Neural basis of fatigue in post-COVID syndrome and relationships with cognitive complaints and cognition.

The main objective was to evaluate structural and functional connectivity correlates of fatigue in post-COVID syndrome, and to investigate the relationships with an objective measure of mental fatigue and with subjective cognitive complaints. One-hundred and twenty-nine patients were recruited after 14.79 ± 7.17 months. Patients were evaluated with fatigue, neuropsychological, and subjective cognitive complaints assessments. Structural and functional magnetic resonance imaging were acquired, and functional connectivity, white matter diffusivity and grey matter volume were evaluated. Fatigue was present in 86 % of patients, and was highly correlated to subjective cognitive complaints. Fatigue was associated with structural and functional connectivity mostly in frontal areas but also temporal, and cerebellar areas, showing mental fatigue different pattern of functional connectivity correlates compared to physical fatigue. White matter diffusivity correlates were similar in fatigue and subjective cognitive complaints, located in the forceps minor, anterior corona radiata and anterior cingulum. Findings confirm that fatigue in post-COVID syndrome is related to cerebral connectivity patterns, evidencing its brain substrates. Moreover, results highlight the relationship between fatigue and subjective cognitive complaints. These findings point out the relevance of the multidisciplinary assessment of post-COVID syndrome patients with subjective cognitive complaints, in order to unravel the symptomatology beneath the patient's complaints.

Long Term Follow-Up Observation in Small Choroidal Melanocytic Tumors.

BACKGROUND: The purpose of this study is to analyze the long-term evolution of patients with small choroidal melanocytic tumors (SCMTs) undergoing observation, and to assess their rate of transformation into melanomas and survival. METHODS: A retrospective single-cohort study of patients with SCMTs (1-3 mm in height and 5-10 mm in base) diagnosed from January 1992 to February 2023 was carried out, with observation as the initial treatment. The main criterion for a transformation into melanoma is considered to be an increase in size of more than 1 mm in height and/or more than 1 mm in base measured on an ultrasound/retinography, recorded in two consecutive visits separated by one to three months. RESULTS: 243 patients were included with a mean age of 65.3 years and a mean follow-up of 7.9 years (6 months-27.9 years); 27 patients showed tumor growth. The probabilities of growth at 5, 10, and 15 years are 10%, 14%, and 17%, respectively. Regarding survival, 22 patients died and only 3 deaths were due to melanoma metastasis. Survival rates at 5 and 10 years are 99% and 97%. CONCLUSIONS: Observation is a viable therapeutic option for SCMTs, avoiding the side effects of treatment, considering the majority of these tumors do not progress to melanoma. With close monitoring, patients can be treated promptly upon detecting a transformation. Additionally, the findings confirm that small melanocytic tumors can lead to metastatic disease, albeit at a low rate.

The Cashew Pseudofruit (Anacardium occidentale): Composition, Processing Effects on Bioactive Compounds and Potential Benefits for Human Health.

The fruit of the cashew, a tree belonging to the family Anacardiaceae, is composed of approximately 10% nut (cashew) and 90% stalk or pseudofruit, usually discarded in situ and fermented in the soil. This review identifies cashew pseudofruit's physicochemical characteristics and bioactive compounds and their possible relationship to health benefits. Different processing techniques have been used to preserve the pseudofruit, and the effect of these techniques on its nutrients is also reviewed in this work. Cashew is a highly perishable product with moisture content above 80% w/w and 10% w/w sugars. It also has a high content of polyphenols, flavonoids, and tannins and high antioxidant properties that are best preserved by nonthermal processing techniques. The pseudofruit presents the high inhibitory activity of α-amylase and lipase enzymes, has anti-inflammatory and body weight reduction properties and healing activity, and controls glucose levels, insulinemia, and insulin resistance. For all these reasons, cashews have been promoted as a propitious food/ingredient for preventive and therapeutic management of different pathologies such as diabetes, dyslipidemia, obesity, hypertension, fatty liver, and acne. Moreover, it has positive effects on the intestinal microflora, among others. This pseudofruit has a high potential for the development of functional foods.

Impact of radiological follow-up frequency on resected lung cancer: a propensity score matching analysis.

