Se comparan las métricas de 37 modelos climáticos globales (GCMs, por sus siglas en inglés) de la Fase 6 del Proyecto de Intercomparación de Modelos Acoplados (CMIP6) con el objetivo de simular el ...clima de Guatemala del periodo de 1971 al 2014. La temperatura y precipitación mensual fue comparada con los datos de observación de la Unidad De Investigación Climática de la Universidad del este de Anglia (CRU). Se generó un ranquin de modelos basado en la menor distancia entre tres dimisiones basado en tres métricas; Coeficiente de Correlación de Pearson (CCP), Error medio cuadrático (RMSE) y Desviación estándar (DS). Este ordenamiento coincide con los mejores valores de eficiencia Nash-Sutcliffe (NSE) para temperatura y eficiencia Kling-Gupta (KGE) para la precipitación, demás se calculan las métricas; coeficiente de correlación de Spearman (CCS), errores de sesgo medio (MBE) y el absoluto medio (MAE). Para precipitación los primeros 5 modelos presentan valores KGE de entre 0.5 y 0.7, el CCP y CCS entre 0.7 a 0.8 comparados con CRU. Para temperatura los primeros 5 modelos presenta valores de NSE de entre 0.5 a 0.6, CCP y CCS de 0.8. Los modelos sobreestiman levemente la temperatura y subestiman la precipitación. Los modelos con mejor habilidad fueron CIESM para temperatura y el modelo IPSL-CM6A-LR para precipitación. Adicionalmente se compara el promedio de 66 estaciones locales con CRU, presentando un KGE 0.51, CCP 0.77 para precipitación y NSE -0.17 y un CCP 0.20 para temperatura. Finalmente, se presenta una tabla con los 10 primeros modelos para cada variable.
Soil bacteria and fungi play key roles in the functioning of terrestrial ecosystems, yet our understanding of their responses to climate change lags significantly behind that of other organisms. This ...gap in our understanding is particularly true for drylands, which occupy ∼41% of Earth´s surface, because no global, systematic assessments of the joint diversity of soil bacteria and fungi have been conducted in these environments to date. Here we present results from a study conducted across 80 dryland sites from all continents, except Antarctica, to assess how changes in aridity affect the composition, abundance, and diversity of soil bacteria and fungi. The diversity and abundance of soil bacteria and fungi was reduced as aridity increased. These results were largely driven by the negative impacts of aridity on soil organic carbon content, which positively affected the abundance and diversity of both bacteria and fungi. Aridity promoted shifts in the composition of soil bacteria, with increases in the relative abundance ofChloroflexiand α-Proteobacteriaand decreases inAcidobacteriaandVerrucomicrobia. Contrary to what has been reported by previous continental and global-scale studies, soil pH was not a major driver of bacterial diversity, and fungal communities were dominated byAscomycota. Our results fill a critical gap in our understanding of soil microbial communities in terrestrial ecosystems. They suggest that changes in aridity, such as those predicted by climate-change models, may reduce microbial abundance and diversity, a response that will likely impact the provision of key ecosystem services by global drylands.
Intransitive competition networks, those in which there is no single best competitor, may ensure species coexistence. However, their frequency and importance in maintaining diversity in real‐world ...ecosystems remain unclear. We used two large data sets from drylands and agricultural grasslands to assess: (1) the generality of intransitive competition, (2) intransitivity–richness relationships and (3) effects of two major drivers of biodiversity loss (aridity and land‐use intensification) on intransitivity and species richness. Intransitive competition occurred in > 65% of sites and was associated with higher species richness. Intransitivity increased with aridity, partly buffering its negative effects on diversity, but was decreased by intensive land use, enhancing its negative effects on diversity. These contrasting responses likely arise because intransitivity is promoted by temporal heterogeneity, which is enhanced by aridity but may decline with land‐use intensity. We show that intransitivity is widespread in nature and increases diversity, but it can be lost with environmental homogenisation.
Roads can substantially impact the population connectivity of a wide range of terrestrial vertebrates, often resulting in loss of genetic diversity and an increase of spatial genetic structure. We ...studied the Western Diamond-backed Rattlesnake (
Crotalus atrox
), a large and abundant venomous predator, to test the hypothesis that a large and relatively new roadway in Arizona (Interstate Highway I-10) is a barrier that impacts gene flow and population genetics via habitat fragmentation. Based on 72
C
.
atrox
sampled from three specific sampling sites (“subpopulations”) on both the west and east corridors of I-10, we used 30 nuclear microsatellite DNA loci and three mitochondrial DNA genes (2615 bp) to assess genetic diversity and structure, estimate effective population size (
N
e
), and describe patterns of gene flow. We found no evidence for loss of genetic diversity or a decrease in
N
e
between the three subpopulations. Our microsatellite analysis showed that two subpopulations in close proximity (4 km), but separated by I-10, showed greater levels of genetic differentiation than two subpopulations that were separated by a greater distance (7 km) and not by I-10 or any other obvious barriers. Mitochondrial DNA analyses showed no significant genetic differentiation nor any indication of historically impeded gene flow. Tajima’s
D
and mismatch distribution tests revealed that demographic expansion is occurring in the overall population (all three subpopulations). Bayesian clustering and spatial genetic autocorrelation analyses of microsatellite data showed resistance to gene flow at the approximate location of I-10. Simulations that investigated gene flow between the subpopulations (with and without a highway barrier present) were consistent with our molecular results. We conclude that I-10 has reduced gene flow in a population of an important reptilian predator of the Sonoran Desert in southern Arizona and make conservation recommendations for reversing this trend.
