Contrasting toxicity response to a mixture of azithromycin and ivermectin between a freshwater and a euryhaline rotifer.

Organisms are usually exposed to mixtures of emerging pollutants in aquatic environments. Due to their widespread use and environmental relevance, the individual and combined effects of the drugs azithromycin (AZT) and ivermectin (IVM) on the freshwater rotifer Lecane papuana and the euryhaline rotifer Proales similis were investigated. Rotifers showed greater sensitivity to IVM compared to AZT. The LC50 values of IVM and AZT for L. papuana and P. similis were 0.163 and 0.172 mg/L, and 13.52 and 20.00 mg/L, respectively. Population growth rates, assessed in chronic toxicity assays, responded negatively to increasing concentrations of both toxicants, either individually or in combination. Our results revealed two distinct combined toxicity responses: a strong synergistic effect in the freshwater rotifer and a marked antagonistic impact of the AZT-IVM mixtures in the euryhaline rotifer.

Effect of emerging pollutants on the gut microbiota of freshwater animals: Focusing on microplastics and pesticides.

In recent years, emerging environmental pollutants have increasingly endangered the health of freshwater organisms. The gut microbiota exhibits sensitivity to medications, dietary factors and environmental pollutants, rendering it a novel target for toxicological studies. The gut microbiota can be a potential exposure route affecting the host's health. Herein, we review the current knowledge on two different but concurrent pollutants, microplastics and pesticides, regarding their impact on the gut microbiota, which includes alterations in microbial composition, gene expression, function, and health effects in the hosts. Moreover, synergetic interactions between microplastics and pesticides can exacerbate dysbiosis and health risks. We discuss health-related implications of gut microbial changes based on the consequences in metabolism, immunity, and physiology function. Further research is needed to discover the mechanisms underlying these effects and develop strategies for mitigating their harmful impacts on freshwater animals.

Methylotrophic methanogenesis induced by ammonia nitrogen in an anaerobic digestion system.

OBJECTIVES: This lab-scale study aimed to investigate the effect of total ammonia nitrogen (TAN) stress on the methanogenic activity and the taxonomic and functional profiles of the microbial community of anaerobic sludge (AS) from a full-scale bioreactor. METHODS: The AS was subjected to a stepwise increase in TAN every 14 days at concentrations of 1, 2, 2.5, 3, 3.5, and 4 g TAN/L (Acclimated-AS or AAS). This acclimation stage was followed by an ammonia stress stage (4 g/L). A blank-AS (BAS) was maintained without TAN during the acclimation stage. In the second stress stage (ST), the BAS was divided into two new treatments: a control (BAS') and one that received a shock load of TAN of 4 g/L (SBAS'). Methane production was measured, and a metagenomic analysis was conducted to describe the microbial community. RESULTS: A decrease in the relative abundance of Methanothrix soehngenii of 16 % was related to a decrease of 23 % in the methanogenic capacity of AAS when comparing with the final stage of BAS. However, recovery was observed at 3.5 g TAN/L, and a shift to methylotrophic metabolism occurred, indicated by a 4-fold increase in abundance of Methanosarcina mazei. The functional analysis of sludge metagenomes indicated that no statistical differences (p > 0.05, RM ANOVA) were found in the relative abundance of methanogenic genes that initiate acetoclastic and hydrogenotrophic pathways (acetyl-CoA synthetase, ACSS; acetate kinase, ackA; phosphate acetyltransferase, pta; and formylmethanofuran dehydrogenase subunit A, fwdA) into the BAS and AAS during the acclimation phase. The same was observed between groups of genes associated with methanogenesis from methylated compounds. In contrast, statistical differences (p < 0.05, one-way ANOVA) in the relative abundance of these genes were recorded during ST. The functional profiles of the genes involved in acetoclastic, hydrogenotrophic, and methylotrophic methanogenic pathways were brought to light for acclimatation and stress experimental stages. CONCLUSIONS: TAN inhibited methanogenic activity and acetoclastic metabolism. The gradual acclimatization to TAN leads to metabolic and taxonomic changes that allow for the subsequent recovery of methanogenic functionality. The study highlights the importance of adequate management of anaerobic bioprocesses with high nitrogen loads to maintain the methanogenic functionality of the microbial community.

