTIVE: Asthma occurs in â¼17% of Australian pregnancies and is associated with adverse perinatal outcomes, which worsen with poor asthma control. Consequently, the South Australian 'Asthma in Pregnancy' perinatal guidelines were revised in 2012 to address management according to severity. This study investigated if these revised guidelines reduced the impact of maternal asthma on risks of adverse perinatal outcomes before (Epoch 1, 2006-2011) and after the revision (Epoch 2, 2013-2018). METHODS: Routinely collected perinatal and neonatal datasets from the Women's and Children's Hospital (Adelaide, Australia) were linked. Maternal asthma (prevalence:7.5%) was defined as asthma medication use or symptoms described to midwives. In imputation (n = 59131) and complete case datasets (n = 49594), analyses were conducted by inverse proportional weighting and multivariate logistic regression, accounting for confounders. RESULTS: Overall, maternal asthma was associated with increased risks of any antenatal corticosteroid treatment for threatened preterm birth (aOR 1.319, 95% CI 1.078-1.614), any Cesarean section (aOR 1.196, 95% CI 1.059-1.351), Cesarean section without labor (aOR 1.241, 95% CI 1.067-1.444), intrauterine growth restriction (IUGR, aOR 1.285, 95% CI 1.026-1.61), and small for gestational age (aOR 1.324, 95% CI 1.136-1.542). After guideline revision, asthma-associated risks of any Cesarean section (p < 0.001), any antenatal corticosteroids (p = 0.041), and small for gestational age (p = 0.050), but not IUGR and Cesarean section without labor, were reduced. CONCLUSIONS: Clinical practice guidelines based on the latest evidence do not guarantee clinical efficacy. Since adverse perinatal outcomes did not all improve, this work highlights the need to evaluate the ongoing impact of guidelines on clinical outcomes.
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Asma , Complicaciones del Embarazo , Nacimiento Prematuro , Niño , Embarazo , Femenino , Recién Nacido , Humanos , Resultado del Embarazo/epidemiología , Complicaciones del Embarazo/tratamiento farmacológico , Complicaciones del Embarazo/epidemiología , Cesárea , Estudios Retrospectivos , Nacimiento Prematuro/epidemiología , Asma/tratamiento farmacológico , Asma/epidemiología , Asma/complicaciones , AustraliaRESUMEN
The elastic light-scatter (ELS) technique, which detects and discriminates microbial organisms based on the light-scatter pattern of their colonies, has demonstrated excellent classification accuracy in pathogen screening tasks. The implementation of the multispectral approach has brought further advantages and motivated the design and validation of a hyperspectral elastic light-scatter phenotyping instrument (HESPI). The newly developed instrument consists of a supercontinuum (SC) laser and an acousto-optic tunable filter (AOTF). The use of these two components provided a broad spectrum of excitation light and a rapid selection of the wavelength of interest, which enables the collection of multiple spectral patterns for each colony instead of relying on single band analysis. The performance was validated by classifying microflora of green-leafed vegetables using the hyperspectral ELS patterns of the bacterial colonies. The accuracy ranged from 88.7% to 93.2% when the classification was performed with the scattering pattern created at a wavelength within the 473-709 nm region. When all of the hyperspectral ELS patterns were used, owing to the vastly increased size of the data, feature reduction and selection algorithms were utilized to enhance the robustness and ultimately lessen the complexity of the data collection. A new classification model with the feature reduction process improved the overall classification rate to 95.9%.
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Bacterias , Elasticidad , Luz , Fenómenos Fisiológicos Bacterianos , AlgoritmosRESUMEN
The mesolimbic dopamine system is an evolutionarily conserved set of brain circuits that play a role in attention, appetitive behavior, and reward processing. In this circuitry, ascending dopaminergic projections from the ventral midbrain innervate targets throughout the limbic forebrain, such as the ventral striatum/nucleus accumbens (NAc). Dopaminergic signaling in the NAc has been widely studied for its role in behavioral reinforcement, reward prediction error encoding, and motivational salience. Less well characterized is the role of dopaminergic neurotransmission in the response to surprising or alerting sensory events. To address this, we used the genetically encoded dopamine sensor dLight1 and fiber photometry to explore the ability of striatal dopamine release to encode the properties of salient sensory stimuli in mice, such as threatening looming discs. Here, we report that lateral NAc (LNAc) dopamine release encodes the rate and magnitude of environmental luminance changes rather than the visual stimulus threat level. This encoding is highly sensitive, as LNAc dopamine could be evoked by light intensities that were imperceptible to human experimenters. We also found that light-evoked dopamine responses are wavelength-dependent at low irradiances, independent of the circadian cycle, robust to previous exposure history, and involve multiple phototransduction pathways. Thus, we have further elaborated the mesolimbic dopamine system's ability to encode visual information in mice, which is likely relevant to a wide body of scientists employing light sources or optical methods in behavioral research involving rodents.
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Dopamina , Estriado Ventral , Ratones , Humanos , Animales , Dopamina/metabolismo , Núcleo Accumbens/fisiología , Estriado Ventral/metabolismo , Motivación , Mesencéfalo/metabolismo , Área Tegmental Ventral/fisiología , Recompensa , Neuronas Dopaminérgicas/fisiologíaRESUMEN
The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.