Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Systemic Inflammatory Changes in Spinal Cord Injured Patients after Adding Aquatic Therapy to Standard Physiotherapy Treatment.

Spinal cord injury (SCI) is a severe medical condition resulting in substantial physiological and functional consequences for the individual. People with SCI are characterised by a chronic, low-grade systemic inflammatory state, which contributes to further undesirable secondary injuries. This study aimed to evaluate the effect of adding aquatic therapy to the standard physiotherapy treatment, implemented in two different schedules, on systemic inflammation in SCI patients. Additionally, the relationship between cytokine blood levels and changes in functionality (measured with the 6MWT, 10MWT, WISCI, BBS, and TUG tests) throughout the study was assessed. A quantitative multiplexed antibody assay was performed to measure the expression level of 20 pro- and anti-inflammatory cytokines in blood samples from SCI patients at three time points: baseline, week 6, and immediately post-intervention (week 12). This study identified a complex signature of five cytokines (IL-12p70, IL-8, MCP-1, IL-1α, and IP10) associated with the time course of the two physiotherapy programs. Two other cytokines (IL-4 and TNF-α) were also associated with the functional recovery of patients. These could be important indicators for SCI prognosis and provide a basis for developing novel targeted therapies.

Tunable control of insect pheromone biosynthesis in Nicotiana benthamiana.

Previous work has demonstrated that plants can be used as production platforms for molecules used in health, medicine, and agriculture. Production has been exemplified in both stable transgenic plants and using transient expression strategies. In particular, species of Nicotiana have been engineered to produce a range of useful molecules, including insect sex pheromones, which are valued for species-specific control of agricultural pests. To date, most studies have relied on strong constitutive expression of all pathway genes. However, work in microbes has demonstrated that yields can be improved by controlling and balancing gene expression. Synthetic regulatory elements that provide control over the timing and levels of gene expression are therefore useful for maximizing yields from heterologous biosynthetic pathways. In this study, we demonstrate the use of pathway engineering and synthetic genetic elements for controlling the timing and levels of production of Lepidopteran sex pheromones in Nicotiana benthamiana. We demonstrate that copper can be used as a low-cost molecule for tightly regulated inducible expression. Further, we show how construct architecture influences relative gene expression and, consequently, product yields in multigene constructs. We compare a number of synthetic orthogonal regulatory elements and demonstrate maximal yields from constructs in which expression is mediated by dCas9-based synthetic transcriptional activators. The approaches demonstrated here provide new insights into the heterologous reconstruction of metabolic pathways in plants.

Effectiveness of transcranial direct current stimulation on balance and gait in patients with multiple sclerosis: systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Motor impairments are very common in neurological diseases such as multiple sclerosis. Noninvasive brain stimulation could influence the motor function of patients. OBJECTIVE: The aim of this meta-analysis was to evaluate the effectiveness of transcranial direct current stimulation (tDCS) on balance and gait ability in patients with multiple sclerosis. Additionally, a secondary aim was to compare the influence of the stimulation location of tDCS on current effectiveness. METHODS: A search was conducted for randomized controlled trials published up to May 2023 comparing the application of tDCS versus a sham or control group. The primary outcome variables were balance and gait ability. RESULTS: Eleven studies were included in the qualitative analysis, and ten were included in the quantitative analysis, which included 230 patients with multiple sclerosis. The average effect of tDCS on gait functionality was superior to that of the control group (SMD = -0.71; 95% CI, -1.05 to -0.37). However, the overall results of the tDCS vs. sham effect on static balance did not show significant differences between groups (MD = 1.26, 95% CI, -1.31 to 3.82). No significant differences were found when different locations of tDCS were compared. CONCLUSIONS: These results reveal that tDCS is an effective treatment for improving gait ability with a low quality of evidence. However, the application of tDCS has no effect on static balance in patients with multiple sclerosis with very low quality of evidence. Similarly, there seems to be no difference regarding the stimulation area with tDCS.

Plasma disposition of florfenicol after intramuscular administration in rabbits pretreated with pentoxifylline.

