Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.

Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression.

CD4+ effector T cells (Teff cells) and regulatory T cells (Treg cells) undergo metabolic reprogramming to support proliferation and immunological function. Although signaling via the lipid kinase PI(3)K (phosphatidylinositol-3-OH kinase), the serine-threonine kinase Akt and the metabolic checkpoint kinase complex mTORC1 induces both expression of the glucose transporter Glut1 and aerobic glycolysis for Teff cell proliferation and inflammatory function, the mechanisms that regulate Treg cell metabolism and function remain unclear. We found that Toll-like receptor (TLR) signals that promote Treg cell proliferation increased PI(3)K-Akt-mTORC1 signaling, glycolysis and expression of Glut1. However, TLR-induced mTORC1 signaling also impaired Treg cell suppressive capacity. Conversely, the transcription factor Foxp3 opposed PI(3)K-Akt-mTORC1 signaling to diminish glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. Notably, Glut1 expression was sufficient to increase the number of Treg cells, but it reduced their suppressive capacity and Foxp3 expression. Thus, inflammatory signals and Foxp3 balance mTORC1 signaling and glucose metabolism to control the proliferation and suppressive function of Treg cells.

Achievement of Target Gain Larger than Unity in an Inertial Fusion Experiment.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Planetary health education in the United States: four curricular models, one goal.

Global environmental crises demand scaled-up investment in education about planetary health. We identified college and university programs in the United States that focus on the human-animal-ecosystem nexus by systematically searching the 2023-2024 catalogs of more than 1000 schools. We identified four frequently-used curricular models: (1) One Health programs offered by universities with veterinary and agriculture schools that emphasize zoonotic diseases, antimicrobial resistance, food safety, and wildlife conservation; (2) climate change and health (climate medicine) programs for graduate and professional students at large universities with medical and public health schools; (3) global environmental public health programs focused on pollution and other exposures; and (4) sustainability and health programs emphasizing food security, environmental justice, and other health issues that can be improved with ethical design and engineering. Highlighting the shared goals of these distinct academic models may help make planetary health a more visible area of teaching, research, and practice.

Pleural effusion in a child with a correctly placed ventricle-peritoneal shunt.

Pleural effusions in children (PE) due to ventricle-peritoneal shunt (VPS) is very rare, with few cases reported. We present a new case of an infant with VPS who had a massive hydrothorax not associated with misplacement or migration of the distal catheter or with ascites. After the evacuation of the PE we managed the patient by adjusting the pressure of the adjustable valve (AV). Sequential thoracic ultrasounds showed a satisfactory outcome. We review the literature thoroughly and describe the possible pathophysiological mechanisms.

Lawson Criterion for Ignition Exceeded in an Inertial Fusion Experiment.

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Incidence of Melanoma in the Basque Province of Álava, Spain, From 2015 to 2018: A Descriptive Study. / Estudio descriptivo de los pacientes diagnosticados de melanoma en la provincia de Álava (País Vasco) entre los años 2015 y 2018.

INTRODUCTION: The incidence of cutaneous melanoma is rising fast, and its prevalence has doubled in the past 3 decades. Detailed local epidemiological information is essential for informing community-based prevention strategies and optimizing hospital resources. MATERIAL AND METHODS: We included all patients diagnosed with cutaneous melanoma at Hospital Universitario Araba in the Basque province of Álava, Spain, between January 2015 and December 2018. We described clinical and pathologic characteristics and calculated annual incidence rates adjusted to the European standard population. RESULTS: A total of 242 new cases of melanoma were diagnosed between 2015 and 2018. The age-standardized annual incidence rose from 12.92 cases per 100 000 population in 2015 to 18.30 cases per 100 000 population in 2018. CONCLUSIONS: The incidence of melanoma in our area is higher than that reported for Spanish series in 2017 and 2018. Lentigo maligna accounted for a high proportion of cases and was the second largest histologic subgroup.

DNA barcode analysis of the endangered green turtle (Chelonia mydas) in Mexico1.

