Interplay of Postprandial Triglyceride-Rich Lipoprotein Composition and Adipokines in Obese Adolescents.

In the context of the alarming rise of infant obesity and its health implications, the present research aims to uncover disruptions in postprandial lipid metabolism and the composition of triglyceride-rich lipoproteins in obese adolescents. A double-blind, controlled clinical trial in the postprandial phase on 23 adolescents aged 12 to 16 years was carried out. Twelve participants were categorized as obese (BMI > 30 kg/m2 and percentile > 95) and 11 as normal-weight (BMI = 20-25 kg/m2, percentile 5-85). Blood samples were collected after a 12-h overnight fast and postprandially after consumption of a standardized breakfast containing olive oil, tomato, bread, orange juice, and skimmed milk. Obese adolescents exhibited elevated triglyceride concentrations in both fasting and postprandial states and higher TG/apo-B48 ratios, indicating larger postprandial triglyceride-rich lipoprotein (TRL) particle size, which suggests impaired clearance. Obese subjects also exhibited higher n-6 PUFA concentrations, potentially linked to increased TRL hydrolysis and the release of pro-inflammatory adipokines. In contrast, TRL from normal-weight individuals showed higher concentrations of oleic acid and DHA (n-3 PUFA), with possible anti-inflammatory effects. The results indicate an interplay involving postprandial TRL metabolism and adipokines within the context of adolescent obesity, pointing to potential cardiovascular implications in the future.

AHP algorithm used to select suitable abandoned underground mines for energy storage infrastructure - iCAES technology. A specific case study for León (Spain).

In the energy transition, the promotion of renewable sources entails the development of storage technologies to manage the mismatch between energy production and demand. In this scenario, the use of CAES (Compressed Air Energy Storage) technology enables the efficient and cost-effective storage of large amounts of energy. However, this technology is developed in salt domes who have an inherent risk associated of underground exploration phase. To address this, we propose to develop an infrastructure (iCAES) in abandoned underground mines, where the exploration phase is completed and well known. For its implementation, this paper defines a structure hierarchization method gathers the technical and socio-economic criteria. It involves a multi-criteria problem, and the correct selection of the location must be based on specific mathematical algorithms. For this case the Analytic Hierarchy Process (AHP) from multi-criteria decision making (MCDM) methods allows quantified by means of a scientific and mathematical scale and the assignment of weights, so that it is possible to evaluate different alternatives. This is possible thanks to the application of the AHP model in absolute terms. The information gathering has been based on the specific case study of coal basins in the north of Spain, in the region of León. Considering the proposed methodology, the most suitable alternative locations to implement iCAES in the region of León were identified.

Bioavailability and systemic transport of oleanolic acid in humans, formulated as a functional olive oil.

Evidence of the pharmacological activity of oleanolic acid (OA) suggests its potential therapeutic application. However, its use in functional foods, dietary supplements, or nutraceuticals is hindered by limited human bioavailability studies. The BIO-OLTRAD trial is a double-blind, randomized controlled study with 22 participants that received a single dose of 30 mg OA formulated as a functional olive oil. The study revealed that the maximum serum concentration of OA ranged from 500 to 600 ng mL-1, with an AUC0-∞ value of 2862.50 ± 174.50 ng h mL-1. Furthermore, we discovered a physiological association of OA with serum albumin and triglyceride-rich lipoproteins (TRL). UV absorption spectra showed conformational changes in serum albumin due to the formation of an adduct with OA. Additionally, we demonstrated that TRL incorporate OA, reaching a maximum concentration of 140 ng mL-1 after 2-4 hours. We conjecture that both are efficient carriers to reach target tissues and to yield high bioavailability.

Muscle and Bone Health in Young Chilean Adults with Phenylketonuria and Different Degrees of Compliance with the Phenylalanine Restricted Diet.