This work aimed to assess the effects of the coadministration of pentoxifylline (PTX) on the pharmacokinetic profile of florfenicol (FFC) after intramuscular administration in rabbits. Ten New Zealand white rabbits, 1 year of age and 3.9 ± 0.1 kg body weight, were assigned according to a randomized block design to Group 1 (FFC): treated with 30 mg/kg of FFC intramuscularly, and Group 2 (PTX + FFC) treated with an oral dose of 30 mg/kg PTX 45 min before the intramuscular injection of 30 mg/kg FFC. Blood samples were collected before and at different times between 0.5 and 12.0 h after drug administration. FFC plasma concentrations were determined by high-performance liquid chromatography. Results showed that IM injection of the long-acting formulation of FFC in rabbits resulted in a slow increase in mean plasma concentrations reaching a Cmax of 3.09 ± 0.52 ug/mL at 2.8 ± 0.45 h (Tmax ) after drug administration. While coadministration of PTX and FFC decreased the time to achieve the maximal concentration by modifying the absorption of FFC without changes in the other pharmacokinetic parameters.

Time-series transcriptomics reveals a BBX32-directed control of acclimation to high light in mature Arabidopsis leaves.

The photosynthetic capacity of mature leaves increases after several days' exposure to constant or intermittent episodes of high light (HL) and is manifested primarily as changes in chloroplast physiology. How this chloroplast-level acclimation to HL is initiated and controlled is unknown. From expanded Arabidopsis leaves, we determined HL-dependent changes in transcript abundance of 3844 genes in a 0-6 h time-series transcriptomics experiment. It was hypothesized that among such genes were those that contribute to the initiation of HL acclimation. By focusing on differentially expressed transcription (co-)factor genes and applying dynamic statistical modelling to the temporal transcriptomics data, a regulatory network of 47 predominantly photoreceptor-regulated transcription (co-)factor genes was inferred. The most connected gene in this network was B-BOX DOMAIN CONTAINING PROTEIN32 (BBX32). Plants overexpressing BBX32 were strongly impaired in acclimation to HL and displayed perturbed expression of photosynthesis-associated genes under LL and after exposure to HL. These observations led to demonstrating that as well as regulation of chloroplast-level acclimation by BBX32, CRYPTOCHROME1, LONG HYPOCOTYL5, CONSTITUTIVELY PHOTOMORPHOGENIC1 and SUPPRESSOR OF PHYA-105 are important. In addition, the BBX32-centric gene regulatory network provides a view of the transcriptional control of acclimation in mature leaves distinct from other photoreceptor-regulated processes, such as seedling photomorphogenesis.

Insect pest management in the age of synthetic biology.

Arthropod crop pests are responsible for 20% of global annual crop losses, a figure predicted to increase in a changing climate where the ranges of numerous species are projected to expand. At the same time, many insect species are beneficial, acting as pollinators and predators of pest species. For thousands of years, humans have used increasingly sophisticated chemical formulations to control insect pests but, as the scale of agriculture expanded to meet the needs of the global population, concerns about the negative impacts of agricultural practices on biodiversity have grown. While biological solutions, such as biological control agents and pheromones, have previously had relatively minor roles in pest management, biotechnology has opened the door to numerous new approaches for controlling insect pests. In this review, we look at how advances in synthetic biology and biotechnology are providing new options for pest control. We discuss emerging technologies for engineering resistant crops and insect populations and examine advances in biomanufacturing that are enabling the production of new products for pest control.

Effectiveness of Transcranial Direct Current Stimulation Combined With Exercising in People With Fibromyalgia: A Randomized Sham-Controlled Clinical Trial.

