Changed NMDA receptor (NMDAr) physiology is implicated with cognitive deficit resulting from conditions ranging from normal aging to neurological disease. Using intermittent hypoxia (IH) to ...experimentally model untreated sleep apnea, a clinical condition whose comorbidities include neurocognitive impairment, we recently demonstrated that IH causes a pro-oxidant condition that contributes to deficits in spatial memory and in NMDAr-dependent long-term potentiation (LTP). However, the impact of IH on additional forms of synaptic plasticity remains ill-defined. Here we show that IH prevents the induction of NMDAr-dependent LTP and long-term depression (LTD) in hippocampal brain slices from mice exposed to ten days of IH (IH10) yet spares NMDAr-independent forms of synaptic plasticity. Deficits in synaptic plasticity were accompanied by a reduction in hippocampal GluN1 expression. Acute manipulation of redox state using the reducing agent, Dithiothreitol (DTT) stimulated the NMDAr-dependent fEPSP following IH10. However, acute use of either DTT or MnTMPyP did not restore NMDAr-dependent synaptic plasticity after IH10 or prevent the IH-dependent reduction in GluN1, the obligatory subunit of the NMDAr. In contrast, MnTMPyP during IH10 (10-MnTMPyP), prevented the suppressive effects of IH on both NMDAr-dependent synaptic plasticity and GluN1 expression. These findings indicate that while the IH-dependent pro-oxidant state causes reversible oxidative neuromodulation of NMDAr activity, acute manipulation of redox state is ineffective in rescuing two key effects of IH related to the NMDAr within the hippocampus. These IH-dependent changes associated with the NMDAr may be a primary avenue by which IH enhances the vulnerability to impaired learning and memory when sleep apnea is left untreated in normal aging and in disease.
•Intermittent hypoxia (IH) impairs NMDAr-dependent synaptic plasticity yet spares other forms of synaptic plasticity.•Acute modulation of redox state after IH enhances NMDAr activity but does not restore NMDAr dependent synaptic plasticity.•IH reduces expression of GluN1 without altering the ratio of GluN2A to GluN2B expression.•While IH phenocopies the effects of aging on NMDAr-dependent synaptic plasticity, the basis differs between the phenomena.
Bromodomain and extraterminal (BET) proteins are essential to pro-inflammatory gene transcription. The BET family proteins, BRD2, BRD3, BRD4, and testis-specific BRDT, couple chromatin remodeling to ...gene transcription, acting as histone acetyltransferases, scaffolds for transcription complexes, and markers of histone acetylation. To initiate an inflammatory response, cells undergo de novo gene transcription requiring histone-modifying proteins to make DNA wrapped around histones more or less readily available to transcription complexes. Because BET proteins are the gatekeepers of nuclear factor-κB (NF-κB)-dependent gene transcription, we hypothesized that degradation of BET proteins, particularly BRD2 and BRD4, with the proteolysis-targeting chimera (PROTAC) dBET1 would dampen the pro-inflammatory response in microglia subjected to lipopolysaccharide (LPS) challenge. Degradation of BRD2 and BRD4 was associated with significantly reduced expression of several pro-inflammatory genes: inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-1β, tumor necrosis factor-a (TNF-α), IL-6, chemokine (C-C motif) ligand 2 (CCL2), and matrix metalloproteinase-9 (MMP-9). This is the first study showing that dBET1-mediated targeted degradation of BET proteins robustly dampens pro-inflammatory responses in LPS-stimulated microglia. These data suggest that BET degradation with dBET1 will likely reduce expression of pro-inflammatory genes in in vivo neuroinflammatory models associated with microglial/immune cell activation.
•dBET1 degrades BRD2 and BRD4 in a time- and concentration-dependent manner.•BRD2/BRD4 degradation with dBET1 is associated with decreased LPS-induced iNOS and COX-2 levels.•dBET1 potently reduces pro-inflammatory gene expression including iNOS, COX-2, IL-1β, TNFα, CCL2, IL-6, and MMP-9.
La aceleración e intensidad de los actuales procesos migratorios en diversas partes del mundo nos reta a hilar fino para poder distinguir las particularidades de las diferentes maneras en que se ...producen las movilidades humanas. La migración por causas económicas, políticas, sociales y por los altos índices de violencia ha acaparado la mayor atención en nuestros análisis. Si bien los desplazamientos ambientales forzados están sobre la mesa de los debates, hoy es más importante que nunca continuar discusiones y propuestas que posibiliten la formulación de acciones y políticas que los atiendan. Este artículo se acerca, en la primera parte, a la reflexión sobre la pertinencia de entender un marco conceptual del desplazamiento ambiental y desplazamiento ambiental forzado referidos a personas afectadas por eventos hidrometeorológicos. La segunda parte, toma el emblemático caso de los afectados de la localidad Juan del Grijalva, en el norte de Chiapas, que en 2007 sufrió las consecuencias del deslizamiento de la ladera ribereña que inundó el poblado. La Ciudad Rural Sustentable fue la solución que el Estado implementó para reubicar a los desplazados por el desastre, provocado por razones asociadas al evento hidrometeorológico y al inadecuado manejo de los embalses de la presa Peñitas en el río Grijalva, que condujo a los pobladores a emergentes vulnerabilidades y a otras múltiples movilidades. Interesa asimismo conocer las percepciones y las interpretaciones que las personas afectadas tuvieron y, aún hoy día, tienen sobre el evento que trastocó su vida toda.