Synthesis and Raman Detection of 5-Amino-2-mercaptobenzimidazole Self-Assembled Monolayers in Nanoparticle-on-a-Mirror Plasmonic Cavity Driven by Dielectric Waveguides.

Functionalization of metallic surfaces by molecular monolayers is a key process in fields such as nanophotonics or biotechnology. To strongly enhance light-matter interaction in such monolayers, nanoparticle-on-a-mirror (NPoM) cavities can be formed by placing metal nanoparticles on such chemically functionalized metallic monolayers. In this work, we present a novel functionalization process of gold surfaces using 5-amino-2-mercaptobenzimidazole (5-A-2MBI) molecules, which can be used for upconversion from THz to visible frequencies. The synthesized surfaces and NPoM cavities are characterized by Raman spectroscopy, atomic force microscopy (AFM), and advancing-receding contact angle measurements. Moreover, we show that NPoM cavities can be efficiently integrated on a silicon-based photonic chip performing pump injection and Raman-signal extraction via silicon nitride waveguides. Our results open the way for the use of 5-A-2MBI monolayers in different applications, showing that NPoM cavities can be effectively integrated with photonic waveguides, enabling on-chip enhanced Raman spectroscopy or detection of infrared and THz radiation.

Combinatorial selective ER-phagy remodels the ER during neurogenesis.

The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis, where a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodelling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of the ER and the role of individual ER-phagy receptors is limited. Here we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodelling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodelling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both the magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodelling and versatile genetic toolkit provide a quantitative framework for understanding the contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.

Sexual selection buffers the negative consequences of population fragmentation on adaptive plastic responses to increasing temperatures.

Whether sexual selection facilitates or hampers the ability to plastically respond to novel environments might depend on population structure, via its effects on sexual interactions and associated fitness payoffs. Using experimentally evolved lines of the seed beetle Callosobruchus maculatus, we tested whether individuals evolving under different sexual selection (monogamy vs. polygamy) and population spatial structure (metapopulation vs. undivided populations) treatments differed in their response across developmental thermal conditions (control, hot, or stressful) in a range of fitness and fitness-associated traits. We found that individuals from subdivided populations had lower lifetime reproductive success at hot temperatures, but only in lines evolving under relaxed sexual selection, revealing a complex interaction between sexual selection, population structure, and thermal environmental stress on fitness. We also found an effect of population structure on several traits, including fertility and adult emergence success, under exposure to high thermal conditions. Finally, we found a strong negative effect of hot and stressful temperatures on fitness and associated traits. Our results show that population structure can exacerbate the impact of a warming climate, potentially leading to declines in population viability, but that sexual selection can buffer the negative influence of population subdivision on adaptation to warm temperatures.

Mode II Delamination under Static and Fatigue Loading of Adhesive Joints in Composite Materials Exposed to Saline Environment.

This study investigates the fatigue delamination behavior of adhesive joints in epoxy carbon composite materials under Mode II fracture loading. The joints were characterized using the End-Notched Flexure (ENF) test, comprising adhesive joints formed by bonding two unidirectional carbon fiber epoxy matrix laminates with epoxy adhesive. These joints were subjected to different exposure periods (1, 2, 4, and 12 weeks) in a saline environment. Prior to dynamic fatigue testing, critical Mode II energy release rate values were determined through quasi-static tests, serving as a reference for subsequent fatigue characterization. This study aimed to comprehend how exposure duration to a saline environment affected the initial stage of fatigue delamination growth and employed a probabilistic model based on the Weibull distribution to analyze the experimental data. The results, gathered over a two-year experimental program, revealed varying behaviors in adhesive joint resistance to delamination based on exposure duration. A noteworthy reduction in fatigue strength capacity was observed, with fracture energies for infinite fatigue life reaching approximately 20% of their static loading capacity. This study sheds light on the deterioration of adhesive joints when exposed to a saline environment.

Tomosyn affects dense core vesicle composition but not exocytosis in mammalian neurons.