OBJECTIVE: To evaluate the effectiveness of transcranial direct current stimulation (tDCS) combined with exercising in people with fibromyalgia. DESIGN: Randomized, triple-blind, sham-controlled, clinical trial. SETTING: Primary health care center. PARTICIPANTS: A total of 120 volunteer participants (N=120) between 18 and 65 years old and diagnosed with fibromyalgia. Four participants dropped out of the study for causes unrelated to the intervention. INTERVENTION: Participants were randomized into 3 groups (active tDCS+exercising, sham tDCS+exercising, no-intervention control). The intervention was delivered in 5 sessions over 2 weeks. MAIN OUTCOME MEASURES: Pain intensity and referred pain area after suprathreshold pressure stimulation. RESULTS: Pain intensity further decreased in the active tDCS group vs control (mean, -14.43; 95% confidence interval, -25.27 to -3.58) at post intervention, unlike the sham tDCS group. Both tDCS groups did not achieve greater reductions in referred pain vs control. In the active tDCS group, health status (mean, -14.80; 95% confidence interval, -23.10 to -6.50) and pain catastrophizing (mean, -6.68, 95% confidence interval, -11.62 to -1.73) improved at post intervention, and so did health status (mean, -8.81; 95% confidence interval, -17.11 to -0.51), pain catastrophizing (mean, -7.00; 95% confidence interval, -12.13 to -1.87), and depression (mean, -3.52; 95% confidence interval, -6.86 to -0.19) after 1 month. In the sham tDCS group, improvements were recorded in health status (mean, -13.21; 95% confidence interval, -21.52 to -4.91) and depression (mean, -3.35; 95% confidence interval, -6.35 to -0.35) at post intervention and in health status (mean, -8.77; 95% confidence interval, -17.06 to -0.47), pain catastrophizing (mean, -5.68; 95% confidence interval, -10.80 to -0.55), and depression (mean, -3.98; 95% confidence interval, -7.31 to -0.64) after 1 month. No intergroup differences were observed between active and sham tDCS. CONCLUSIONS: Active and sham tDCS improved health status, pain catastrophizing, and depression vs control, but pain intensity decreased only in the active tDCS group.

Capacitive resistive monopolar radiofrequency at 448 kHz plus exercising versus exercising alone for subacromial pain: A sham-controlled randomized clinical trial.

OBJECTIVE: To investigate the effectiveness of thermal and sub-thermal capacitive-resistive monopolar radiofrequency at 448 kHz plus exercising compared to sham radiofrequency plus exercising on pain, functionality, and quality of life in patients with subacromial pain. DESIGN: Randomized, controlled, parallel, double-blind, three-arm clinical trial. SETTING: Hospital and Primary Care. SUBJECTS: Eighty-one participants with subacromial pain in three intervention groups. INTERVENTIONS: Three interventions with capacitive-resistive radiofrequency (thermal, sub-thermal, and sham) over 9 sessions (3 per week) plus an exercising protocol identical for all groups over 15 sessions (5 per week). OUTCOME MEASURES: Visual analogue scale and pressure pain threshold for pain, Shoulder Pain and Disability Index and Quick-Disabilities of the Arm, Shoulder and Hand for functionality, and quality of life via the European Quality of Life-Five Dimensions were assessed at baseline, immediately posttreatment, and 1 month and 3 months post-intervention. RESULTS: No between-group differences were found in the pain visual analogue scale (F = 1.0; P = 0.37), Shoulder Pain and Disability Index (F = 1.0; P = 0.36), European Quality of Life-Five Dimensions (F = 0.76; P = 0.47), and pressure pain (F = 0.14; P = 0.86) outcomes, with a statistical power < 0.30 for all comparisons. Between-group differences were found in the Quick-Disabilities of the Arm, Shoulder and Hand (F = 3.4; P < 0.038), with an improvement of -14.1 points (confidence interval at 95% (95% CI) -28.1 to -0.1) in the thermal versus the sham group at 1 month follow-up. The mobility dimension of European Quality of Life-Five Dimensions improved in a greater proportion of participants in the thermal group (22.2% thermal, 7.4% sub-thermal, and 0.0% sham; P = 0.02). CONCLUSION: Adding thermal radiofrequency to exercising can further improve slightly functionality and mobility in people with subacromial pain in the short term, but not pain perception. Future studies with larger sample sizes are warranted to increase statistical power.

Immunomodulatory Effect of Human Lactoferrin on Toll-like Receptors 2 Expression as Therapeutic Approach for Keratoconus.

Keratoconus (KC) is a corneal disorder whose etiology shares a close relationship with Lactoferrin (LTF) dysregulation and Toll-like Receptors 2 (TLR2) overexpression. This study shows how these two important biomarkers are clinically and molecularly interrelated, increasing knowledge about KC pathophysiology, and opening the door to future therapies. In this prospective clinical study, serum and tear LTF concentrations were quantified in 90 KC patients and 60 controls. A correlation analysis with multiple blood and tear immunoinflammatory mediators, and KC-associated tomographic parameters, was performed. An in vitro study using HEK-BlueTMhTLR2 cell cultures was also conducted to determine the expression and functionality of TLR2 under the influence of LTF treatment. As a result, a LTF decreased was observed in KC patients compared to controls (p < 0.0001), evidencing the strong correlation with TLR2 overexpression at systemic and ocular surface level, with inflammatory mediator upregulation and with KC severity. In stimulated cell cultures, TLR2 expression was decreased using 2 mg/mL of LTF. The levels of secreted embryonic alkaline phosphatase (SEAP) and interleukin-8 (IL-8) were also reduced in supernatants after LTF treatment. As conclusions, the dysregulation of LTF and TLR2 in the ocular surface of KC patients contributes to KC severity by maintaining a detrimental chronic immune−inflammatory state. The immunomodulatory properties of LTF on TLR2 expression suggest its potential as a therapeutic approach for KC.