Technological and analytical advances to study evolutionary biology, ecology, and conservation of green turtles (Chelonia mydas) are realized through molecular approaches including DNA barcoding. We characterized the usefulness of COI DNA barcodes in green turtles in Mexico to better understand genetic divergence and other genetic parameters of this species. We analyzed 63 sequences, including 25 from green turtle field specimens collected from the Gulf of Mexico and from the Mexican Pacific and 38 already present in the Barcode of Life Data Systems (BOLD). A total of 13 haplotypes were identified with four novel haplotypes from the Pacific Ocean and three novel haplotypes from the Atlantic Ocean. Intraspecific distance values among COI gene sequences by two different models were 0.01, demonstrating that there is not a subdivision for green turtle species. Otherwise, the interspecific distance interval ranged from 0.07 to 0.13, supporting a clear subdivision among all sea turtle species. Haplotype and total nucleotide diversity values of the COI gene reflect a medium genetic diversity average. Green turtles of the Mexican Pacific showed common haplotypes to some Australian and Chinese turtles, but different from the haplotypes of the Mexican Atlantic. COI analysis revealed new haplotypes and confirmed that DNA barcodes were useful for evaluation of the population diversity of green turtles in Mexico.

Pediatric Barcelona Olfactory Test ̶ 6 (pBOT-6): Validation of a Combined Odor Identification and Threshold Screening Test in Healthy Spanish Children and Adolescents.

BACKGROUND AND OBJECTIVE: Few odor tests have been developed for children. Objectives: The aim of the present study was to develop and validate a simple and quick olfactory test to evaluate odor identification and threshold in a Spanish pediatric population. METHODS: The Pediatric Barcelona Olfactory Test-6 (pBOT-6) consisted of a set of 6 odorants for a forced choice identification test and a 6-dilution phenyl ethyl alcohol geometric series for the threshold test. The pBOT-6 was compared with the Universal Sniff test (a validated international pediatric smell test) in 131 healthy Spanish volunteers aged 6-17 years. A Bland-Altman plot was used to determine the agreement between the 2 tests. Reliability was analyzed in 15 volunteers using the intraclass correlation coefficient. Normative data were obtained, and 8 children diagnosed with subjective loss of smell were tested for validation. RESULTS: The Bland-Altman analysis demonstrated a minimal bias of -1.71% with upper and lower limits of agreement of -31.1% and 27.6%, respectively. The intraclass correlation coefficient was 0.83 (95%CI, 0.6-0.96) for the identification test and 0.73 (95%CI, 0.36-0.9) for the threshold test, with excellent and good consistency between measurements over time. Mean pBOT-6 scores were significantly higher in healthy volunteers than in patients with loss of smell. Discrimination between normosmia and loss of smell was achieved with a sensitivity of 96.9% and a specificity of 100%. CONCLUSIONS: pBOT-6 offers an effective and fast method that is useful in clinical routine to distinguish, with high sensitivity and specificity, between pediatric patients with normosmia and those with loss of smell.

Presence of chelonid herpesvirus 5 (ChHV5) in sea turtles in northern Sinaloa, Mexico.

The presence of fibropapilloma and its associated chelonid herpesvirus 5 (ChHV5) was assessed in 82 wild sea turtles. Olive ridley turtles Lepidochelys olivacea (n = 58) were caught in the pelagic Area of Marine Influence (AMI) (off the coast of Guasave, Sinaloa), and black turtles Chelonia mydas agassizii (n = 24) were captured in the Navachiste Lagoon System. The apparent physical condition was evaluated as 'good' or 'poor' by physical examination. The population structure and general health status was determined by condition index, hematocrit and total plasma protein. Detection of ChHV5 from skin samples was done by PCR. The overall physical condition of black turtles was good and all the individuals were tumor-free. Likewise, the physical condition of most olive ridley turtles was good, except for 10 individuals with poor condition. Of these, 4 had fibropapilloma-like tumors. PCR analyses showed that 3 tumors were ChHV5-positive. The DNA sequence showed 96% identity with ChHV5. All other skin samples from black or olive ridley turtles were ChHV5-negative. This is the first report of fibropapillomatosis-ChHV5 in foraging grounds off northern Sinaloa. The virus was present in a small proportion of L. olivacea individuals, a free-ranging species. It is suggested that infected turtles acquired the virus at a different location somewhere during their development before arriving in the AMI zone. This finding makes the case for setting up a health monitoring program for turtle populations in the area, enforcing sanitary measures to reduce the spread of the pathogen.