Calmodulin (CaM) and S100A1 fine‐tune skeletal muscle Ca2+ release via opposite modulation of the ryanodine receptor type 1 (RyR1). Binding to and modulation of RyR1 by CaM and S100A1 occurs ...predominantly at the region ranging from amino acid residue 3614‐3640 of RyR1 (here referred to as CaMBD2). Using synthetic peptides, it has been shown that CaM binds to two additional regions within the RyR1, specifically residues 1975‐1999 and 4295‐4325 (CaMBD1 and CaMBD3, respectively). Because S100A1 typically binds to similar motifs as CaM, we hypothesized that S100A1 could also bind to CaMBD1 and CaMBD3. Our goals were: (1) to establish whether S100A1 binds to synthetic peptides containing CaMBD1 and CaMBD3 using isothermal calorimetry (ITC), and (2) to identify whether S100A1 and CaM modulate RyR1 Ca2+ release activation via sites other than CaMBD2 in RyR1 in its native cellular context. We developed the mouse model (RyR1D‐S100A1KO), which expresses point mutation RyR1‐L3625D (RyR1D) that disrupts the modulation of RyR1 by CaM and S100A1 at CaMBD2 and also lacks S100A1 (S100A1KO). ITC assays revealed that S100A1 binds with different affinities to CaMBD1 and CaMBD3. Using high‐speed Ca2+ imaging and a model for Ca2+ binding and transport, we show that the RyR1D‐S100A1KO muscle fibers exhibit a modest but significant increase in myoplasmic Ca2+ transients and enhanced Ca2+ release flux following field stimulation when compared to fibers from RyR1D mice, which were used as controls to eliminate any effect of binding at CaMBD2, but with preserved S100A1 expression. Our results suggest that S100A1, similar to CaM, binds to CaMBD1 and CaMBD3 within the RyR1, but that CaMBD2 appears to be the primary site of RyR1 regulation by CaM and S100A1.
Calmodulin (CaM) binds to the skeletal muscle calcium release channel RyR1 at three binding domains, CaMBD1, 2, and 3. The interaction of CaM and S100A1 with the CaMBD2 modulates calcium release. Whether S100A1 binds to and modulates RyR1 activity via CaMBD1 and CaMBD3 is unclear. Our results show that S100A1, similar to CaM, binds to CaMBD1 and CaMBD3 within the RYR1 as well as to CaMBD2. However, CaMBD2 appears to be the primary site of RyR1 regulation by CaM and S100A1.
Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder that has no cure and very limited treatment options. MSA is characterized by deposition of fibrillar α-synuclein ...(α-syn) in glial cytoplasmic inclusions in oligodendrocytes. Similar to other synucleinopathies, α-syn self-assembly is thought to be a key pathologic event and a prominent target for disease modification in MSA. Molecular tweezers are broad-spectrum nanochaperones that prevent formation of toxic protein assemblies and enhance their clearance. The current lead compound, CLR01, has been shown to inhibit α-syn aggregation but has not yet been tested in the context of MSA. To fill this gap, here, we conducted a proof-of-concept study to assess the efficacy of CLR01 in remodeling MSA-like α-syn pathology in the PLP-α-syn mouse model of MSA. Six-month-old mice received intracerebroventricular CLR01 (0.3 or 1 mg/kg per day) or vehicle for 32 days. Open-field test revealed a significant, dose-dependent amelioration of an anxiety-like phenotype. Subsequently, immunohistochemical and biochemical analyses showed dose-dependent reduction of pathological and seeding-competent forms of α-syn, which correlated with the behavioral phenotype. CLR01 treatment also promoted dopaminergic neuron survival in the substantia nigra. To our knowledge, this is the first demonstration of an agent that reduces formation of putative high-molecular-weight oligomers and seeding-competent α-syn in a mouse model of MSA, supporting the view that these species are key to the neurodegenerative process and its cell-to-cell progression in MSA. Our study suggests that CLR01 is an attractive therapeutic candidate for disease modification in MSA and related synucleinopathies, supporting further preclinical development.
Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene,
(bone morphogenetic ...protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.
