In this paper, we analyze the implications of macroprudential and monetary policies for business cycles, welfare, and financial stability. We consider a dynamic stochastic general equilibrium (DSGE) ...model with housing and collateral constraints. A macroprudential rule for the loan-to-value ratio (LTV), which responds to credit growth, interacts with a traditional Taylor rule for monetary policy. We compute the optimal parameters of these rules both when monetary and macroprudential policies act in a coordinated and in a non-coordinated way. We find that both policies acting together unambiguously improves the stability of the system. In both cases, this interaction is welfare improving for the society, especially in the case of the non-coordinated game. There is though a trade-off between borrowers and savers. However, borrowers can compensate the saver’s welfare loss àla Kaldor–Hicks to achieve a Pareto-superior outcome.
KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations ...in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared with other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution of the active site induced by the G13D mutation as shown by X-ray crystallography. High-resolution X-ray structures are also provided for the GDP-bound forms of KRAS G12V, G12R, and Q61L and reveal additional insight. Overall, the structural data and measurements, obtained herein, indicate that measurable biochemical properties provide clues for identifying KRAS-driven tumors that preferentially signal through RAF.
Biochemical profiling and subclassification of KRAS-driven cancers will enable the rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors.
Sea-level rise (SLR) poses a particularly ominous threat to human habitations and infrastructure in the coastal zone because 10% of the world's population lives in low-lying coastal regions within ...10m elevation of present sea level. There has been much discussion about projected (and the sources of projection) vs. measured SLR rates. Which rates should coastal scientists and managers apply in their studies, and what is the degree of confidence of such forecasts, are still open questions.
This paper reviews the patterns and effects of relative SLR (RSLR) in coastal lagoons. Three main components are presented in the review: (a) a summary of the main approaches used in predicting medium- to long-term trends in RSLR, (b) a summary of the main evolutionary trends of coastal lagoons and the tools used to examine such trends, and (c) an identification of future research needs.
The review reveals that the major source of uncertainty is how and when RSLR will manifest itself at different spatio-temporal scales in coastal lagoon systems, and how its effects can be mitigated. Most of the studies reviewed herein articulate a natural ‘defence’ mechanism of barriers in coastal lagoons by landward barrier retreat through continuous migration, and a gradual change in basin hypsometry during the retreat process. So far, only a relatively small number of detailed studies have integrated and quantified human impacts and coastal lagoon evolution induced by RSLR. We conclude that much more research about adaptation measures is needed, taking into consideration not only the physical and ecological systems but also social, cultural, and economic impacts. Future challenges include a downscaling of SLR approaches from the global level to regional and local levels, with a detailed application of coastal evolution prediction to individual coastal lagoon systems.
•Viroids, small non-protein-coding RNAs, replicate and incite diseases in plants.•Viroid rolling-circle replication is catalyzed by host enzymes and viroid ribozymes.•Viroids trigger in their hosts ...an RNA silencing defensive response.•Viroid infection may be additionally restricted by other mechanisms.•At least some viroids induce disease though RNA silencing pathways.
The discovery of viroids about 45 years ago heralded a revolution in Biology: small RNAs comprising around 350nt were found to be able to replicate autonomously—and to incite diseases in certain plants—without encoding proteins, fundamental properties discriminating these infectious agents from viruses. The initial focus on the pathological effects usually accompanying infection by viroids soon shifted to their molecular features—they are circular molecules that fold upon themselves adopting compact secondary conformations—and then to how they manipulate their hosts to be propagated. Replication of viroids—in the nucleus or chloroplasts through a rolling-circle mechanism involving polymerization, cleavage and circularization of RNA strands—dealt three surprises: (i) certain RNA polymerases are redirected to accept RNA instead of their DNA templates, (ii) cleavage in chloroplastic viroids is not mediated by host enzymes but by hammerhead ribozymes, and (iii) circularization in nuclear viroids is catalyzed by a DNA ligase redirected to act upon RNA substrates. These enzymes (and ribozymes) are most probably assisted by host proteins, including transcription factors and RNA chaperones. Movement of viroids, first intracellularly and then to adjacent cells and distal plant parts, has turned out to be a tightly regulated process in which specific RNA structural motifs play a crucial role. More recently, the advent of RNA silencing has brought new views on how viroids may cause disease and on how their hosts react to contain the infection; additionally, viroid infection may be restricted by other mechanisms. Representing the lowest step on the biological size scale, viroids have also attracted considerable interest to get a tentative picture of the essential characteristics of the primitive replicons that populated the postulated RNA world.
Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We ...demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.
The core symptoms of autism spectrum disorder (ASD) mainly relate to social communication and interactions. ASD assessment involves expert observations in neutral settings, which introduces ...limitations and biases related to lack of objectivity and does not capture performance in real‐world settings. To overcome these limitations, advances in technologies (e.g., virtual reality) and sensors (e.g., eye‐tracking tools) have been used to create realistic simulated environments and track eye movements, enriching assessments with more objective data than can be obtained via traditional measures. This study aimed to distinguish between autistic and typically developing children using visual attention behaviors through an eye‐tracking paradigm in a virtual environment as a measure of attunement to and extraction of socially relevant information. The 55 children participated. Autistic children presented a higher number of frames, both overall and per scenario, and showed higher visual preferences for adults over children, as well as specific preferences for adults' rather than children's faces on which looked more at bodies. A set of multivariate supervised machine learning models were developed using recursive feature selection to recognize ASD based on extracted eye gaze features. The models achieved up to 86% accuracy (sensitivity = 91%) in recognizing autistic children. Our results should be taken as preliminary due to the relatively small sample size and the lack of an external replication dataset. However, to our knowledge, this constitutes a first proof of concept in the combined use of virtual reality, eye‐tracking tools, and machine learning for ASD recognition.
Lay Summary
Core symptoms in children with ASD involve social communication and interaction. ASD assessment includes expert observations in neutral settings, which show limitations and biases related to lack of objectivity and do not capture performance in real settings. To overcome these limitations, this work aimed to distinguish between autistic and typically developing children in visual attention behaviors through an eye‐tracking paradigm in a virtual environment as a measure of attunement to, and extraction of, socially relevant information.
Layered double hydroxides (LDHs) are low-dimensional materials that act as benchmark catalysts for the oxygen evolution reaction (OER). Many LDH properties affecting the OER have been studied to ...reach the optimal efficiency, but no systematic studies concerning the influence of the interlayer space have been developed. In this context, these materials allow a large tunability in their chemical composition enabling the substitution of the interlayer anion and therefore modifying exclusively the basal space. Here, we synthesize by anion exchange reactions a surfactant-intercalated family of NiFe–LDHs with increasing basal spacing ranging from 8.0 to 31.6 Å (one of the largest reported so far for a NiFe–LDH), while the electrochemical OER performance of this family of compounds was explored to analyze the interlayer distance effect keeping similar morphology, dimensions, and metallic composition. Results show the increase of the LDH basal space undergoes to lower Tafel slopes, higher electrochemical surface area, and a reduction of the resistance related to the chemisorption of oxygen leading to better kinetic behavior, showing an optimum enhancement of the electrocatalytic performance for the NiFe–dodecyl sulfate (basal space of 25 Å). Interestingly, the NiFe–dodecyl sulfate exhibits optimum proton diffusion values; indeed, a further increment in the basal space compromises the onset potential, a fact that could be related to an increase in the hydrophobicity between the layers. Moreover, by judicious tuning of the interlayer space, it is possible to reach a Tafel slope value for the most spaced LDH (NiFe–octadecyl sulfate, basal space of 31.6 Å) similar to the one obtained for exfoliated NiFe nanosheets, showing a much better long-time stability due to the three-dimensional robustness of the catalysts. This work illustrates the importance of molecular engineering in the design of novel highly active catalysts and provides important insights into the understanding of basic principles of oxygen evolution reaction in NiFe–LDHs.