SPServer: split-statistical potentials for the analysis of protein structures and protein-protein interactions.

BACKGROUND: Statistical potentials, also named knowledge-based potentials, are scoring functions derived from empirical data that can be used to evaluate the quality of protein folds and protein-protein interaction (PPI) structures. In previous works we decomposed the statistical potentials in different terms, named Split-Statistical Potentials, accounting for the type of amino acid pairs, their hydrophobicity, solvent accessibility and type of secondary structure. These potentials have been successfully used to identify near-native structures in protein structure prediction, rank protein docking poses, and predict PPI binding affinities. RESULTS: Here, we present the SPServer, a web server that applies the Split-Statistical Potentials to analyze protein folds and protein interfaces. SPServer provides global scores as well as residue/residue-pair profiles presented as score plots and maps. This level of detail allows users to: (1) identify potentially problematic regions on protein structures; (2) identify disrupting amino acid pairs in protein interfaces; and (3) compare and analyze the quality of tertiary and quaternary structural models. CONCLUSIONS: While there are many web servers that provide scoring functions to assess the quality of either protein folds or PPI structures, SPServer integrates both aspects in a unique easy-to-use web server. Moreover, the server permits to locally assess the quality of the structures and interfaces at a residue level and provides tools to compare the local assessment between structures. SERVER ADDRESS: https://sbi.upf.edu/spserver/ .

Identification of novel seed longevity genes related to oxidative stress and seed coat by genome-wide association studies and reverse genetics.

Seed longevity is a polygenic trait of relevance for agriculture and for understanding the effect of environment on the ageing of biological systems. In order to identify novel longevity genes, we have phenotyped the natural variation of 270 ecotypes of the model plant, Arabidopsis thaliana, for natural ageing and for three accelerated ageing methods. Genome-wide analysis, using publicly available single-nucleotide polymorphisms (SNPs) data sets, identified multiple genomic regions associated with variation in seed longevity. Reverse genetics of 20 candidate genes in Columbia ecotype resulted in seven genes positive for seed longevity (PSAD1, SSLEA, SSTPR, DHAR1, CYP86A8, MYB47 and SPCH) and five negative ones (RBOHD, RBOHE, RBOHF, KNAT7 and SEP3). In this uniform genetic background, natural and accelerated ageing methods provided similar results for seed-longevity in knock-out mutants. The NADPH oxidases (RBOHs), the dehydroascorbate reductase (DHAR1) and the photosystem I subunit (PSAD1) highlight the important role of oxidative stress on seed ageing. The cytochrome P-450 hydroxylase, CYP86A8, and the transcription factors, MYB47, KNAT7 and SEP3, support the protecting role of the seed coat during seed ageing.

Evaluation of the MD Anderson tumor score for diffuse large B-cell lymphoma in the rituximab era.

OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. METHODS: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). RESULTS: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. CONCLUSIONS: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.

Experience with ambulatory high-dose methotrexate administration as CNS prophylaxis in patients with non-Hodgkin lymphoma.

BACKGROUND: We describe the feasibility and safety of an oral administration schedule of hydration, alkalinization and leucovorin rescue with an ambulatory high-dose methotrexate regimen. METHODS: Single-centre prospective observational study conducted within a tertiary hospital where all patients have received systemic high-dose methotrexate (3.5 g/m2). Patients were instructed to keep an adequate ambulatory oral hydration and alkalinization to monitor urine pH and to adjust bicarbonate according to our institution's treatment protocol. High-dose methotrexate was infused over 4 h. Urine pH was checked before high-dose methotrexate administration, and for any value less than 7 a sodium bicarbonate bolus was given. Leucovorin at a standard dose was begun 24 h after high-dose methotrexate. methotrexate serum concentrations were monitored daily from 24 h after administration until clearance (level ≤ 0.1 µmol/L). RESULTS: From January 2016 to June 2018, 49 ambulatory high-dose methotrexate courses were given to 18 patients. No dose reduction was required afterwards. All patients completed succesfully the planned three doses in an outpatient basis, except four patients, one of them due to pneumonitis. Previous to methotrexate infusion, urinary pH > 7 was achieved in 35 (79.5%) cycles. Methotrexate clearance was achieved by 72 h in 35 courses (71.4%), and by 96 h in 100%. Neutropenia/trombocytopenia grades III/IV were observed in four cycles (8.16%) and two (4.08%) cycles, respectively. Around 20.40% were associated with stomatitis, 14.20% vomiting, 10.20% asthenia, 8.16% diarrhea and 6.12% with renal toxicity. CONCLUSIONS: Ambulatory administration of high-dose methotrexate as CNS prophylaxis is safe and feasible following the described approach, allowing us to optimize healthcare resources.