Tomosyn is a large, non-canonical SNARE protein proposed to act as an inhibitor of SNARE complex formation in the exocytosis of secretory vesicles. In the brain, tomosyn inhibits the fusion of synaptic vesicles (SVs), whereas its role in the fusion of neuropeptide-containing dense core vesicles (DCVs) is unknown. Here, we addressed this question using a new mouse model with a conditional deletion of tomosyn (Stxbp5) and its paralogue tomosyn-2 (Stxbp5l). We monitored DCV exocytosis at single vesicle resolution in tomosyn-deficient primary neurons using a validated pHluorin-based assay. Surprisingly, loss of tomosyns did not affect the number of DCV fusion events but resulted in a strong reduction of intracellular levels of DCV cargos, such as neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). BDNF levels were largely restored by re-expression of tomosyn but not by inhibition of lysosomal proteolysis. Tomosyn's SNARE domain was dispensable for the rescue. The size of the trans-Golgi network and DCVs was decreased, and the speed of DCV cargo flux through Golgi was increased in tomosyn-deficient neurons, suggesting a role for tomosyns in DCV biogenesis. Additionally, tomosyn-deficient neurons showed impaired mRNA expression of some DCV cargos, which was not restored by re-expression of tomosyn and was also observed in Cre-expressing wild-type neurons not carrying loxP sites, suggesting a direct effect of Cre recombinase on neuronal transcription. Taken together, our findings argue against an inhibitory role of tomosyns in neuronal DCV exocytosis and suggests an evolutionary conserved function of tomosyns in the packaging of secretory cargo at the Golgi.

Combinatorial selective ER-phagy remodels the ER during neurogenesis.

The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis: a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodeling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of ER and the role of individual ER-phagy receptors is limited. Here, we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodeling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodeling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodeling and versatile genetic toolkit provides a quantitative framework for understanding contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.

Plasma-Induced Surface Modification of Sapphire and Its Influence on Graphene Grown by Plasma-Enhanced Chemical Vapour Deposition.

In this work, we study the influence of the different surface terminations of c-plane sapphire substrates on the synthesis of graphene via plasma-enhanced chemical vapor deposition. The different terminations of the sapphire surface are controlled by a plasma process. A design of experiments procedure was carried out to evaluate the major effects governing the plasma process of four different parameters: i.e., discharge power, time, pressure and gas employed. In the characterization of the substrate, two sapphire surface terminations were identified and characterized by means of contact angle measurements, being a hydrophilic (hydrophobic) surface and the fingerprint of an Al- (OH-) terminated surface, respectively. The defects within the synthesized graphene were analyzed by Raman spectroscopy. Notably, we found that the ID/IG ratio decreases for graphene grown on OH-terminated surfaces. Furthermore, two different regimes related to the nature of graphene defects were identified and, depending on the sapphire terminated surface, are bound either to vacancy or boundary-like defects. Finally, studying the density of defects and the crystallite area, as well as their relationship with the sapphire surface termination, paves the way for increasing the crystallinity of the synthesized graphene.

Trigeminal neuralgia secondary to vascular compression and neurocysticercosis: illustrative case.

BACKGROUND: Trigeminal neuralgia (TN) is a frequent neurosurgical problem negatively influencing the quality of life of patients. The standard surgical treatment is microvascular decompression for primary cases and decompression of the mass effect, mainly tumors, for secondary cases. Neurocysticercosis (NCC) in the cerebellopontine angle is a rare etiology of TN. The authors report a case in which NCC cysts around the trigeminal nerve coexisted with a vascular loop, which compressed the exit of the trigeminal nerve from the pons. OBSERVATIONS: A 78-year-old woman presented with a 3-year history of persistent severe pain in the left side of her face, refractory to medical treatment. On gadolinium-enhanced magnetic resonance imaging, cystic lesions were observed around the left trigeminal nerve and a vascular loop was also present and in contact with the nerve. A retrosigmoid approach for cyst excision plus microvascular decompression of the trigeminal nerve was successfully performed. There were no complications. The patient was discharged without facial pain. LESSONS: Albeit rare, TN secondary to NCC cysts should be considered in the differential diagnosis in NCC-endemic regions. In this case, the cause of the neuralgia was probably both problems, because when both were treated, the patient improved.

Micronuclei in embryos of eight seabird species in northwestern Mexico: A biomarker of exposure to coastal pollution?