Application of an Acoustic Doppler Velocimeter to Analyse the Performance of the Hydraulic Agitation System of an Agricultural Sprayer.

An acoustic Doppler velocimeter (ADV) was used to analyse the impact of an agricultural sprayer's agitation system settings on fluid velocities inside the tank. A 3000 L capacity sprayer equipped with a 4-nozzle hydraulic agitation system was used. ADV measurements were carried at 32 points inside the tank under the following settings: circuit pressures of 8, 10, or 12 bar; water level in the tank of 1000, 2000, or 3000 L; 2 or 4 active nozzles. An agitation test with a concentration of 0.4% copper oxychloride was employed to analyse the concentration of active matter as a function of tank fill level and number of active nozzles. All parameters significantly affected the fluid velocity, which increased with increasing pressure, but decreased with increasing water level in the tank and an increased number of active nozzles. Concentration tests showed greater active matter concentrations when higher velocities were recorded by the ADV. The ADV was shown to be a useful tool for the rapid assessment of fluid velocities; in the future, it could be used to validate the design of agitation systems, and to estimate their capacity to ensure an adequate level of active matter concentration in the fluid.

Patients' experience during weaning of invasive mechanical ventilation: A review of the literature. / Experiencias del paciente durante la retirada de la ventilación mecánica invasiva: una revisión de la literatura.

OBJECTIVE: Weaning from invasive mechanical ventilation (IMV) is influenced by physiological and psychological factors, the latter being the least studied. The aim was to identify, through the literature, patients' experiences during weaning from IMV and report its influencing factors. METHOD: The literature search was conducted using the Pubmed, CINAHL and PsycINFO databases. The search terms were: "patient", "experience" and "ventilator weaning". The research limits were: age (>19years) and language (English, Spanish and Finnish). RESULTS: Fifteen publications were analysed. The main results were grouped into three main categories according to patient's perceptions, feelings and experiences, influence of professionals' attention and determinants for successful weaning. Patients remember IMV weaning as a stressful process where they experience anxiety, frustration, despair or uncertainty. Nurses have a key role in improving communication with patients and foreseeing their needs. Family support and the care provided by the caregivers were shown as essential during the process. The patient's self-determination, self-motivation and confidence are identified as important factors to achieve successful IMV weaning. CONCLUSIONS: Psychological care, in addition to physical and technical care, is important at providing holistic care. Interventional studies are needed to improve the care during the weaning experience.

The macroecology of infectious diseases: a new perspective on global-scale drivers of pathogen distributions and impacts.

Identifying drivers of infectious disease patterns and impacts at the broadest scales of organisation is one of the most crucial challenges for modern science, yet answers to many fundamental questions remain elusive. These include what factors commonly facilitate transmission of pathogens to novel host species, what drives variation in immune investment among host species, and more generally what drives global patterns of parasite diversity and distribution? Here we consider how the perspectives and tools of macroecology, a field that investigates patterns and processes at broad spatial, temporal and taxonomic scales, are expanding scientific understanding of global infectious disease ecology. In particular, emerging approaches are providing new insights about scaling properties across all living taxa, and new strategies for mapping pathogen biodiversity and infection risk. Ultimately, macroecology is establishing a framework to more accurately predict global patterns of infectious disease distribution and emergence.

Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.

Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an 'SDH-like' molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P = 0.007) and multiple tumors (P = 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.

Complex systems approach for sports injuries: moving from risk factor identification to injury pattern recognition-narrative review and new concept.