Background: Despite advances in lung cancer treatment and the subsequent improvement in oncological outcomes, the optimal frequency of radiological follow-up remains unclear. Current recommendations lack consensus and do not consider individual patient characteristics and tumor factors. This study aimed to examine the impact of radiological follow-up frequency on oncological outcomes following lung cancer resection. Methods: A prospective multicenter study, involving patients who underwent anatomical lung resection in the GEVATS database between December 2016 and March 2018. The relationship between surveillance frequency and oncological outcomes was evaluated. Two groups were established based on follow-up frequency: low frequency (LF) and high frequency (HF). Subgroup analyses were performed based on tumor stage, histology, lymphadenectomy, and adjuvant therapy. Propensity score matching (PSM) was applied to balance the groups. Results: A total of 1,916 patients were included in the study, LF 444 (23.17%), HF 1,472 (76.83%). Factors associated with HF surveillance included higher stage, adjuvant chemotherapy and adjuvant radiotherapy. Subanalyses were performed after PSM for various factors, revealing significant differences between LF and HF groups in cancer-specific survival among who received adjuvant therapy {LF 53.021 months [95% confidence interval (CI): 48.622-57.421] vs. HF 58.836 months (95% CI: 55.343-62.330); HR 0.453, 95% CI: 0.242-0.849; P=0.013}, as well as overall survival for patients with squamous cell carcinoma [LF 54.394 months (95% CI: 51.424-57.364) vs. HF 61.578 months (95% CI: 59.091-64.065); HR 0.491, 95% CI: 0.299-0.806; P=0.005] and those who received adjuvant therapy LF 50.176 months [95% CI: 45.609-54.742) vs. HF 57.189 months (95% CI: 53.599-60.778); HR 0.503, 95% CI: 0.293-0.865; P=0.013]. Conclusions: Findings suggest that high-frequency surveillance only improves survival outcomes in lung cancer patients who received adjuvant treatment or had squamous cell carcinoma. Therefore, future guidelines for lung cancer follow-up should consider individualizing the frequency of radiological surveillance based on patients' risk profiles.

New functional dissociations between prefrontal and parietal cortex during task switching: A combined fMRI and TMS study.

Preparatory control in task-switching has been suggested to rely upon a set of distributed regions within a frontoparietal network, with frontal and parietal cortical areas cooperating to implement switch-specific preparation processes. Although recent causal evidence using transcranial magnetic stimulation (TMS) have generally supported this model, alternative results from both functional neuroimaging and neurophysiological studies have questioned the switch-specific role of both frontal and parietal cortices. The aim of the present study was to clarify the involvement of prefrontal and parietal areas in preparatory cognitive control. With this purpose, an fMRI study was conducted to identify the brain areas activated during cue events in a task-switching paradigm, indicating whether to switch or to repeat among numerical tasks. Then, TMS was applied over the specific coordinates previously identified through fMRI, that is, the right inferior frontal gyrus (IFG) and right intraparietal sulcus (IPS). Results revealed that TMS over the right IFG disrupted performance in both switch and repeat trails in terms of delayed responses as compared to Sham condition. In contrast, TMS over the right IPS selectively interfered performance in switch trials. These findings support a multi-component model of executive control with the IFG being involved in more general switch-unspecific process such as the episodic retrieval of goals, and the IPS being related to the implementation of switch-specific preparation mechanisms for activating stimulus-response mappings. The results are discussed within the framework of contemporary hierarchical models of prefrontal cortex organization, suggesting that distinct prefrontal areas may carry out coordinated functions in preparatory control.

Improving ED admissions forecasting by using generative AI: An approach based on DGAN.

BACKGROUND AND OBJECTIVE: Generative Deep Learning has emerged in recent years as a significant player in the Artificial Intelligence field. Synthesizing new data while maintaining the features of reality has revolutionized the field of Deep Learning, proving to be particularly useful in contexts where obtaining data is challenging. The objective of this study is to employ the DoppelGANger algorithm, a cutting-edge approach based on Generative Adversarial Networks for time series, to enhance patient admissions forecasting in a hospital Emergency Department. METHODS: We employed the DoppelGANger algorithm in a sequential methodology, conditioning generated time series with unique attributes to optimize data utilization. After confirming the successful creation of synthetic data with new attribute values, we adopted the Train-Synthetic-Test-Real framework to ensure the reliability of our synthetic data validation. We then augmented the original series with synthetic data to enhance the Prophet model's performance. This process was applied to two datasets derived from the original: one with four years of training followed by one year of testing, and another with three years of training and two years of testing. RESULTS: The experimental results show that the generative model outperformed Prophet on the forecasting task, improving the SMAPE from 7.30 to 6.99 with the four-year training set, and from 22.84 to 7.41 for the three-year training set, all in daily aggregations. For the data replacement task, the Prophet SMAPE values decreased to 6.84 and 7.18 for four and three-year sets on the same aggregation. Additionally, data augmentation reduced the SMAPE to 6.79 for a one-year test set and achieved 8.56 for the two-year test set, surpassing the performance achieved by the same Prophet model when trained only on real data. Results for the remaining aggregations were consistent. CONCLUSIONS: The findings of this study suggest that employing a generative algorithm to extend a training dataset can effectively enhance predictive models within the domain of Emergency Department admissions. The improvement can lead to more efficient resource allocation and patient management.