The acceleration and intensity of current migration processes in different parts of the world challenges us to distinguish the particularities of the various ways in which human mobility occurs. Migration for economic, political, and social reasons, as well as due to high rates of violence, has attracted the most attention in our analyses. Although forced environmental displacements are subjects of debates, currently it is more important than ever to continue discussions and proposals that enable the formulation of actions and policies to address them. In the first part of this article, we reflect on the relevance of understanding a conceptual framework for environmental displacement and forced environmental displacement in relation to people affected by hydrometeorological events. The second part takes the emblematic case of those affected in the town of Juan del Grijalva, in northern Chiapas, which in 2007 suffered the consequences of flooding from a river landslide. The Sustainable Rural City was the solution implemented by the State to relocate those displaced by the disaster, caused by reasons associated with the hydrometeorological event and the inadequate management of the reservoirs of the Peñitas dam on the Grijalva river, which led the inhabitants to emerging vulnerabilities and other multiple mobilities. It is also interesting to know the perceptions and interpretations that the affected people had, and still have today, about the event that disrupted their entire lives.
Summary
One of the major challenges for plant scientists is increasing wheat (Triticum aestivum) yield potential (YP). A significant bottleneck for increasing YP is achieving increased biomass ...through optimization of radiation use efficiency (RUE) along the crop cycle. Exotic material such as landraces and synthetic wheat has been incorporated into breeding programmes in an attempt to alleviate this; however, their contribution to YP is still unclear. To understand the genetic basis of biomass accumulation and RUE, we applied genome‐wide association study (GWAS) to a panel of 150 elite spring wheat genotypes including many landrace and synthetically derived lines. The panel was evaluated for 31 traits over 2 years under optimal growing conditions and genotyped using the 35K wheat breeders array. Marker‐trait association identified 94 SNPs significantly associated with yield, agronomic and phenology‐related traits along with RUE and final biomass (BM_PM) at various growth stages that explained 7%–17% of phenotypic variation. Common SNP markers were identified for grain yield, BM_PM and RUE on chromosomes 5A and 7A. Additionally, landrace and synthetic derivative lines showed higher thousand grain weight (TGW), BM_PM and RUE but lower grain number (GM2) and harvest index (HI). Our work demonstrates the use of exotic material as a valuable resource to increase YP. It also provides markers for use in marker‐assisted breeding to systematically increase BM_PM, RUE and TGW and avoid the TGW/GM2 and BM_PM/HI trade‐off. Thus, achieving greater genetic gains in elite germplasm while also highlighting genomic regions and candidate genes for further study.
International Incidence and Outcomes of Biliary Atresia Jimenez‐Rivera, Carolina; Jolin‐Dahel, Kheira S.; Fortinsky, Kyle J. ...
Journal of pediatric gastroenterology and nutrition,
2013-April, Letnik:
56, Številka:
4
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
Objectives:
International trends in incidence and outcomes of biliary atresia (BA) are controversial and a wide range of estimates have been reported worldwide. We reviewed the ...population‐based literature to assess international variation of BA incidence and outcomes, and to assess the evidence for seasonal variation in incidence, centralization of Kasai hepatoportoenterostomy, and newborn screening.
Methods:
We conducted a systematic review (registration number CRD42011001441) of observational or interventional research within MEDLINE, EMBASE, and the Cochrane Database, which reported incidence, prevalence, or outcomes of infants with BA. Population‐based studies, defined by inclusion of an entire population or representative sample, were included. Outcomes included overall survival, native liver survival (NLS), and time to Kasai hepatoportoenterostomy. Single‐ or multicenter studies were excluded unless those centers captured all potential patients within a jurisdiction. Two independent data extractors reviewed the s and articles.
Results:
A total of 40 studies were included following review of 3128 references. A wide range of incidence was reported internationally. Ten‐year overall survival ranged from 66.7% to 89%. NLS ranged from 20.3% to 75.8% at 1 to 3 years and 24% to 52.8% at 10 years. Earlier age at Kasai was a predictor of improved NLS. Seasonality was reported in 11 studies, and 3 reported an increased incidence during the months of August to March. The evidence for centralization of Kasai to high‐volume centers is promising but does not account for all case‐mix, provider, or health system factors involved in volume–outcome relations. Stool color card screening resulted in earlier Kasai and improved NLS in Taiwan.