Effect of agitation speed and aeration rate on fructosyltransferase production of Aspergillus oryzae IPT-301 in stirred tank bioreactor.

OBJECTIVE: Fructooligosaccharides (FOS) are prebiotic substances that have been extensively incorporated in different products of food industry mostly for their bifidogenic properties and economic value. The main commercial FOS production comes from the biotransformation of sucrose and intracellular and extracellular microbial enzymes-fructosyltransferases (FTase). Aspergillus oryzae IPT-301 produces FTase. In order to increase its production, this study focuses on evaluating the effects of different agitation speed and aeration rates which affect yields in a stirred tank bioreactor. RESULTS: Agitation had more influence on cell growth than aeration. The maximum intracellular FTase activity and the volumetric productivity of total intracellular FTase were obtained at 800 rpm and 0.75 vvm, and reached values of 2100 U g-1 and 667 U dm-3 h-1, respectively. The agitation speed had a strong influence on the activity of extracellular FTase produced which reached the maximum amount of 53 U cm-3. The higher value of total activity obtained was 22,831 U dm-3 at 0.75 vvm and 800 rpm. CONCLUSION: Aeration rates and agitation speed showed strong influence upon the growth and production of fructosyltransferase from Aspergillus oryzae IPT-301 in media containing sucrose as carbon source. The control of aeration rate and agitation speed can be a valuable fermentation strategy to improve enzyme production.

Biological effectiveness of very high gamma dose rate and its implication for radiological protection.

Many experimental studies are carried out to compare biological effectiveness of high dose rate (HDR) with that of low dose rate (LDR). The rational for this is the uncertainty regarding the value of the dose rate effectiveness factor (DREF) used in radiological protection. While a LDR is defined as 0.1 mGy/min or lower, anything above that is seen as HDR. In cell and animal experiments, a dose rate around 1 Gy/min is usually used as representative for HDR. However, atomic bomb survivors, the reference cohort for radiological protection, were exposed to tens of Gy/min. The important question is whether gamma radiation delivered at very high dose rate (VHDR-several Gy/min) is more effective in inducing DNA damage than that delivered at HDR. The aim of this investigation was to compare the biological effectiveness of gamma radiation delivered at VHDR (8.25 Gy/min) with that of HDR (0.38 Gy/min or 0.79 Gy/min). Experiments were carried out with human peripheral mononuclear cells (PBMC) and the human osteosarcoma cell line U2OS. Endpoints related to DNA damage response were analysed. The results show that in PBMC, VHDR is more effective than HDR in inducing gene expression and micronuclei. In U2OS cells, the repair of 53BP1 foci was delayed after VHDR indicating a higher level of damage complexity, but no VHDR effect was observed at the level of micronuclei and clonogenic cell survival. We suggest that the DREF value may be underestimated when the biological effectiveness of HDR and LDR is compared.

Deletion of the Cold Thermoreceptor TRPM8 Increases Heat Loss and Food Intake Leading to Reduced Body Temperature and Obesity in Mice.