There are concerns about muscle and bone health in patients with Phenylketonuria (PKU). Our aim was to compare muscle mass, function, and bone health among young adults with PKU who maintained or suspended dietary treatment. METHODS: Three groups were considered-PKU-1: 10 patients who used a protein substitute (PS) without phenylalanine (Phe); PKU-2: 14 patients who used the PS without Phe until eighteen years old and then practiced mostly a vegan diet; and 24 matched healthy controls. A 24 h recall survey, blood parameters, body composition and bone mineral density through DEXA, rectus femoris thickness by ultrasound, hand grip strength, submaximal exercise test, and walking speed were assessed. RESULTS: PKU-1 patients had lower hand grip strength than their matched controls, but no other differences. Compared to controls, the PKU-2 group had lower fat-free mass (p = 0.01), less spine and femoral bone mineral density (p = 0.04 and p < 0.01, respectively), and peak workload on the incremental test (p = 0.03). When comparing PKU groups, blood Phe levels were significantly lower in the PKU-1 group (p = 0.02). CONCLUSIONS: Among PKU patients, abandoning the dietary treatment and maintaining high blood Phe concentrations could be deleterious for muscles and bones. However, we cannot discard other causes of bone and muscle damage in these patients.

Transcriptomic Analysis Reveals JAK2/MPL-Independent Effects of Calreticulin Mutations in a C. elegans Model.

There is growing evidence that Ph-negative myeloproliferative neoplasms (MPNs) are disorders in which multiple molecular mechanisms are significantly disturbed. Since their discovery, CALR driver mutations have been demonstrated to trigger pathogenic mechanisms apart from the well-documented activation of JAK2/MPL-related pathways, but the lack of experimental models harboring CALR mutations in a JAK2/MPL knockout background has hindered the research on these non-canonical mechanisms. In this study, CRISPR/Cas9 was performed to introduce homozygous patient-like calreticulin mutations in a C. elegans model that naturally lacks JAK2 and MPL orthologs. Whole-genome transcriptomic analysis of these worms was conducted, and some of the genes identified to be associated with processes involved in the pathogenesis of MPNs were further validated by qPCR. Some of the transcriptomic alterations corresponded to typically altered genes and processes in cancer and Ph-negative MPN patients that are known to be triggered by mutant calreticulin without the intervention of JAK2/MPL. However, interestingly, we have also found altered other processes described in these diseases that had not been directly attributed to calreticulin mutations without the intervention of JAK2 or MPL. Thus, these results point to a new experimental model for the study of the JAK2/MPL-independent mechanisms of mutant calreticulin that induce these biological alterations, which could be useful to study unknown non-canonical effects of the mutant protein. The comparison with a calreticulin null strain revealed that the alteration of all of these processes seems to be a consequence of a loss of function of mutant calreticulin in the worm, except for the dysregulation of Hedgehog signaling and flh-3. Further analysis of this model could help to delineate these mechanisms, and the verification of these results in mammalian models may unravel new potential therapeutic targets in MPNs. As far as we know, this is the first time that a C. elegans strain with patient-like mutations is proposed as a potential model for leukemia research.

Heparin versus 0.9% sodium chloride locking for prevention of occlusion in central venous catheters in adults.