Detection of cerebrospinal fluid biomarkers changes of Alzheimer's disease using a cognitive stress test in persons with subjective cognitive decline and mild cognitive impairment.

Introduction: Timely and accurate diagnosis of the earliest manifestations of Alzheimer's disease (AD) is critically important. Cognitive challenge tests such as the Loewenstein Acevedo Scales for Semantic Interference and Learning (LASSI-L) have shown favorable diagnostic properties in a number of previous investigations using amyloid or FDG PET. However, no studies have examined LASSI-L performance against cerebrospinal fluid biomarkers of AD, which can be affected before the distribution of fibrillar amyloid and other changes that can be observed in brain neuroimaging. Therefore, we aimed to evaluate the relationship between LASSI-L scores and CSF biomarkers and the capacity of the cognitive challenge test to detect the presence of amyloid and tau deposition in patients with subjective cognitive decline and amnestic mild cognitive impairment (MCI). Methods: One hundred and seventy-nine patients consulting for memory loss without functional impairment were enrolled. Patients were examined using comprehensive neuropsychological assessment, the LASSI-L, and cerebrospinal fluid (CSF) biomarkers (Aß1-42/Aß1-40 and ptau181). Means comparisons, correlations, effect sizes, and ROC curves were calculated. Results: LASSI-L scores were significantly associated with CSF biomarkers Aß1-42/Aß1-40 in patients diagnosed with MCI and subjective cognitive decline, especially those scores evaluating the capacity to recover from proactive semantic interference effects and delayed recall. A logistic regression model for the entire sample including LASSI-L and age showed an accuracy of 0.749 and an area under the curve of 0.785 to detect abnormal amyloid deposition. Conclusion: Our study supports the biological validity of the LASSI-L and its semantic interference paradigm in the context of the early stages of AD. These findings emphasize the utility and the convenience of including sensitive cognitive challenge tests in the assessment of patients with suspicion of early stages of AD.

Foetal gluten immunogenic peptides during pregnancy: a new determinant on the coeliac exposome.

BACKGROUND: The increasing incidence of coeliac disease is leading to a growing interest in active search for associated factors, even the intrauterine and early life. The exposome approach to disease encompasses a life course perspective from conception onwards has recently been highlighted. Knowledge of early exposure to gluten immunogenic peptides (GIP) in utero could challenge the chronology of early prenatal tolerance or inflammation, rather than after the infant's solid diet after birth. METHODS: We developed an accurate and specific immunoassay to detect GIP in amniotic fluid (AF) and studied their accumulates, excretion dynamics and foetal exposure resulting from AF swallowing. One hundred twenty-five pregnant women with different gluten diets and gestational ages were recruited. RESULTS: GIP were detectable in AF from at least the 16th gestational week in gluten-consuming women. Although no significant differences in GIP levels were observed during gestation, amniotic GIP late pregnancy was not altered by maternal fasting, suggesting closed-loop entailing foetal swallowing of GIP-containing AF and subsequent excretion via the foetal kidneys. CONCLUSIONS: The study shows evidence, for the first time, of the foetal exposure to gluten immunogenic peptides and establishes a positive correlation with maternal gluten intake. The results obtained point to a novel physiological concept as they describe a plausible closed-loop circuit entailing foetal swallowing of GIP contained in AF and its subsequent excretion through the foetal kidneys. The study adds important new information to understanding the coeliac exposome.

Impact of the COVID-19 pandemic on the self-care and health condition of the older adults. CUIDAMOS+75. A mixed methods study protocol.

