Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

11 pages, 6 figures, 1 table.Background The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of 1phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Methodology/Principal Findings Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. Conclusion/Significance This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.This work has been supported by grants to JCL from Comunidad de Madrid (GR-SAL-0821-2004), Ministerio de Ciencia e Innovación (SAF2008-03750, RD06/0020/0016), Fundación Mutua Madrileña, and by a grant to ARM from Fundación Mutua Madrileña.Peer reviewe

Effects of resistance training program on muscle mass and muscle strength and the relationship with cognition in Older Women

The aim of this study was to study the effects of a resistance training programme on Maximal Dynamic Strength (MDS) and muscle morphology of the upper limbs (UL) and lower limbs (LL), as well as to analyse their association with cognition, in a population of older women. The study had a duration of 24 months and a total of 93 Chilean older women participated. The participants were divided into two groups: The Physical Activity Group (PAG, n = 45, age (X ± SD) 77.93 ± 3.54 years), and the Sedentary Group (SG, n = 48, age (X ± SD) 77.71 ± 3.41 years). The PAG carried out a muscle strength training routine twice per week. The following variables were evaluated: Muscle function through maximal dynamic strength (1RM), muscle morphology through arm and calf circumference (AC and CC, respectively), and cognition (Mini Mental State Examination: MMSE). The results show that the SG recorded significant decreases (percent changes; p < 0.05) in the analysed variables: MMSE (-3.5%), MDS in UL (-3.3%), MDS in LL (-4.1%), AC (-4.5%), CC (-4.1%), and BMI (-3.1%). However, the PAG improved significantly in all the analysed variables except in BMI: MMSE (3.9%), MDS in UL (3.6%), MDS in LL (3.5%), AC (1.8%), and CC (2.5%). Moreover, there was a significant association (p < 0.05) between the changes in the muscle strength variables and the changes in cognition level. Therefore, it can be concluded that a two-year muscle strength training programme (load intensity between 30-55% 1RM) in older women improves Maximal Dynamic Strength in UL and LL, as well as muscle mass in arms and calves. Furthermore, it can be asserted that the changes in muscle strength levels could predict the changes in the levels of cognition in older women. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

A new way of valorizing biomaterials: the use of sunflower protein for 1 a-tocopherol microencapsulation

Biopolymer based microparticles were efficiently prepared from sunflower protein (SP) wall material and a-tocopherol (T) active core using a spray-drying technique. Protein enzymatic hydrolysis and/or N-acylation were carried out to make some structural modifications to the vegetable protein. Native and hydrolyzed SP were characterized by Asymmetrical Flow Field-Flow Fractionation (AsFlFFF). Results of AsFlFFF confirmed that size of proteinic macromolecules was influenced by degree of hydrolysis. The effect of protein modifications and the influence of wall/core ratio on both emulsions and microparticle properties were evaluated. Concerning emulsion properties, enzymatic hydrolysis involved a decrease in viscosity, whereas acylation did not significantly affect emulsion droplet size and viscosity. Microparticles obtained with hydrolyzed SP wall material showed lower retention efficiency (RE) than native SP microparticles (62-80% and 93% respectively). Conversely, acylation of both hydrolyzed SP and native SP allowed a higher RE to be reached (up to 100%). Increasing T concentration increased emulsion viscosity, emulsion droplet size, microparticle size, and enhanced RE. These results demonstrated the feasibility of high loaded (up to 79.2% T) microparticles

Natural Distribution of Parasitoids of Larvae of the Fall Armyworm, Spodoptera frugiperda, in Argentina

To develop a better understanding of the natural distribution of the fall armyworm, Spodoptera frugiperda (Smith) (Lepidoptera: Noctuidae), and to update the knowledge of the incidence of its complex of parasitoids. S. frugiperda, samplings in whorl-stage corn were carried out in provinces of Argentina from 1999 to 2003. S. frugiperda larvae were collected from corn in localities of the provinces of Tucumán, Salta, Jujuy, Santiago del Estero, La Rioja, Córdoba, San Luis, Chaco and Misiones. In each locality 30 corn plants were sampled and only larvae located in those plants were collected. The parasitoids that emerged from S. frugiperda larvae were identified and counted. The abundance of the parasitoids and the parasitism rate were estimated. The S. frugiperda parasitoids collected were Campoletis grioti (Blanchard) (Hymenoptera: Ichneumonidae), Chelonus insularis (Cresson) (Hymenoptera: Braconidae), Archytas marmoratus (Townsend) (Diptera Tachinidae) and/or A. incertus (Macquart), Ophion sp. (Hymenoptera: Ichneumonidae), Euplectrus platyhypenae Howard (Hymenoptera: Eulophidae), and Incamyia chilensis (Aldrich) (Diptera Tachinidae). C. grioti was the most abundant and frequent during the five-year survey. Similar diversity of parasitoids was obtained in all the provinces, with the exception of I. chilensis and E. platyhypenae that were recovered only in the province of Salta. In the Northwestern region, in Tucumán, C. grioti and species of Archytas were the most abundant and frequent parasitoids. On the contrary, in Salta and Jujuy Ch. insularis was the parasitoid most abundant and frequently recovered. The parasitism rate obtained in Tucumán, Salta and Jujuy provinces were 21.96%, 17.87% and 6.63% respectively with an average of 18.93%. These results demonstrate that hymenopteran and dipteran parasitoids of S. frugiperda occurred differentially throughout the Argentinian provinces and played an important role on the natural control of the S. frugiperda larval population