BACKGROUND: Intermittent locking of central venous catheters (CVCs) is undertaken to help maintain their patency and performance. There are systematic variations in care: some practitioners use heparin (at different concentrations), whilst others use 0.9% sodium chloride (normal saline). This review looks at the effectiveness and safety of intermittent locking with heparin compared to normal saline, to see if the evidence establishes whether one is better than the other. This is an update of an earlier Cochrane Review. OBJECTIVES: To evaluate the benefits and harms of intermittent locking of CVCs with heparin versus normal saline in adults to prevent occlusion. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 20 October 2021. SELECTION CRITERIA: We included randomised controlled trials in adults ≥ 18 years of age with a CVC that compared intermittent locking with heparin at any concentration versus normal saline. We excluded studies on infants and children from this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were occlusion of CVCs and duration of catheter patency. Our secondary outcomes were CVC-related bloodstream infections and CVC-related colonisation, mortality, haemorrhage, heparin-induced thrombocytopaenia, CVC-related thrombosis, number of additional CVC insertions, abnormality of coagulation profile and allergic reactions to heparin. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified one new RCT with 30 participants for this update. We included a total of 12 RCTs with 2422 participants. Data for meta-analysis were available from all RCTs. We noted differences in methods used by the included studies and variation in heparin concentrations (10 to 5000 IU/mL), time to follow-up (1 to 251.8 days), and the unit of analysis used (participant, catheter, line access). Five studies included ICU (intensive care unit) patients, two studies included oncology patients, and the remaining studies included miscellaneous patients (chronic kidney disease, haemodialysis, home care patients, etc.). Primary outcomes Overall, combined results may show fewer occlusions with heparin compared to normal saline but this is uncertain (risk ratio (RR) 0.70, 95% confidence interval (CI) 0.51 to 0.95; 10 studies; 1672 participants; low-certainty evidence). We pooled studies that used participant or catheter as the unit of analysis. We carried out subgroup analysis by unit of analysis. No clear differences were detected after testing for subgroup differences (P = 0.23). We found no clear evidence of a difference in the duration of catheter patency with heparin compared to normal saline (mean difference (MD) 0.44 days, 95% CI -0.10 to 0.99; 6 studies; 1788 participants; low-certainty evidence). Secondary outcomes We found no clear evidence of a difference in the following outcomes: CVC-related bloodstream infections (RR 0.66, 95% CI 0.08 to 5.80; 3 studies; 1127 participants; very low-certainty evidence); mortality (RR 0.76, 95% CI 0.44 to 1.31; 3 studies; 1100 participants; very low-certainty evidence); haemorrhage (RR 1.54, 95% CI 0.41 to 5.74; 3 studies; 1197 participants; very low-certainty evidence); or heparin-induced thrombocytopaenia (RR 0.21, 95% CI 0.01 to 4.27; 3 studies; 443 participants; very low-certainty evidence). The main reasons for downgrading the certainty of evidence for the primary and secondary outcomes were unclear allocation concealment, suspicion of publication bias, imprecision and inconsistency. AUTHORS' CONCLUSIONS: Given the low-certainty evidence, we are uncertain whether intermittent locking with heparin results in fewer central venous catheter occlusions than intermittent locking with normal saline in adults. Low-certainty evidence suggests that heparin may have little or no effect on catheter patency duration. Although we found no evidence of differences in safety (CVC-related bloodstream infections, mortality, or haemorrhage), the combined studies were not powered to detect rare adverse events such as heparin-induced thrombocytopaenia. Further research conducted over longer periods would reduce the current uncertainties.

NXN Gene Epigenetic Changes in an Adult Neurogenesis Model of Alzheimer's Disease.

In view of the proven link between adult hippocampal neurogenesis (AHN) and learning and memory impairment, we generated a straightforward adult neurogenesis in vitro model to recapitulate DNA methylation marks in the context of Alzheimer's disease (AD). Neural progenitor cells (NPCs) were differentiated for 29 days and Aß peptide 1-42 was added. mRNA expression of Neuronal Differentiation 1 (NEUROD1), Neural Cell Adhesion Molecule 1 (NCAM1), Tubulin Beta 3 Class III (TUBB3), RNA Binding Fox-1 Homolog 3 (RBFOX3), Calbindin 1 (CALB1), and Glial Fibrillary Acidic Protein (GFAP) was determined by RT-qPCR to characterize the culture and framed within the multistep process of AHN. Hippocampal DNA methylation marks previously identified in Contactin-Associated Protein 1 (CNTNAP1), SEPT5-GP1BB Readthrough (SEPT5-GP1BB), T-Box Transcription Factor 5 (TBX5), and Nucleoredoxin (NXN) genes were profiled by bisulfite pyrosequencing or bisulfite cloning sequencing; mRNA expression was also measured. NXN outlined a peak of DNA methylation overlapping type 3 neuroblasts. Aß-treated NPCs showed transient decreases of mRNA expression for SEPT5-GP1BB and NXN on day 9 or 19 and an increase in DNA methylation on day 29 for NXN. NXN and SEPT5-GP1BB may reflect alterations detected in the brain of AD human patients, broadening our understanding of this disease.