The micronucleus (MN) test may be used to evaluate genome instability in birds and the potential of different species to function as biomarkers of genotoxicity. However, little is known regarding genome instability in seabird embryos or the instability present among embryonic development stages. Therefore, the present study aimed to describe the frequencies of micronucleated erythrocytes (MNE) and micronucleated polychromatic erythrocytes (MNPCE) in blood samples collected from the embryos of eight seabird species nesting on the coast of Sinaloa, Mexico. An additional description of blood cell maturation along with embryo development during incubation was conducted based on the proportion of polychromatic erythrocytes (PCE), and the potential relationships between metals (Hg and Cd concentrations in egg content) and the MN frequencies in embryo blood were evaluated. The PCE proportion appears to decline as incubation advances (initial stage > intermediate stage > advanced stage), and the values varied between species (Suliformes/Pelecaniformes < Charadriiformes: Laridae), which may be related to differences among incubation periods and reproductive strategies. Interspecific variation in the MNPCE frequency was found in embryos showing advanced development, which could be related to both variations in life-history traits and ecological factors and not Hg or Cd exposure. The genomic instability values in this study are the first to be reported for embryos of seabird species nesting in a subtropical coastal region.

[Analysis of the relationship between ambient air pollution and the severity of heart failure decompensations in two Spanish metropolises (Barcelona and Madrid)]. / Análisis de la relación entre la contaminación del aire ambiente y la gravedad de las descompensaciones por insuficiencia cardiaca en dos metrópolis españolas (Barcelona y Madrid).

OBJECTIVES: To analyze whether the high levels of air pollutants are related to a greater severity of decompensated heart failure (HF). METHOD: Patients diagnosed with decompensated HF in the emergency department of 4 hospitals in Barcelona and 3 in Madrid were included. Clinical data (age, sex, comorbidities, baseline functional status), atmospheric (temperature, atmospheric pressure) and pollutant data (SO2, NO2, CO, O3, PM10, PM2.5) were collected in the city on the day of emergency care. The severity of decompensation was estimated using 7-day mortality (primary indicator) and the need for hospitalization, in-hospital mortality, and prolonged hospitalization (secondary indicators). The association adjusted for clinical, atmospheric and city data between pollutant concentration and severity was investigated using linear regression (linearity assumption) and restricted cubic spline curves (no linearity assumption). RESULTS: A total of 5292 decompensations were included, with a median age of 83 years (IQR=76-88) and 56% women. The medians (IQR) of the daily pollutant averages were: SO2=2.5µg/m3 (1.4-7.0), NO2=43µg/m3 (34-57), CO=0.48mg/m3 (0.35-0.63), O3=35µg/m3 (25-48), PM10=22µg/m3 (15-31) and PM2.5=12µg/m3 (8-17). Mortality at 7 days was 3.9%, and hospitalization, in-hospital mortality, and prolonged hospitalization were 78.9, 6.9, and 47.5%, respectively. SO2 was the only pollutant that showed a linear association with the severity of decompensation, since each unit of increase implied an OR for the need for hospitalization of 1.04 (95% CI 1.01-1.08). The restricted cubic spline curves study also did not show clear associations between pollutants and severity, except for SO2 and hospitalization, with OR of 1.55 (95% CI 1.01-2.36) and 2.71 (95% CI 1.13-6.49) for concentrations of 15 and 24µg/m3, respectively, in relation to a reference concentration of 5µg/m3. CONCLUSION: Exposure to ambient air pollutants, in a medium to low concentration range, is generally not related to the severity of HF decompensations, and only SO2 may be associated with an increased need for hospitalization.

Cluster analysis and forecasting of viruses incidence growth curves: Application to SARS-CoV-2.

The sanitary emergency caused by COVID-19 has compromised countries and generated a worldwide health and economic crisis. To provide support to the countries' responses, numerous lines of research have been developed. The spotlight was put on effectively and rapidly diagnosing and predicting the evolution of the pandemic, one of the most challenging problems of the past months. This work contributes to the existing literature by developing a two-step methodology to analyze the transmission rate, designing models applied to territories with similar pandemic behavior characteristics. Virus transmission is considered as bacterial growth curves to understand the spread of the virus and to make predictions about its future evolution. Hence, an analytical clustering procedure is first applied to create groups of locations where the virus transmission rate behaved similarly in the different outbreaks. A curve decomposition process based on an iterative polynomial process is then applied, obtaining meaningful forecasting features. Information of the territories belonging to the same cluster is merged to build models capable of simultaneously predicting the 14-day incidence in several locations using Evolutionary Artificial Neural Networks. The methodology is applied to Andalusia (Spain), although it is applicable to any region across the world. Individual models trained for a specific territory are carried out for comparison purposes. The results demonstrate that this methodology achieves statistically similar, or even better, performance for most of the locations. In addition to being extremely competitive, the main advantage of the proposal lies in its complexity cost reduction. The total number of parameters to be estimated is reduced up to 93.51% for the short term and 93.31% for the mid-term forecasting, respectively. Moreover, the number of required models is reduced by 73.53% and 58.82% for the short- and mid-term forecasting horizons.

Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders.

Autism spectrum disorders (ASDs) have been linked to genes with enriched expression in the brain, but it is unclear how these genes converge into cell-type-specific networks. We built a protein-protein interaction network for 13 ASD-associated genes in human excitatory neurons derived from induced pluripotent stem cells (iPSCs). The network contains newly reported interactions and is enriched for genetic and transcriptional perturbations observed in individuals with ASDs. We leveraged the network data to show that the ASD-linked brain-specific isoform of ANK2 is important for its interactions with synaptic proteins and to characterize a PTEN-AKAP8L interaction that influences neuronal growth. The IGF2BP1-3 complex emerged as a convergent point in the network that may regulate a transcriptional circuit of ASD-associated genes. Our findings showcase cell-type-specific interactomes as a framework to complement genetic and transcriptomic data and illustrate how both individual and convergent interactions can lead to biological insights into ASDs.

Epitaxial growth of crystal phase quantum dots in III-V semiconductor nanowires.

Crystal phase quantum dots (QDs) are formed during the axial growth of III-V semiconductor nanowires (NWs) by stacking different crystal phases of the same material. In III-V semiconductor NWs, both zinc blende (ZB) and wurtzite (WZ) crystal phases can coexist. The band structure difference between both crystal phases can lead to quantum confinement. Thanks to the precise control in III-V semiconductor NW growth conditions and the deep knowledge on the epitaxial growth mechanisms, it is nowadays possible to control, down to the atomic level, the switching between crystal phases in NWs forming the so-called crystal phase NW-based QDs (NWQDs). The shape and size of the NW bridge the gap between QDs and the macroscopic world. This review is focused on crystal phase NWQDs based on III-V NWs obtained by the bottom-up vapor-liquid-solid (VLS) method and their optical and electronic properties. Crystal phase switching can be achieved in the axial direction. In contrast, in the core/shell growth, the difference in surface energies between different polytypes can enable selective shell growth. One reason for the very intense research in this field is motivated by their excellent optical and electronic properties both appealing for applications in nanophotonics and quantum technologies.

Assessing metal(loid)s concentrations and biomarkers in tilapia (Oreochromis niloticus) and largemouth bass (Micropterus salmoides) of three ecosystems of the Yaqui River Basin, Mexico.

Aquatic ecosystems have been suffering deleterious effects due to the development of different economic activities. Metal(loid)s are one of the most persistent chemicals in environmental reservoirs, and may produce adverse effects on different organisms. Since fishes have been largely used in studies of metal(loid)s exposure, tilapia and largemouth bass were collected in three ecosystems from the Yaqui River Basin to measure the concentrations of metal(loid)s (chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), zinc (Zn) arsenic (As), mercury (Hg), and selenium (Se)) and some biomarkers (somatic indices, metallothionein expression and histopathological analysis) in tissues of both species. Metal(loid) concentrations varied seasonally among ecosystems in tissues of both species. The elements varied seasonally and spatially in tissues of both species, with a general distribution of liver > gills > gonads. Also, biomarkers showed variations indicative that the fish species were exposed to different environmental stressor conditions. The highest values of some biomarkers were in largemouth bass, possibly due to differences in their biological characteristics, mainly feeding habits. The multivariate analysis showed positive associations between metal(loid)s and biomarkers, which are usually associated to the use of these elements in metabolic and/or regulatory physiological processes. Both fish species presented histological damage at different levels, from SI types (changes that are reversible for organ structure) to SII types (changes that are more severe but may be repairable). Taken together, the results from this study suggest that the Yaqui River Basin is moderately impacted by metals and metalloids.