Injury prediction is one of the most challenging issues in sports and a key component for injury prevention. Sports injuries aetiology investigations have assumed a reductionist view in which a phenomenon has been simplified into units and analysed as the sum of its basic parts and causality has been seen in a linear and unidirectional way. This reductionist approach relies on correlation and regression analyses and, despite the vast effort to predict sports injuries, it has been limited in its ability to successfully identify predictive factors. The majority of human health conditions are complex. In this sense, the multifactorial complex nature of sports injuries arises not from the linear interaction between isolated and predictive factors, but from the complex interaction among a web of determinants. Thus, the aim of this conceptual paper was to propose a complex system model for sports injuries and to demonstrate how the implementation of complex system thinking may allow us to better address the complex nature of the sports injuries aetiology. According to this model, we should identify features that are hallmarks of complex systems, such as the pattern of relationships (interactions) among determinants, the regularities (profiles) that simultaneously characterise and constrain the phenomenon and the emerging pattern that arises from the complex web of determinants. In sports practice, this emerging pattern may be related to injury occurrence or adaptation. This novel view of preventive intervention relies on the identification of regularities or risk profile, moving from risk factors to risk pattern recognition.

Fructans from Agave tequilana with a Lower Degree of Polymerization Prevent Weight Gain, Hyperglycemia and Liver Steatosis in High-Fat Diet-Induced Obese Mice.

Fructans from agave have received specific attention because of their highly branched fructan content. We have previously reported that the degree of polymerization (dp) influences their biological activity. Therefore, the aim of this study was to investigate the effect of unfractionated and fractionated fructans (higher and lower dps) from Agave tequilana in high-fat diet-induced (HFD) obese mice. Fructans with a lower dp (HFD+ScF) decreased weight gain by 30 %, body fat mass by 51 %, hyperglycemia by 25 % and liver steatosis by 40 %. Interestingly, unfractionated fructans (HFD+F) decreased glucose and triglycerides (TG), whereas fractionated fructans with a higher dp (HFD+LcF) decreased TG but not glucose; in contrast, HFD+ScF decreased glucose but not TG. Our findings suggest that both higher and lower dp agave fructans have complementary effects in metabolic disorders related to obesity. These findings may contribute to the development of improved food supplements with a specific ratio combination of fructans with different dps.

Predicting short-term mortality in patients with acute exacerbation of chronic heart failure: The EAHFE-3D scale. / Predicción de la mortalidad a muy corto plazo de los pacientes con insuficiencia cardiaca crónica agudizada: escala EAHFE-3D.

INTRODUCTION AND OBJECTIVES: Prognostic scales are needed in acute exacerbation of chronic heart failure to detect early mortality. The objective of this study is to create a prognostic scale (scale EAHFE-3D) to stratify the risk of death the very short term. PATIENTS AND METHOD: We used the EAHFE database, a multipurpose, multicenter registry with prospective follow-up currently including 6,597 patients with acute heart failure attended at 34 Spanish Emergency Departments from 2007 to 2014. The following variables were collected: demographic, personal history, data of acute episode and 3-day mortality. The derivation cohort included patients recruited during 2009 and 2011 EAHFE registry spots (n=3,640). The classifying variable was all-cause 3-day mortality. A prognostic scale (3D-EAHFE scale) with the results of the multivariate analysis based on the weight of the OR was created. The 3D-EAHFE scale was validated using the cohort of patients included in 2014 spot (n=2,957). RESULTS: A total of 3,640 patients were used in the derivation cohort and 102 (2.8%) died at 3 days. The final scale contained the following variables (maximum 165 points): age≥75 years (30 points), baseline NYHA III-IV (15 points), systolic blood pressure<110mmHg (20 points), room-air oxygen saturation<90% (30 points), hyponatremia (20 points), inotropic or vasopressor treatment (30 points) and need for noninvasive mechanical ventilation (20 points); with a ROC curve of 0.80 (95% CI 0.76-0.84; P<.001). The validation cohort included 2,957 patients (66 died at 3 days, 2.2%), and the scale obtained a ROC curve of 0.76 (95% CI 0.70-0.82; P<.001). The risk groups consisted of very low risk (0-20 points), low risk (21-40 points), intermediate risk (41-60 points), high risk (61-80 points) and very high risk (>80 points), with a mortality (derivation/validation cohorts) of 0/0.5, 0.8/1.0, 2.9/2.8, 5.5/5.8 and 12.7/22.4%, respectively. CONCLUSIONS: EAHFE-3D scale may help to predict the very short term prognosis of patients with acute heart failure in 5 risk groups.

Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.