Microbial Decontamination of Bee Pollen by Direct Ozone Exposure.

The bee pollen is a complete and healthy food with important nutritional properties. Usually, bee pollen is consumed dehydrated, but it is possible to market it as fresh frozen pollen, favoring the maintenance of its properties and greatly increasing its palatability, compared to dried pollen. However, fresh frozen pollen maintains a high microbiological load that can include some pathogenic genus to human health. In this work, ozonation combined with drying is applied to reduce the microbiological load. The lowest timing exposure to ozone (30 min) was chosen together with hot-air drying during 15 min to evaluate the shelf-life of treated bee-pollen under cold storage (4 °C), and initial reductions of 3, 1.5, and 1.7 log cycles were obtained for Enterobacteriaceae, mesophilic aerobes, and molds and yeasts counting, respectively. Six weeks after treatment the microbial load was held at a lower level than initially observed in fresh bee-pollen. In addition, ozone treatment did not have a negative impact on the polyphenols evaluated. Likewise, the sensory profile of the bee pollen under different treatments was studied. For all these assays the results have been favorable, so we can say that ozonation of fresh pollen is safe for human consumption, which maintains its polyphenols composition and organoleptically is better valued than dried pollen.

[Hepatic glycogen storage diseases: Symptoms, management and associated mutations]. / Enfermedades por depósito de glucógeno hepático: Clínica, manejo y mutaciones asociadas.

Glycogen storage diseases (GSD) are rare diseases derived from altered glycogen metabolism. This leads to glycogen storage in different organs such as muscle, kidney, and liver, resulting in a variety of clinical manifestations. GSD with liver involvement are classified into types I, III, IV, VI, and IX, depending on the enzymes affected. They are clinically characterized by hypoglycemia and hepato megaly as cardinal signs. Their diagnosis is initially based on clinical manifestations and laboratory test results. Nevertheless, diagnostic certainty requires a genetic study that identifies the specific mutation. Multiple mutations have been associated with each GSD. In Chile, since patients often lack the genetic study, the GSD genetic local characteristics are unknown. The treatment is based on dietary restrictions modulated according to the identified mutation. Today, the international consen sus indicates that early diagnosis allows better metabolic control and improves the patient's quality of life and prognosis. In this review, the information on GSD with liver involvement is updated to optimize the diagnosis, treatment, and follow-up of these patients, emphasizing specific nutritional and gastroenterological management.

The Mitochondrial Na+/Ca2+ Exchanger Inhibitor CGP37157 Preserves Muscle Structure and Function to Increase Lifespan and Healthspan in Caenorhabditis elegans.

We have reported recently that the mitochondrial Na+/Ca2+ exchanger inhibitor CGP37157 extends lifespan in Caenorhabditis elegans by a mechanism involving mitochondria, the TOR pathway and the insulin/IGF1 pathway. Here we show that CGP37157 significantly improved the evolution with age of the sarcomeric regular structure, delaying development of sarcopenia in C. elegans body wall muscle and increasing the average and maximum speed of the worms. Similarly, CGP37157 favored the maintenance of a regular mitochondrial structure during aging. We have also investigated further the mechanism of the effect of CGP37157 by studying its effect in mutants of aak-1;aak-2/AMP-activated kinase, sir-2.1/sirtuin, rsks-1/S6 kinase and daf-16/FOXO. We found that this compound was still effective increasing lifespan in all these mutants, indicating that these pathways are not involved in the effect. We have then monitored pharynx cytosolic and mitochondrial Ca2+ signalling and our results suggest that CGP37157 is probably inhibiting not only the mitochondrial Na+/Ca2+ exchanger, but also Ca2+ entry through the plasma membrane. Finally, a transcriptomic study detected that CGP37157 induced changes in lipid metabolism enzymes and a four-fold increase in the expression of ncx-6, one of the C. elegans mitochondrial Na+/Ca2+ exchangers. In summary, CGP37157 increases both lifespan and healthspan by a mechanism involving changes in cytosolic and mitochondrial Ca2+ homeostasis. Thus, Ca2+ signalling could be a promising target to act on aging.