Aims: To assess the impact of the COVID-19 pandemic on the health condition of people ≥75 years of age and on their family caregivers in Spain. Design: Multicentric, mixed method concurrent study. Methods: This work, which will be conducted within the primary care setting in 11 administrative regions of Spain, will include three coordinated studies with different methodologies. The first is a population-based cohort study that will use real-life data to analyze the rates and evolution of health needs, care provision, and services utilization before, during, and after the pandemic. The second is a prospective cohort study with 18 months of follow-up that will evaluate the impact of COVID-19 disease on mortality, frailty, functional and cognitive capacity, and quality of life of the participants. Finally, the third will be a qualitative study with a critical social approach to understand and interpret the social, political, and economic dimensions associated with the use of health services during the pandemic. We have followed the SPIRIT Checklist to address trial protocol and related documents. This research is being funded by the Instituto de Salud Carlos III since 2021 and was approved by its ethics committee (June 2022). Discussion: The study findings will reveal the long-term impact of the COVID-19 pandemic on the older adults and their caregivers. This information will serve policymakers to adapt health policies to the needs of this population in situations of maximum stress, such as that produced by the COVID-19 pandemic. Trial Registration: Identifier: NCT05249868 [ClinicalTrials.gov].

Antiemetic prophylaxis regimens in haematologic malignancies patients undergoing a hematopoietic stem cell transplantation. Which is the best standard of care? A systematic review.

INTRODUCTION: This systematic review, adhering to PRISMA guidelines, aimed to evaluate the efficacy and safety of antiemetic prophylaxis in haematological patients undergoing high-dose chemotherapy as part of their hematopoietic stem cell transplantation (HSCT) conditioning regimens. METHODS: We performed a comprehensive search in PubMed, EMBASE, ClinicalTrials.gov and the Cochrane database to identify randomised controlled trials (RCTs) and systematic reviews of antiemetic prophylaxis. Studies in English, French, Italian or Spanish were included. This review is registered with PROSPERO, ID CRD42023406380. RESULTS: Eight RCTs were analysed. The antiemetic regimens evaluated ranged from monotherapy with 5-Hydroxytryptamine Receptor 3 antagonists (5-HT3RAs) to complex combinations including olanzapine, neurokinin-1 receptor antagonists, 5-HT3RAs and corticosteroids. Complete response rates for triplet or quadruple regimens varied between 23.5% and 81.9%. Although no significant adverse effects were observed, minor symptoms such as diarrhoea, constipation, sedation and headaches were reported. CONCLUSION: Existing evidence on HSCT antiemetic therapy highlights its benefits but fails to provide clear clinical directions. The choice between triplet and quadruplet therapies for different patient scenarios is still uncertain. Until more detailed research is available, healthcare providers must rely on the latest guidelines and their judgement to customise antiemetic care for each patient's specific needs and risks.

Transfer of celiac disease-associated immunogenic gluten peptides in breast milk: variability in kinetics of secretion.

Background: Exposure to antigens is crucial for child immune system development, aiding disease prevention and promoting infant health. Some common food antigen proteins are found in human breast milk. However, it is unclear whether gluten antigens linked to celiac disease (CD) are transmitted through breast milk, potentially impacting the development of the infant's immune system. Objective: This study aimed to analyze the passage of gluten immunogenic peptides (GIP) into human breast milk. We evaluated the dynamics of GIP secretion after lactating mothers adopted a controlled gluten-rich diet. Methods: We prospectively enrolled 96 non-CD and 23 CD lactating mothers, assessing total proteins and casein in breast milk, and GIP levels in breast milk and urine. Subsequently, a longitudinal study was conducted in a subgroup of 12 non-CD lactating mothers who adopted a controlled gluten-rich diet. GIP levels in breast milk and urine samples were assayed by multiple sample collections over 96 hours. Results: Analysis of a single sample revealed that 24% of non-CD lactating mothers on a regular unrestricted diet tested positive for GIP in breast milk, and 90% tested positive in urine, with significantly lower concentrations in breast milk. Nevertheless, on a controlled gluten-rich diet and the collection of multiple samples, GIP were detected in 75% and 100% of non-CD participants in breast milk and urine, respectively. The transfer dynamics in breast milk samples were long-enduring and GIP secretion persisted from 0 to 72 h. In contrast, GIP secretion in urine samples was limited to the first 24 h, with inter-individual variations. In the cohort of CD mothers, 82.6% and 87% tested negative for GIP in breast milk and urine, respectively. Conclusions: This study definitively established the presence of GIP in breast milk, with substantial inter-individual variations in secretion dynamics. Our findings provide insights into distinct GIP kinetics observed in sequentially collected breast milk and urine samples, suggesting differential gluten metabolism patterns depending on the organ or system involved. Future research is essential to understand whether GIP functions as sensitizing or tolerogenic agents in the immune system of breastfed infants.

Vitis vinifera L. cv. Falanghina Seed Extracts: Antioxidant Effect of Bioactive Compounds on HepG2 Cells.