The RNA-binding protein TDP-43 regulates RNA metabolism at multiple levels, including transcription, RNA splicing, and mRNA stability. TDP-43 is a major component of the cytoplasmic inclusions ...characteristic of amyotrophic lateral sclerosis and some types of frontotemporal lobar degeneration. The importance of TDP-43 in disease is underscored by the fact that dominant missense mutations are sufficient to cause disease, although the role of TDP-43 in pathogenesis is unknown. Here we show that TDP-43 forms cytoplasmic mRNP granules that undergo bidirectional, microtubule-dependent transport in neurons in vitro and in vivo and facilitate delivery of target mRNA to distal neuronal compartments. TDP-43 mutations impair this mRNA transport function in vivo and in vitro, including in stem cell-derived motor neurons from ALS patients bearing any one of three different TDP-43 ALS-causing mutations. Thus, TDP-43 mutations that cause ALS lead to partial loss of a novel cytoplasmic function of TDP-43.
Estimate the effects of non-pharmacological interventions used to prevent the spread of COVID-19 on the quality of life, measured by Quality Adjusted Life Years (QALYs).
A survey on 1,506 heads of ...households from Chile in May of 2022. Respondents were asked basic socioeconomic questions and a version of the EQ-5D-5L questionnaire that was used to calculate the evolution of HRQoLs. Comparisons of means in HRQoLs measures before the pandemic, at the peak of restrictions, and at the moment of the survey were performed.
The average HRQoL of the population before the pandemic was similar to other countries in the region (0.96). At the peak of restrictions (June 2020-August 2021), the average HRQoL decreased to 0.87 (-9%). At the time of survey (May 2022), the average HQRoL was 0.91 (4%). Assuming the recovery trend continued, pre-pandemic HRQoLs would be reached by January 2024. Altogether, the pandemic would have reduced QALYs by 0.2 in average. The effect is larger and the recovery slower among women. Our estimates imply that the restrictions to manage the pandemic came at a cost of 2.4 months of life years for the average (surviving) person, 1.8 months for men and 3.4 for women.
Our results suggest that COVID-19 had worse effects on life quality than previously thought. These effects are more significant among women than among men. Efforts to improve life quality and speed up its recovery could have large positive consequences for the population.
One of the key questions about wetlands resilience to sea-level rise is whether sediment supply will be enough to keep them coping with growing inundation levels. To address this question, ...researchers have put a lot of effort into field data collection and ecogeomorphic modelling, in an attempt to identify the tipping points of marsh survival. This study uses fieldwork data to characterize the sediment fluxes between the tidal flats and salt marshes, in the Ria Formosa lagoon (Portugal). Sediment fluxes were measured from the tidal channel towards the mid-upper marsh, during neap and spring tide conditions. The flow magnitude was measured, and induced transport was determined based on shear velocities. Deposition rates, instantaneous suspended sediment and near-bed velocities were linked through theoretical formulas and used to characterize time-averaged conditions for sediment delivery and deposition to the site. The results showed that suspended sediment concentrations and sediment deposition varied across the transect with no specific relation to elevation. Maximum water depths were recorded in the vegetated tidal flat, and the maximum currents were flood dominated, in the order of 0.20 m/s, in the low marsh due to flow-plant interactions and an increase of turbulence. Deposition rates ranged between 20 to 45 g/m
/hr, after a complete tidal cycle, and were higher in the mid-upper marsh. Hydroperiod was not the main contributor to sediment deposition in the study area. Sediment transport was tidally driven, strongly two-dimension during the cycle, and highly influenced by the vegetation. Measurements of marsh sediment flux obtained in our work are diverse from the ones found in the literature and evidence the importance of considering spatio-temporal variability of vegetated platforms in assessing overall marsh bed level changes.
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