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile.

Maple urine syrup disease (MSUD) is an autosomal recessive disorder characterized by deficient activity of the branched-chain alpha ketoacid dehydrogenase (BCKAD) enzymatic complex due to biallelic variants in the alpha (BCKDHA) or beta (BCKDHB) subunits or the acyltransferase component (DBT). Treatment consists in leucine (LEU), isoleucine (ILE), and valine (VAL) (branched-chain amino acids) dietary restriction and strict metabolic control. to determine the characteristics of the Chilean cohort with MSUD currently in follow-up at Instituto de Nutrición y Tecnología de los Alimentos, during the 1990-2017 period Retrospective analytical study in 45 MSUD cases. Measured: biochemical parameters (LEU, ILE, and VAL), anthropometric evaluation, and neurocognitive development. In 18 cases undergoing genetic study were analyzed according to the gene and protein location, number of affected alleles, and type of posttranslational modification affected. Then, 45 patients with MSUD diagnosis were identified during the period: 37 were alive at the time of the study. Average diagnosis age was 71 ± 231 days. Average serum diagnosis LEU concentrations: 1.463 ± 854.1 µmol/L, VAL 550 ± 598 µmol/L and ILE 454 ± 458 µmol/L. BCKDHB variants explain 89% cases, while BCKDHA and DBT variants explain 5.5% of cases each. Variants p.Thr338Ile in BCKDHA, p.Pro240Thr and p.Ser342Asn in BCKDHB have not been previously reported in literature. Average serum follow-up LEU concentrations were 252.7 ± 16.9 µmol/L in the <5 years group and 299 ± 123.2 µmol/L in ≥5 years. Most cases presented some degree of developmental delay. Early diagnosis and treatment is essential to improve the long-term prognosis. Frequent blood LEU measurements are required to optimize metabolic control and to establish relationships between different aspects analyzed.

Expanded Newborn Screening and Genomic Sequencing in Latin America and the Resulting Social Justice and Ethical Considerations.

Newborn screening (NBS) has widely been utilized in developed countries as a cost-effective public health strategy that reduces morbidity and mortality. Developing countries, however, are new to the NBS scene and have their own unique challenges, both in instituting the program as well as effectively acting on the results. NBS offers numerous ethical issues on a global scale, however, here we argue that there are unique ethical issues surrounding the development and expansion of newborn screening in Latin America given its highly heterogenous population. Once a NBS program is effectively instated, ethical considerations continue when pursuing expansion of screening to include further conditions. While Latin America grapples with the ethics of expanded newborn screening (ENBS), some developed countries discuss utility of genomic sequencing technologies in the newborn population. When the ability to detect further pathology is expanded, one must know what to do with this information. As rare diseases are identified either on ENBS or via genome sequencing, access to treatments for these rare diseases can be a real challenge. If we consider newborn screening as a global initiative, then we need more than a deontology approach to analyze these challenges; we need an approach that considers the unique characteristics of each territory and tremendous heterogeneity that exists prior to the implementation of these programs. As genomic technology advances further in the developed world, while some developing countries still lack even basic newborn screening, there is a further widening of the gap in global health disparities. The question is posed as to who has responsibility for these newborns' lives on an international level. Without an approach towards newborn screening that accounts for the diverse global population, we believe optimal outcomes for newborns and families across the world will not be achieved.