Vitis vinifera L. is a natural source of bioactive compounds that is already used for cosmeceutical and nutraceutical approaches. However, their phytochemical and antioxidant properties, although studied, have not been fully explored. We aimed to characterize V. vinifera L. cv. Falanghina seed extracts in different polarity solvents (hexane, ethyl acetate, ethanol, and a mixture of acetone-water) for their phytochemical contents, including the total phenolic compound content (TPC), free radical scavenging capacities, and antioxidant ability on HepG2 cells. We directly profiled the functional quality of V. vinifera seed extracts against H2O2-induced oxidative stress in HepG2 cells, focusing on mitochondrial functions. The content of bioactive compounds was characterized by LC-MS. To assess the cytocompatibility of the extracts, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted. Results showed that extraction with ethyl acetate (18.12 mg GAE·g-1) and ethanol solvents (18.07 mg GAE·g-1), through Soxhlet, and with an acetone-water mixture (14.17 mg GAE·g-1), through maceration, yielded extracts rich in (poly)phenols, with good scavenging and antioxidant activity (98.32 I% for ethanol solvents and 96.31 I% for acetone-water mixture). The antioxidant effect of polyphenols is at least partially due to their capacity to maintain mitochondrial biogenesis and mitophagy, which elevates mitochondrial efficiency, resulting in diminished ROS production, hence re-establishing the mitochondrial quality control. These findings highlight the valorization of Vitis by-products to improve food functional characteristics.

Improving the Accuracy of Permeability Data to Gain Predictive Power: Assessing Sources of Variability in Assays Using Cell Monolayers.

The ability to predict the rate of permeation of new compounds across biological membranes is of high importance for their success as drugs, as it determines their efficacy, pharmacokinetics, and safety profile. In vitro permeability assays using Caco-2 monolayers are commonly employed to assess permeability across the intestinal epithelium, with an extensive number of apparent permeability coefficient (Papp) values available in the literature and a significant fraction collected in databases. The compilation of these Papp values for large datasets allows for the application of artificial intelligence tools for establishing quantitative structure-permeability relationships (QSPRs) to predict the permeability of new compounds from their structural properties. One of the main challenges that hinders the development of accurate predictions is the existence of multiple Papp values for the same compound, mostly caused by differences in the experimental protocols employed. This review addresses the magnitude of the variability within and between laboratories to interpret its impact on QSPR modelling, systematically and quantitatively assessing the most common sources of variability. This review emphasizes the importance of compiling consistent Papp data and suggests strategies that may be used to obtain such data, contributing to the establishment of robust QSPRs with enhanced predictive power.

Adverse Effects Related to Paediatric Influenza Vaccination and Its Influence on Vaccination Acceptability. The FLUTETRA Study: A Survey Conducted in the Region of Murcia, Spain.

BACKGROUND: During the 2022-23 season, three autonomous communities recommended influenza vaccination for all children between 6 and 59 months. The objective is to evaluate the adverse effects associated with the administered influenza vaccines in the Region of Murcia, as well as their influence on the recommendation of the same to acquaintances or repetition in future seasons. MATERIAL AND METHODS: Cross-sectional descriptive study with an online questionnaire sent to the parents of vaccinated minors of 6-23 months of age receiving inactivated intramuscular vaccine (IIV) or 24-59 months of age receiving live-attenuated intranasal vaccine (LAIV). RESULTS: Among 4971 surveys received, the most common adverse effect for LAIV and IIV was runny nose (40.90%) and local pain (31.94%), respectively. Sixty percent of adverse effects lasted ≤ 1 day, and around 10% lasted ≥ 3 days. The interference of adverse effects with the minor's daily life was very infrequent (3.32%), as was the need for visiting the medical office (2.68%). Overall, 96.44% of parents would recommend influenza vaccination to friends and relatives after the experience. Only 3.56% would not recommend it, while 1.68% would not vaccinate their child against influenza again. The most frequently cited reason being adverse effects. CONCLUSIONS: Our study shows the safety of influenza vaccines. Despite the low impact of adverse effects, they influence some parents in their intention to continue vaccinating or recommending it to acquaintances, which remarks the need to reinforce the information given to parents so that this fact does not influence decision-making.

Loss of the lysosomal protein CLN3 modifies the lipid content of the nuclear envelope leading to DNA damage and activation of YAP1 pro-apoptotic signaling.