The coupling of energy homeostasis to thermoregulation is essential to maintain homeothermy in changing external environments. We studied the role of the cold thermoreceptor TRPM8 in this interplay in mice of both sexes. We demonstrate that TRPM8 is required for a precise thermoregulation in response to cold, in fed and fasting. Trpm8-/- mice exhibited a fall of 0.7°C in core body temperature when housed at cold temperatures, and a deep hypothermia (<30°C) during food deprivation. In both situations, TRPM8 deficiency induced an increase in tail heat loss. This, together with the presence of TRPM8-sensory fibers innervating the main tail vessels, unveils a major role of this ion channel in tail vasomotor regulation. Finally, TRPM8 deficiency had a remarkable impact on energy balance. Trpm8-/- mice raised at mild cold temperatures developed late-onset obesity and metabolic dysfunction, with daytime hyperphagia and reduction of fat oxidation as plausible causal factors. In conclusion, TRPM8 fine-tunes eating behavior and fuel utilization during thermoregulatory adjustments to mild cold. Persistent imbalances in these responses result in obesity.SIGNIFICANCE STATEMENT The thermosensitive ion channel TRPM8 is required for a precise thermoregulatory response to cold and fasting, playing an important role in tail vasoconstriction, and therefore heat conservation, as well as in the regulation of ingestive behavior and metabolic fuel selection upon cooling. Indeed, TRPM8-deficient mice, housed in a mild cold environment, displayed an increase in tail heat loss and lower core body temperature, associated with the development of late-onset obesity with glucose and lipid metabolic dysfunction. A persistent diurnal hyperphagia and reduced fat oxidation constitute plausible underlying mechanisms in the background of a deficient thermoregulatory adjustment to mild cold ambient temperatures.

Social-Aware Driver Assistance Systems for City Traffic in Shared Spaces.

Shared spaces are gaining presence in cities, where a variety of players and mobility types (pedestrians, bicycles, motorcycles, and cars) move without specifically delimited areas. This makes the traffic they comprise challenging for automated systems. The information traditionally considered (e.g., streets, and obstacle positions and speeds) is not enough to build suitable models of the environment. The required explanatory and anticipation capabilities need additional information to improve them. Social aspects (e.g., goal of the displacement, companion, or available time) should be considered, as they have a strong influence on how people move and interact with the environment. This paper presents the Social-Aware Driver Assistance System (SADAS) approach to integrate this information into traffic systems. It relies on a domain-specific modelling language for social contexts and their changes. Specifications compliant with it describe social and system information, their links, and how to process them. Traffic social properties are the formalization within the language of relevant knowledge extracted from literature to interpret information. A multi-agent system architecture manages these specifications and additional processing resources. A SADAS can be connected to other parts of traffic systems by means of subscription-notification mechanisms. The case study to illustrate the approach applies social knowledge to predict people's movements. It considers a distributed system for obstacle detection and tracking, and the intelligent management of traffic signals.

Differential prognostic impact of GELTAMO-IPI in cell of origin subtypes of Diffuse Large B Cell Lymphoma as defined by the Hans algorithm.

The Grupo Español de Linfomas y Trasplantes de Médula Ósea International Prognostic Index (GELTAMO-IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low-intermediate (LIR), high-intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO-IPI in the DLBCL subtypes defined by the immunohistochaemistry-based Hans algorithm, Germinal Centre B (GCB) and non-GCB. A multivariate Cox regression model including GELTAMO-IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non-GCB) and both the GELTAMO-IPI and the COO subtype in 780 (353 GCB; 427 non-GCB). There were no differences in 5-year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO-IPI risk groups and the COO subtypes (P = 0·005), indicating that GELTAMO-IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5-year OS of 100%, 75% and 52%, respectively. In the non-GCB subtype, LR, the combined LIR+HIR and HR had a 5-year OS of, 97%, 82% and 35% respectively. GELTAMO-IPI identifies a genuine poor outcome group of patients in the DLBCL non-GCB subtype.

Design, Fabrication and Testing of a High-Sensitive Fibre Sensor for Tip Clearance Measurements.

A highly sensitive fibre bundle-based reflective optical sensor has been designed and fabricated for Tip Clearance measurements in a turbine rig. The sensor offers high spatial and temporal resolution. The sensor probe consists of a single-mode transmitting fibre and two concentric rings of receiving multimode fibres that collect reflected light in a differential detection gain configuration, yielding a highly linear calibration curve for distance measurements. The clearance measurement range is approximately 2 mm around the central point fixed at 3.2 mm from the probe tip, and the sensitivity of the probe is 61.73 mm-1. The fibre bundle has been designed to ensure that the distance security specifications required for the experimental program of the turbine are met. The optical sensor has operated under demanding conditions set by the blade and casing design. The experimental results obtained so far are promising and lead us to think that the optical sensor has great potential for online clearance measurements with high precision.