A conserved cysteine-based redox mechanism sustains TFEB/HLH-30 activity under persistent stress.

Mammalian TFEB and TFE3, as well as their ortholog in Caenorhabditis elegans HLH-30, play an important role in mediating cellular response to a variety of stress conditions, including nutrient deprivation, oxidative stress, and pathogen infection. In this study, we identify a novel mechanism of TFEB/HLH-30 regulation through a cysteine-mediated redox switch. Under stress conditions, TFEB-C212 undergoes oxidation, allowing the formation of intermolecular disulfide bonds that result in TFEB oligomerization. TFEB oligomers display increased resistance to mTORC1-mediated inactivation and are more stable under prolonged stress conditions. Mutation of the only cysteine residue present in HLH-30 (C284) significantly reduced its activity, resulting in developmental defects and increased pathogen susceptibility in worms. Therefore, cysteine oxidation represents a new type of TFEB post-translational modification that functions as a molecular switch to link changes in redox balance with expression of TFEB/HLH-30 target genes.

Clinical and Nutritional Evolution of 24 Patients with Glutaric Aciduria Type 1 in Follow-up at a Center Specialized in Inborn Errors of Metabolism in Chile

Abstract Introduction: Glutaric Aciduria Type 1 (GA-1) is produced by the enzymatic deficiency of glutaryl-CoA-dehydrogenase (GCDH), leading to the accumulation of glutaric acid (GA). 90% of patients without early treatment present acute encephalopathic crisis (AEC), followed by disabling neurological symptoms. The treatment consists of a low lysine (Lys) diet, protein substitute lys-free, tryptophan-reduced (PS) and L-carnitine. Objectives: Describe the clinical and nutritional evolution of a cohort of GA-1 patients at a national referral center in Chile. Methodology: Retrospective study of 24 patients diagnosed with GA-1 between 1998-2020 and referred to the Institute of Nutrition and Food Technology (INTA) of University of Chile. Results: Age at diagnosis was 19±27 months; 10/24 presented AEC and neurological sequelae. The cases without AEC (14/24) 8 presented neurological compromise: psychomotor development delay, abnormal movements and pyramidal syndrome. Nutritional evaluation: 12/24 were malnourished by deficiency, <6 years old group (12/24): 11 cases were found to have Lys and PS, ≥6 years old (12/24): 9/12 did not receive PS. All had normal free carnitine levels. Conclusion: GA-1 has variable symptoms with neurological involvement AEC or insidious start. Is essential to maintain a long-term follow-up and consider its inclusion in neonatal screening programs.

Case report: Maternal tyrosinemia type 1a under NTBC treatment with tyrosine- and phenylalanine restricted diet in Chile.

We report the case of a 17-year-old girl with Tyrosinemia type 1a who carried a planned pregnancy to term while being under 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone) treatment and a tyrosine- and phenylalanine-restricted diet. She was on treatment since 2 months of age with poor metabolic control prior to her pregnancy (tyrosine 838 ± 106 umol/L). NTBC and a low tyrosine and phenylalanine diet were continued during her pregnancy. She unfortunately suffered from urinary tract infection and anemia during her pregnancy, with median plasma tyrosine and phenylalanine levels of 613 ± 106 umol/L (200-400 umol/L) and 40.2 ± 8 umol/L (35-90 umol/L), respectively. After 40 weeks of gestation, the patient gave birth to a healthy boy, with no adverse effects related to the use of NTBC. The newborn presented with a transitory elevation of plasma tyrosine levels and normal phenylalanine, methionine, and succinylacetone levels. By 12 months of age, the child was determined to have normal psychomotor development. At 20 months old, he was diagnosed with a mild developmental delay; however, global cognitive evaluation with the Wechsler Intelligence Scale for Children (WISC) test at 5 years old showed normal performance. Here, we discuss one of the few reported cases of nitisinone treatment during pregnancy and demonstrate a lack of teratogenicity and long-term cognitive disabilities.