In vitro, calmodulin (CaM) and S100A1 activate the skeletal muscle ryanodine receptor ion channel (RyR1) at submicromolar Ca(2+) concentrations, whereas at micromolar Ca(2+) concentrations, CaM ...inhibits RyR1. One amino acid substitution (RyR1-L3625D) has previously been demonstrated to impair CaM binding and regulation of RyR1. Here we show that the RyR1-L3625D substitution also abolishes S100A1 binding. To determine the physiological relevance of these findings, mutant mice were generated with the RyR1-L3625D substitution in exon 74, which encodes the CaM and S100A1 binding domain of RyR1. Homozygous mutant mice (Ryr1(D/D)) were viable and appeared normal. However, single RyR1 channel recordings from Ryr1(D/D) mice exhibited impaired activation by CaM and S100A1 and impaired CaCaM inhibition. Isolated flexor digitorum brevis muscle fibers from Ryr1(D/D) mice had depressed Ca(2+) transients when stimulated by a single action potential. However, during repetitive stimulation, the mutant fibers demonstrated greater relative summation of the Ca(2+) transients. Consistently, in vivo stimulation of tibialis anterior muscles in Ryr1(D/D) mice demonstrated reduced twitch force in response to a single action potential, but greater summation of force during high-frequency stimulation. During repetitive stimulation, Ryr1(D/D) fibers exhibited slowed inactivation of sarcoplasmic reticulum Ca(2+) release flux, consistent with increased summation of the Ca(2+) transient and contractile force. Peak Ca(2+) release flux was suppressed at all voltages in voltage-clamped Ryr1(D/D) fibers. The results suggest that the RyR1-L3625D mutation removes both an early activating effect of S100A1 and CaM and delayed suppressing effect of CaCaM on RyR1 Ca(2+) release, providing new insights into CaM and S100A1 regulation of skeletal muscle excitation-contraction coupling.
The role of S100A1 in skeletal muscle is just beginning to be elucidated. We have previously shown that skeletal muscle fibers from S100A1 knockout (KO) mice exhibit decreased action potential ...(AP)-evoked Ca(2+) transients, and that S100A1 binds competitively with calmodulin to a canonical S100 binding sequence within the calmodulin-binding domain of the skeletal muscle ryanodine receptor. Using voltage clamped fibers, we found that Ca(2+) release was suppressed at all test membrane potentials in S100A1(-/-) fibers. Here we examine the role of S100A1 during physiological AP-induced muscle activity, using an integrative approach spanning AP propagation to muscle force production. With the voltage-sensitive indicator di-8-aminonaphthylethenylpyridinium, we first demonstrate that the AP waveform is not altered in flexor digitorum brevis muscle fibers isolated from S100A1 KO mice. We then use a model for myoplasmic Ca(2+) binding and transport processes to calculate sarcoplasmic reticulum Ca(2+) release flux initiated by APs and demonstrate decreased release flux and greater inactivation of flux in KO fibers. Using in vivo stimulation of tibialis anterior muscles in anesthetized mice, we show that the maximal isometric force response to twitch and tetanic stimulation is decreased in S100A1(-/-) muscles. KO muscles also fatigue more rapidly upon repetitive stimulation than those of wild-type counterparts. We additionally show that fiber diameter, type, and expression of key excitation-contraction coupling proteins are unchanged in S100A1 KO muscle. We conclude that the absence of S100A1 suppresses physiological AP-induced Ca(2+) release flux, resulting in impaired contractile activation and force production in skeletal muscle.
Calmodulin (CaM) and S100A1 fine-tune skeletal muscle Ca
release via opposite modulation of the ryanodine receptor type 1 (RyR1). Binding to and modulation of RyR1 by CaM and S100A1 occurs ...predominantly at the region ranging from amino acid residue 3614-3640 of RyR1 (here referred to as CaMBD2). Using synthetic peptides, it has been shown that CaM binds to two additional regions within the RyR1, specifically residues 1975-1999 and 4295-4325 (CaMBD1 and CaMBD3, respectively). Because S100A1 typically binds to similar motifs as CaM, we hypothesized that S100A1 could also bind to CaMBD1 and CaMBD3. Our goals were: (1) to establish whether S100A1 binds to synthetic peptides containing CaMBD1 and CaMBD3 using isothermal calorimetry (ITC), and (2) to identify whether S100A1 and CaM modulate RyR1 Ca
release activation via sites other than CaMBD2 in RyR1 in its native cellular context. We developed the mouse model (RyR1D-S100A1KO), which expresses point mutation RyR1-L3625D (RyR1D) that disrupts the modulation of RyR1 by CaM and S100A1 at CaMBD2 and also lacks S100A1 (S100A1KO). ITC assays revealed that S100A1 binds with different affinities to CaMBD1 and CaMBD3. Using high-speed Ca
imaging and a model for Ca
binding and transport, we show that the RyR1D-S100A1KO muscle fibers exhibit a modest but significant increase in myoplasmic Ca
transients and enhanced Ca
release flux following field stimulation when compared to fibers from RyR1D mice, which were used as controls to eliminate any effect of binding at CaMBD2, but with preserved S100A1 expression. Our results suggest that S100A1, similar to CaM, binds to CaMBD1 and CaMBD3 within the RyR1, but that CaMBD2 appears to be the primary site of RyR1 regulation by CaM and S100A1.
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