Wideband 67-116 GHz cryogenic receiver development for ALMA Band 2

The Atacama Large Millimeter/sub-millimeter Array (ALMA) is already revolutionising our understanding of the Universe. However, ALMA is not yet equipped with all of its originally planned receiver bands, which will allow it to observe over the full range of frequencies from 35-950 GHz accessible through the Earth's atmosphere. In particular Band 2 (67-90 GHz) has not yet been approved for construction. Recent technological developments in cryogenic monolithic microwave integrated circuit (MMIC) high electron mobility transistor (HEMT) amplifier and orthomode transducer (OMT) design provide an opportunity to extend the originally planned on-sky bandwidth, combining ALMA Bands 2 and 3 into one receiver cartridge covering 67-116 GHz. The IF band definition for the ALMA project took place two decades ago, when 8 GHz of on-sky bandwidth per polarisation channel was an ambitious goal. The new receiver design we present here allows the opportunity to expand ALMA's wideband capabilities, anticipating future upgrades across the entire observatory. Expanding ALMA's instantaneous bandwidth is a high priority, and provides a number of observational advantages, including lower noise in continuum observations, the ability to probe larger portions of an astronomical spectrum for, e.g., widely spaced molecular transitions, and the ability to scan efficiently in frequency space to perform surveys where the redshift or chemical complexity of the object is not known a priori. Wider IF bandwidth also reduces uncertainties in calibration and continuum subtraction that might otherwise compromise science objectives. Here we provide an overview of the component development and overall design for this wideband 67-116 GHz cryogenic receiver cartridge, designed to operate from the Band 2 receiver cartridge slot in the current ALMA front end receiver cryostat.Comment: 8 pages, proceedings from the 8th ESA Workshop on Millimetre-Wave Technology and Applications (https://atpi.eventsair.com/QuickEventWebsitePortal/millimetre-wave/mm-wave

Assessment of Platelet REACtivity After Transcatheter Aortic Valve Replacement : The REAC-TAVI Trial

The REAC-TAVI (Assessment of platelet REACtivity after Transcatheter Aortic Valve Implantation) trial enrolled patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) pre-treated with aspirin + clopidogrel, aimed to compare the efficacy of clopidogrel and ticagrelor in suppressing high platelet reactivity (HPR) after TAVI. Current recommendations support short-term use of aspirin + clopidogrel for patients with severe AS undergoing TAVR despite the lack of compelling evidence. This was a prospective, randomized, multicenter investigation. Platelet reactivity was measured at 6 different time points with the VerifyNow assay (Accriva Diagnostics, San Diego, California). HPR was defined as (P2Y reaction units (PRU) ≥208. Patients with HPR before TAVR were randomized to either aspirin + ticagrelor or aspirin + clopidogrel for 3 months. Patients without HPR continued with aspirin + clopidogrel (registry cohort). The primary endpoint was non-HPR status (PRU <208) in ≥70% of patients treated with ticagrelor at 90 days post-TAVR. A total of 68 patients were included. Of these, 48 (71%) had HPR (PRU 273 ± 09) and were randomized to aspirin + ticagrelor (n = 24, PRU 277 ± 08) or continued with aspirin + clopidogrel (n = 24, PRU 269 ± 49). The remaining 20 patients (29%) without HPR (PRU 133 ± 12) were included in the registry. Overall, platelet reactivity across all the study time points after TAVR was lower in patients randomized to ticagrelor compared with those treated with clopidogrel, including those enrolled in the registry (p < 0.001). The primary endpoint was achieved in 100% of patients with ticagrelor compared with 21% with clopidogrel (p < 0.001). Interestingly, 33% of clopidogrel responder patients at baseline developed HPR status during the first month after TAVR. HPR to clopidogrel is present in a considerable number of patients with AS undergoing TAVR. Ticagrelor achieves a better and faster effect, providing sustained suppression of HPR to these patients. (Platelet Reactivity After TAVI: A Multicenter Pilot Study [REAC-TAVI]; NCT02224066