4D Microscopy: Unraveling Caenorhabditis elegans Embryonic Development Using Nomarski Microscopy.

4D microscopy is an invaluable tool for unraveling the embryonic developmental process in different animals. Over the last decades, Caenorhabditis elegans has emerged as one of the best models for studying development. From an optical point of view, its size and transparent body make this nematode an ideal specimen for DIC (Differential Interference Contrast or Nomarski) microscopy. This article illustrates a protocol for growing C. elegans nematodes, preparing and mounting their embryos, performing 4D microscopy and cell lineage tracing. The method is based on multifocal time-lapse records of Nomarski images and analysis with specific software. This technique reveals embryonic developmental dynamics at the cellular level. Any embryonic defect in mutants, such as problems in spindle orientation, cell migration, apoptosis or cell fate specification, can be efficiently detected and scored. Virtually every single cell of the embryo can be followed up to the moment the embryo begins to move. Tracing the complete cell lineage of a C. elegans embryo by 4D DIC microscopy is laborious, but the use of specific software greatly facilitates this task. In addition, this technique is easy to implement in the lab. 4D microscopy is a versatile tool and opens the possibility of performing an unparalleled analysis of embryonic development.

Reduction of mRNA export unmasks different tissue sensitivities to low mRNA levels during Caenorhabditis elegans development.

Animal development requires the execution of specific transcriptional programs in different sets of cells to build tissues and functional organs. Transcripts are exported from the nucleus to the cytoplasm where they are translated into proteins that, ultimately, carry out the cellular functions. Here we show that in Caenorhabditis elegans, reduction of mRNA export strongly affects epithelial morphogenesis and germline proliferation while other tissues remain relatively unaffected. Epithelialization and gamete formation demand a large number of transcripts in the cytoplasm for the duration of these processes. In addition, our findings highlight the existence of a regulatory feedback mechanism that activates gene expression in response to low levels of cytoplasmic mRNA. We expand the genetic characterization of nuclear export factor NXF-1 to other members of the mRNA export pathway to model mRNA export and recycling of NXF-1 back to the nucleus. Our model explains how mutations in genes involved in general processes, such as mRNA export, may result in tissue-specific developmental phenotypes.

Cooking a Research Project: New Trends in the Kitchen and in Scientific Policies.

The culture of chefs from the world's best restaurants is substituted by new trends paradigmatically epitomized by the TV program Masterchef. The authors feel that a similar transformation affects modern research. Recent scientific policies constrict the design of research grants with the aim of short-term maximization of the monetary value generated by the researcher.

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation.

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans loss-of-function mutants for the glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human, as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH-depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.

Disruption of the Caenorhabditis elegans Integrator complex triggers a non-conventional transcriptional mechanism beyond snRNA genes.

Gene expression is generally regulated by recruitment of transcription factors and RNA polymerase II (RNAP II) to specific sequences in the gene promoter region. The Integrator complex mediates processing of small nuclear RNAs (snRNAs) as well as the initiation and release of paused RNAP II at specific genes in response to growth factors. Here we show that in C. elegans, disruption of the Integrator complex leads to transcription of genes located downstream of the snRNA loci via a non-conventional transcription mechanism based on the lack of processing of the snRNAs. RNAP II read-through generates long chimeric RNAs containing snRNA, the intergenic region and the mature mRNA of the downstream gene located in sense. These chimeric sn-mRNAs remain as untranslated long non-coding RNAs, in the case of U1- and U2-derived sn-mRNAs, but can be translated to proteins in the case of SL-derived sn-mRNAs. The transcriptional effect caused by disruption of the Integrator complex is not restricted to genes located downstream of the snRNA loci but also affects key regulators of signal transduction such as kinases and phosphatases. Our findings highlight that these transcriptional alterations may be behind the correlation between mutations in the Integrator complex and tumor transformation.