Conclusions:
Large, international studies could help fill the gaps in knowledge identified by this review.
Recent clinical trials of as-needed fixed-dose combination of inhaled corticosteroid (ICS)/formoterol have provided new evidence that may warrant a reconsideration of current practice. A Task Force ...was set up by the European Respiratory Society to provide evidence-based recommendations on the use of as-needed ICS/formoterol as treatment for mild asthma. The Task Force defined two questions that were assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. The Task Force utilised the outcomes to develop recommendations for a pragmatic guideline for everyday clinical practice. The Task Force suggests that adults with mild asthma use as-needed ICS/formoterol instead of regular ICS maintenance treatment plus as-needed short-acting β
-antagonist (SABA) and that adolescents with mild asthma use either as-needed ICS/formoterol or ICS maintenance treatment plus as-needed SABA (conditional recommendation; low certainty of evidence). The recommendation for adults places a relatively higher value on the reduction of systemic corticosteroid use and the outcomes related to exacerbations, and a relatively lower value on the small differences in asthma control. Either treatment option is suggested for adolescent patients as the balance is very close and data more limited. The Task Force recommends that adult and adolescent patients with mild asthma use as-needed ICS/formoterol instead of as-needed SABA (strong recommendation; low certainty of evidence). This recommendation is based on the benefit of as-needed ICS/formoterol in mild asthma on several outcomes and the risks related to as-needed SABA in the absence of anti-inflammatory treatment. The implementation of this recommendation is hampered in countries (including European Union countries) where as-needed ICS/formoterol is not approved for mild asthma.
Over one billion adults worldwide are estimated to suffer from sleep apnea, a condition with wide-reaching effects on brain health. Sleep apnea causes cognitive decline and is a risk factor for ...neurodegenerative conditions such as Alzheimer's disease. Rodents exposed to intermittent hypoxia (IH), a hallmark of sleep apnea, exhibit spatial memory deficits associated with impaired hippocampal neurophysiology and dysregulated adult neurogenesis. We demonstrate that IH creates a pro-oxidant condition that reduces the Tbr2
neural progenitor pool early in the process, while also suppressing terminal differentiation of adult born neurons during late adult neurogenesis. We further show that IH-dependent cell-autonomous hypoxia inducible factor 1-alpha (HIF1a) signaling is activated in early neuroprogenitors and enhances the generation of adult born neurons upon termination of IH. Our findings indicate that oscillations in oxygen homeostasis, such as those found in sleep apnea, have complex stage-dependent influence over hippocampal adult neurogenesis.
Aim
Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by deficient tripeptidyl peptidase 1 (TPP1) enzyme, ...leading to progressive deterioration of neurological functions commonly occurring in children aged 2–4 years and culminating in early death. Atypical cases associated with earlier or later symptom onset, or even protracted course, have already been reported. Such variable manifestations may constitute an additional challenge to early diagnosis and initiation of appropriate treatment. The present work aimed to analyse clinical data from a cohort of Latin American CLN2 patients with atypical phenotypes.
Methods
Experts in inborn errors of metabolism from Latin America selected patients from their centres who were deemed by the clinicians to have atypical forms of CLN2, according to the current literature on this topic and their practical experience. Clinical and genetic data from the medical records were retrospectively revised. All cases were presented and analysed by these experts at an Advisory Board Meeting in São Paulo, Brazil, in October 2018.
Results
Seizures, language abnormalities and behavioural disorders were found as the first manifestations, appearing at the median age of 6 years, an older age than classically described for the late infantile form. Three novel mutations were also identified.
Conclusion
Our findings reinforce the inclusion of CLN2 in the differential diagnosis of children presenting with seizures, behavioural disorders and language abnormalities. Early diagnosis will allow early initiation of specific therapy.
Summary
To feed an ever‐increasing population we must leverage advances in genomics and phenotyping to harness the variation in wheat breeding populations for traits like photosynthetic capacity ...which remains unoptimized. Here we survey a diverse set of wheat germplasm containing elite, introgression and synthetic derivative lines uncovering previously uncharacterized variation. We demonstrate how strategic integration of exotic material alleviates the D genome genetic bottleneck in wheat, increasing SNP rate by 62% largely due to Ae. tauschii synthetic wheat donors. Across the panel, 67% of the Ae. tauschii donor genome is represented as introgressions in elite backgrounds. We show how observed genetic variation together with hyperspectral reflectance data can be used to identify candidate genes for traits relating to photosynthetic capacity using association analysis. This demonstrates the value of genomic methods in uncovering hidden variation in wheat and how that variation can assist breeding efforts and increase our understanding of complex traits.
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