The frontal cortex, especially the anterior cingulate cortex area (ACA), is essential for exerting cognitive control after errors, but the mechanisms that enable modulation of attention to improve ...performance after errors are poorly understood. Here we demonstrate that during a mouse visual attention task, ACA neurons projecting to the visual cortex (VIS; ACAVIS neurons) are recruited selectively by recent errors. Optogenetic manipulations of this pathway collectively support the model that rhythmic modulation of ACAVIS neurons in anticipation of visual stimuli is crucial for adjusting performance following errors. 30-Hz optogenetic stimulation of ACAVIS neurons in anesthetized mice recapitulates the increased gamma and reduced theta VIS oscillatory changes that are associated with endogenous post-error performance during behavior and subsequently increased visually evoked spiking, a hallmark feature of visual attention. This frontal sensory neural circuit links error monitoring with implementing adjustments of attention to guide behavioral adaptation, pointing to a circuit-based mechanism for promoting cognitive control.
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•Top-down frontal sensory projections are selectively recruited after error trials•30-Hz optogenetic stimulation of top-down neurons promotes post-error performance•Post-error performance adjustment requires anticipatory top-down activity•30-Hz optogenetic top-down stimulation promotes a hallmark feature of attention
Norman et. al found that behavioral errors recruit frontal sensory projections in mice. 30-Hz optogenetic stimulation of this pathway modulates performance following errors in behaving mice and recapitulates neurophysiological hallmarks of attention in anesthetized mice. Frontal sensory projections therefore link error monitoring with attention adjustments for behavioral adaptation.
Frontal top-down cortical neurons projecting to sensory cortical regions are well-positioned to integrate long-range inputs with local circuitry in frontal cortex to implement top-down attentional ...control of sensory regions. How adolescence contributes to the maturation of top-down neurons and associated local/long-range input balance, and the establishment of attentional control is poorly understood. Here we combine projection-specific electrophysiological and rabies-mediated input mapping in mice to uncover adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are highly functionally integrated into local excitatory circuitry and have heightened activity compared to adulthood. Chemogenetic suppression of top-down neuron activity selectively during adolescence, but not later periods, produces long-lasting visual attentional behavior deficits, and results in excessive loss of local excitatory inputs in adulthood. Our study reveals an adolescent sensitive period when top-down neurons integrate local circuits with long-range connectivity to produce attentional behavior.
OBJECTIVEThe objective of this study was to measure the impact of a structured intervention on pain management in a pediatric emergency department (ED).
METHODSData were prospectively collected from ...children presenting to an urban tertiary care pediatric ED before and after intervention. Data were collected on the rate and timeliness of analgesic administration, the assessment and reassessment of pain, periprocedural anesthesia, and patient satisfaction. The intervention was developed by a multidisciplinary committee composed of physicians, nurses, and child life specialists and was focused on correcting deficiencies identified before intervention data collection. It consisted of a policy defining pain, pain-appropriate analgesia, age-appropriate pain assessment, and adequate preprocedural and periprocedural analgesia. Implementation occurred through provider education, organizational changes, and patient empowerment.
RESULTSOne hundred two patients were enrolled during the preintervention period, and 109 were enrolled in the postintervention period. The percentage of patients in pain receiving any analgesic increased from 34% to 50%, an increase of 16% (95% confidence interval CI, 1%–30%). The median time to medication administration decreased from 97 minutes to 57 minutes, a decrease of 40 minutes (95% CI, −84 to 4 minutes). The percentage of children receiving preprocedural analgesia increased from 10% to 62%, an increase of 52% (95% CI, 12%–74%). Reassessment of pain by physicians increased from 6% to 76%, an increase of 70% (95% CI, 59%–78%).
CONCLUSIONSA structured intervention, tailored to pain management shortcomings commonly found in the pediatric ED, can lead to improvements in the treatment and prevention of pain in childhood emergencies.
Abstract
The Human Metabolome Database or HMDB (www.hmdb.ca) is a web-enabled metabolomic database containing comprehensive information about human metabolites along with their biological roles, ...physiological concentrations, disease associations, chemical reactions, metabolic pathways, and reference spectra. First described in 2007, the HMDB is now considered the standard metabolomic resource for human metabolic studies. Over the past decade the HMDB has continued to grow and evolve in response to emerging needs for metabolomics researchers and continuing changes in web standards. This year's update, HMDB 4.0, represents the most significant upgrade to the database in its history. For instance, the number of fully annotated metabolites has increased by nearly threefold, the number of experimental spectra has grown by almost fourfold and the number of illustrated metabolic pathways has grown by a factor of almost 60. Significant improvements have also been made to the HMDB's chemical taxonomy, chemical ontology, spectral viewing, and spectral/text searching tools. A great deal of brand new data has also been added to HMDB 4.0. This includes large quantities of predicted MS/MS and GC-MS reference spectral data as well as predicted (physiologically feasible) metabolite structures to facilitate novel metabolite identification. Additional information on metabolite-SNP interactions and the influence of drugs on metabolite levels (pharmacometabolomics) has also been added. Many other important improvements in the content, the interface, and the performance of the HMDB website have been made and these should greatly enhance its ease of use and its potential applications in nutrition, biochemistry, clinical chemistry, clinical genetics, medicine, and metabolomics science.
Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative ...strategies for disease modelling, drug discovery and regenerative medicine. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.
The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty in association with the decrease in MKRN3 expression in the medial basal hypothalamus of mice ...before the initiation of reproductive maturation suggests that MKRN3 is acting as a brake on gonadotropin-releasing hormone (GnRH) secretion during childhood. In the current study, we investigated the mechanism by which MKRN3 prevents premature manifestation of the pubertal process. We showed that, as in mice, MKRN3 expression is high in the hypothalamus of rats and nonhuman primates early in life, decreases as puberty approaches, and is independent of sex steroid hormones. We demonstrated that Mkrn3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus and that MKRN3 repressed promoter activity of human KISS1 and TAC3, 2 key stimulators of GnRH secretion. We further showed that MKRN3 has ubiquitinase activity, that this activity is reduced by MKRN3 mutations affecting the RING finger domain, and that these mutations compromised the ability of MKRN3 to repress KISS1 and TAC3 promoter activity. These results indicate that MKRN3 acts to prevent puberty initiation, at least in part, by repressing KISS1 and TAC3 transcription and that this action may involve an MKRN3-directed ubiquitination-mediated mechanism.
African swine fever virus (ASFV) is a contagious, rapidly spreading, transboundary animal disease and a major threat to pork production globally. Although plant-based feed has been identified as a ...potential route for virus introduction onto swine farms, little is known about the risks for ASFV transmission in feed. We aimed to determine the minimum and median infectious doses of the Georgia 2007 strain of ASFV through oral exposure during natural drinking and feeding behaviors. The minimum infectious dose of ASFV in liquid was 10
50% tissue culture infectious dose (TCID
), compared with 10
TCID
in feed. The median infectious dose was 10
TCID
for liquid and 10
TCID
for feed. Our findings demonstrate that ASFV Georgia 2007 can easily be transmitted orally, although higher doses are required for infection in plant-based feed. These data provide important information that can be incorporated into risk models for ASFV transmission.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
PHAST (PHAge Search Tool) and its successor PHASTER (PHAge Search Tool – Enhanced Release) have become two of the most widely used web servers for identifying putative prophages in bacterial ...genomes. Here we review the main capabilities of these web resources, provide some practical guidance regarding their use and discuss possible future improvements. PHAST, which was first described in 2011, made its debut just as whole bacterial genome sequencing and was becoming inexpensive and relatively routine. PHAST quickly gained popularity among bacterial genome researchers because of its web accessibility, its ease of use along with its enhanced accuracy and rapid processing times. PHASTER, which appeared in 2016, provided a number of much-needed enhancements to the PHAST server, including greater processing speed (to cope with very large submission volumes), increased database sizes, a more modern user interface, improved graphical displays and support for metagenomic submissions. Continuing developments in the field, along with increased interest in automated phage and prophage finding, have already led to several improvements to the PHASTER server and will soon lead to the development of a successor to PHASTER (to be called PHASTEST).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous literature suggests that higher ambient temperature may play a role in increasing the risk of suicide. However, no multi-country study has explored the shape of the association and the role ...of moderate and extreme heat across different locations.
We examined the short-term temperature-suicide relationship using daily time-series data collected for 341 locations in 12 countries for periods ranging from 4 to 40 y.
We conducted a two-stage meta-analysis. First, we performed location-specific time-stratified case-crossover analyses to examine the temperature-suicide association for each location. Then, we used a multivariate meta-regression to combine the location-specific lag-cumulative nonlinear associations across all locations and by country.
A total of 1,320,148 suicides were included in this study. Higher ambient temperature was associated with an increased risk of suicide in general, and we observed a nonlinear association (inverted J-shaped curve) with the highest risk at 27°C. The relative risk (RR) for the highest risk was 1.33 (95% CI: 1.30, 1.36) compared with the risk at the first percentile. Country-specific results showed that the nonlinear associations were more obvious in northeast Asia (Japan, South Korea, and Taiwan). The temperature with the highest risk of suicide ranged from the 87th to 88th percentiles in the northeast Asian countries, whereas this value was the 99th percentile in Western countries (Canada, Spain, Switzerland, the UK, and the United States) and South Africa, where nearly linear associations were estimated. The country-specific RRs ranged from 1.31 (95% CI: 1.19, 1.44) in the United States to 1.65 (95% CI: 1.40, 1.93) in Taiwan, excluding countries where the results were substantially uncertain.
Our findings showed that the risk of suicide increased with increasing ambient temperature in many countries, but to varying extents and not necessarily linearly. This temperature-suicide association should be interpreted cautiously, and further evidence of the relationship and modifying factors is needed. https://doi.org/10.1289/EHP4898.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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