Batten disease is characterized by early-onset blindness, juvenile dementia and death during the second decade of life. The most common genetic causes are mutations in the CLN3 gene encoding a lysosomal protein. There are currently no therapies targeting the progression of the disease, mostly due to the lack of knowledge about the disease mechanisms. To gain insight into the impact of CLN3 loss on cellular signaling and organelle function, we generated CLN3 knock-out cells in a human cell line (CLN3-KO), and performed RNA sequencing to obtain the cellular transcriptome. Following a multi-dimensional transcriptome analysis, we identified the transcriptional regulator YAP1 as a major driver of the transcriptional changes observed in CLN3-KO cells. We further observed that YAP1 pro-apoptotic signaling is hyperactive as a consequence of CLN3 functional loss in retinal pigment epithelia cells, and in the hippocampus and thalamus of CLN3exΔ7/8 mice, an established model of Batten disease. Loss of CLN3 activates YAP1 by a cascade of events that starts with the inability of releasing glycerophosphodiesthers from CLN3-KO lysosomes, which leads to perturbations in the lipid content of the nuclear envelope and nuclear dysmorphism. This results in increased number of DNA lesions, activating the kinase c-Abl, which phosphorylates YAP1, stimulating its pro-apoptotic signaling. Altogether, our results highlight a novel organelle crosstalk paradigm in which lysosomal metabolites regulate nuclear envelope content, nuclear shape and DNA homeostasis. This novel molecular mechanism underlying the loss of CLN3 in mammalian cells and tissues may open new c-Abl-centric therapeutic strategies to target Batten disease.

Nutritional Support Reduces Circulating Cytokines in Patients with Heart Failure.

Increased inflammation is associated with the pathogenesis of heart failure (HF). Increased circulating levels of cytokines have been previously reported and generally associated with worse clinical outcomes. In this context, the modulation of inflammation-related parameters seems to be a reasonable therapeutic option for improving the clinical course of the disease. Based on this, we aimed to compare changes in circulating cytokines when Mediterranean diet alone or in combination with hypercaloric, hyperproteic oral nutritional supplements (ONS), enriched with omega-3 (n-3) polyunsaturated fatty acids were administered to patients with HF. Briefly, patients were randomly assigned to receive Mediterranean Diet (control group) vs. Mediterranean Diet plus ONS (intervention group). We observed increased circulating levels of IL-6, IL-8, MCP-1 and IP-10. MCP-1 and IL-6 were associated with overweight and obesity (p = 0.01-0.01-0.04, respectively); IL-6 and IL-8 were positively correlated with fat mass and CRP serum levels (p = 0.02-0.04, respectively). Circulating levels of IL-8 significantly decreased in all patients treated with the Mediterranean diet, while IL-6 and IP-10 only significantly decreased in patients that received plus ONS. In the univariate analysis, MCP-1 and its combination with IL-6 were associated with increased mortality (p = 0.02), while the multivariate analysis confirmed that MCP-1 was an independent factor for mortality (OR 1.01, 95%ci 1.01-1.02). In conclusion, nutritional support using hypercaloric, hyperproteic, n-3 enriched ONS in combination with Mediterranean Diet was associated with decreased circulating levels of some cytokines and could represent an interesting step for improving heart functionality of patients with HF.

Genomic approachesidentifySTT4 as a new component in glucose-induced activation of yeast plasma membrane H+-ATPase.

Many studies have focused on identifying the signaling pathway by which addition of glucose triggers post-translational activation of the plasma membrane H+-ATPase in yeast. They have revealed that calcium signaling is involved in the regulatory pathway, supported for instance by the phenotype of mutants inARG82 that encodes an inositol kinase that phosphorylates inositol triphosphate (IP3). Strong glucose-induced calcium signaling, and high glucose-induced plasma membrane H+-ATPase activation have been observed in a specific yeast strain with the PJ genetic background. In this study, we have applied pooled-segregant whole genome sequencing, QTL analysis and a new bioinformatics methodology for determining SNP frequencies to identify the cause of this discrepancy and possibly new components of the signaling pathway. This has led to the identification of an STT4 allele with 6 missense mutations as a major causative allele, further supported by the observation that deletion of STT4 in the inferior parent caused a similar increase in glucose-induced plasma membrane H+-ATPase activation. However, the effect on calcium signaling was different indicating the presence of additional relevant genetic differences between the superior and reference strains. Our results suggest that phosphatidylinositol-4-phosphate might play a role in the glucose-induced activation of plasma membrane H+-ATPase by controlling intracellular calcium release through the modulation of the activity of phospholipase C.