Agroecosystem energy transitions in the old and new worlds: trajectories and determinants at the regional scale

Energy efficiency in biomass production is a major challenge for a future transition to sustainable food and energy provision. This study uses methodologically consistent data on agroecosystem energy flows and different metrics of energetic efficiency from seven regional case studies in North America (USA and Canada) and Europe (Spain and Austria) to investigate energy transitions in Western agroecosystems from the late nineteenth to the late twentieth centuries. We quantify indicators such as external final energy return on investment (EFEROI, i.e., final produce per unit of external energy input), internal final EROI (IFEROI, final produce per unit of biomass reused locally), and final EROI (FEROI, final produce per unit of total inputs consumed). The transition is characterized by increasing final produce accompanied by increasing external energy inputs and stable local biomass reused. External inputs did not replace internal biomass reinvestments, but added to them. The results were declining EFEROI, stable or increasing IFEROI, and diverging trends in FEROI. The factors shaping agroecosystem energy profiles changed in the course of the transition: Under advanced organic and frontier agriculture of the late nineteenth and early twentieth centuries, population density and biogeographic conditions explained both agroecosystem productivity and energy inputs. In industrialized agroecosystems, biogeographic conditions and specific socio-economic factors influenced trends towards increased agroecosystem specialization. The share of livestock products in a region's final produce was the most important factor determining energy returns on investment

Review of the late Quaternary stratigraphy of the northern Gulf of Cadiz continental margin:New insights into controlling factors and global implications

Over the past decades, the northern Gulf of Cadiz has been the focus of a wide range of late Quaternary seismic and sequence stratigraphic studies, either addressing the slope contourite depositional system (CDS), or the development of the continental shelf. Yet, high-resolution seismic data bridging between these domains and age information have remained sparse. This study, based on new high-resolution reflection seismic profiles calibrated to IODP Expedition 339 sites U1386/U1387, now presents an updated stratigraphic framework, that integrates (for the first time) the late Quaternary records of the northern Gulf of Cadiz middle slope to shelf off the Guadiana River. Seismic stratigraphic analysis of the stacking, depocenter distribution, stratal architecture and facies of the seismic (sub-)units reveals the influence of similar to 100 kyr sea-level variations paced by Milankovitch (eccentricity) cycles, tectonics (manifesting as two pulses of uplift and margin progradation), sediment supply and bottom current activity. This work furthermore contributes to the application and understanding of high-resolution, late Quaternary sequence stratigraphy. Firstly, the proposed sequence stratigraphic interpretation shows that adaptations to the basic models are required to integrate the shelf and slope record, and to account for the presence of a significant alongslope (bottom current-controlled) component. Secondly, the results confirm that the sequences are dominantly composed of regressive deposits, whereas the preservation of transgressive to highstand deposits is more irregular. Significantly, the common assumption that successive major glacial lowstands are consistently recorded as well-marked, shelf-wide erosional unconformities, is demonstrated to be occasionally invalid, as tectonics can obliterate this one-to-one relationship

SMG-1 and mTORC1 Act Antagonistically to Regulate Response to Injury and Growth in Planarians

Planarian flatworms are able to both regenerate their whole bodies and continuously adapt their size to nutrient status. Tight control of stem cell proliferation and differentiation during these processes is the key feature of planarian biology. Here we show that the planarian homolog of the phosphoinositide 3-kinase-related kinase (PIKK) family member SMG-1 and mTOR complex 1 components are required for this tight control. Loss of smg-1 results in a hyper-responsiveness to injury and growth and the formation of regenerative blastemas that remain undifferentiated and that lead to lethal ectopic outgrowths. Invasive stem cell hyper-proliferation, hyperplasia, hypertrophy, and differentiation defects are hallmarks of this uncontrolled growth. These data imply a previously unappreciated and novel physiological function for this PIKK family member. In contrast we found that planarian members of the mTOR complex 1, tor and raptor, are required for the initial response to injury and blastema formation. Double smg-1 RNAi experiments with tor or raptor show that abnormal growth requires mTOR signalling. We also found that the macrolide rapamycin, a natural compound inhibitor of mTORC1, is able to increase the survival rate of smg-1 RNAi animals by decreasing cell proliferation. Our findings support a model where Smg-1 acts as a novel regulator of both the response to injury and growth control mechanisms. Our data suggest the possibility that this may be by suppressing mTOR signalling. Characterisation of both the planarian mTORC1 signalling components and another PIKK family member as key regulators of regeneration and growth will influence future work on regeneration, growth control, and the development of anti-cancer therapies that target mTOR signalling