Multi-and transgenerational synergistic effects of glyphosate and chlorpyrifos at environmentally relevant concentrations in the estuarine rotifer Proales similis.

We evaluated the multi-and transgenerational effects of single and combined environmentally relevant concentrations of glyphosate (GLY) and chlorpyrifos (CPF) in the estuarine rotifer Proales similis. The acute and chronic toxicities of GLY and CPF were determined as individual compounds and as a mixture. Rotifers were exposed to environmental concentrations of GLY (1, 10, 100, and 1000 µg/L) and CPF (0.1, 1, 5, and 10 µg/L). The main findings were as follows: (i) the LC50 values were 33.91 mg/L (GLY) and 280 µg/L (CPF); (ii) the toxic unit (TU50) of the mixture was 0.30, corresponding to 10.17 mg/L GLY and 83 µg/L CPF; (iii) the multigenerational study indicated that the tested concentrations of GLY and CPF, both single and combined, significantly and consistently decreased the growth rates of P. similis from the F0 to F6 generations; (iv) in most cases, GLY and CPF mixtures induced a strong synergistic effect; and (v) transgenerational effects were detected in the F4 generation, especially GLY and CPF in higher equitoxic proportions. These effects seem to dissipate in F5. Across multigeneration, a slight recovery could indicate population resilience to pollution. Our findings suggest that a mixture of GLY and CPF at environmental concentrations is likely to occur under real field conditions, increasing the risk to marine and estuarine invertebrates such as rotifers.

Excessive proteostasis contributes to pathology in fragile X syndrome.

In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1-/y) neurons. Surprisingly, although we find a significant increase in protein degradation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects excessive hippocampal protein synthesis and hyperactivation of neurons in the inferior colliculus (IC) in response to auditory stimulation. Moreover, systemic administration of bortezomib significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1-/y mouse, as does genetic reduction of proteasome, specifically in the IC. Together, these results identify excessive activation of the UPS pathway in Fmr1-/y neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention.

Influence of Meteorological Temperature and Pressure on the Severity of Heart Failure Decompensations.

OBJECTIVE: To investigate the relationship between ambient temperature and atmospheric pressure (AP) and the severity of heart failure (HF) decompensations. METHODS: We analysed patients coming from the Epidemioloy Acute Heart Failure Emergency (EAHFE) Registry, a multicentre prospective cohort study enrolling patients diagnosed with decompensated HF in 26 emergency departments (EDs) of 16 Spanish cities. We recorded patient and demographic data and maximum temperature (Tmax) and AP (APmax) the day before ED consultation. Associations between temperature and AP and severity endpoints were explored by logistic regression. We used restricted cubic splines to model continuous non-linear associations of temperature and AP with each endpoint. RESULTS: We analysed 16,545 patients. Daily Tmax and APmax (anomaly) of the day before patient ED arrival ranged from 0.8 to 41.6° and from - 61.7 to 69.9 hPa, respectively. A total of 12,352 patients (75.2%) were hospitalised, with in-hospital mortality in 1171 (7.1%). The probability of hospitalisation by HF decompensation showed a U-shaped curve versus Tmax and an increasing trend versus APmax. Regarding temperature, hospitalisation significantly increased from 20 °C (reference) upwards (25 °C: OR = 1.12, 95% CI = 1.04-1.21; 40 °C: 1.65, 1.13-2.40) and below 5.4 °C (5 °C: 1.21, 1.01-1.46). Concerning the mean AP of the city (anomaly = 0 hPa), hospitalisation increased when APmax (anomaly) was above + 7.0 hPa (atmospheric anticyclone; + 10 hPa: 1.14, 1.05-1.24; + 30 hPa: 2.02. 1.35-3.03). The lowest probability of mortality also corresponded to cold-mild temperatures and low AP, with a significant increased risk only found for Tmax above 24.3 °C (25 °C: 1.13, 1.01-1.27; 40 °C: 2.05, 1.15-3.64) and APmax (anomaly) above + 3.4 hPa (+ 10 hPa: 1.21, 1.07-1.36; + 30 hPa: 1.73, 1.06-2.81). Sensitivity analysis confirmed the main analysis results. CONCLUSION: Temperature and AP are independently associated with the severity of HF decompensations, with possible different effects on the need for hospitalisation and in-hospital mortality.