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2017. októberétől 2021. októberéig terjedő időszakban vizsgáltuk egy középmagyarországi szántóföld szénforgalmát gázcseremérések segítségével. A mért nettó ökoszisztéma gázcsere (NEE) adatokból kumulált összegeket számoltunk éves bontásban, illetve az egyes növényállományok és ugar időszakok szerint. Gazdálkodási adatok segítségével számoltuk a területre behozott (import) és onnan elvitt (export) szénmennyiségeket, valamint az NEE, az import és az export áramokat összesítve szénmérleget (NECB) számítottunk az NEE összegekhez hasonló bontásban.Az eredmények alapján a szántóföld minden évben szénelnyelőnek bizonyult, annak ellenére, hogy a vizsgált időszak során több vízhiányos periódus is hátráltatta a növények megfelelő fejlődését és ezzel a szénfelvételt. A mért éves átlagos NEE összeg –69,6 g C m–2 év–1 volt. Ezzel szemben a teljes – laterális áramokat is tartalmazó – szénmérleg minden évben és minden növényállomány esetében veszteségesnek bizonyult, átlagosan –168 g C m–2 év–1 volt a szénveszteség mértéke. Ennek a deficitnek a jelentős része a vízhiányos időszakok alatti lecsökkent szénfelvételnek köszönhető, ezt jól mutatja a két őszi búza állomány szénmérlege közötti 66 g C m–2-es különbség, ahol az első állomány jó vízellátás mellett, a második pedig vízhiányos időszak alatt fejlődött. Nedvesebb időszakban vélhetően kevésbé jelentős a szénveszteség mértéke.A szakirodalom alapján nincs olyan módszer, amellyel önmagában kompenzálni lehet egy ilyen mértékű veszteséget, azonban több olyan eljárás is létezik, amelyek kombinációjával jó eredményeket lehet elérni. Fontos lenne a hazánkban jól alkalmazható módszerek feltárása és azok szénmérlegben játszott szerepének számszerűsítése.

Soil respiration is a highly complex process including a wide range of soil biota (autotrophic and heterotrophic functioning) and different pathways of carbon cycling (decomposition, arbon allocation), all being under the control of environmental and biotic drivers. The most important biotic driver is the photosynthetic activity of the vegetation providing supply mainly for the autotrophic component of soil respiration: plant roots and their symbiotic partners - such as arbuscular mycorrhizal fungi (AMF). By acting as a source of CO2 and a pathway of carbon to the SOM, the role of AMF in carbon balance is unquestionable, not to mention that mycorrhizal C allocation could determine the long-term C storage potential of an ecosystem.The objective of this study was to describe the time-lagged relationship between gross primary production (GPP) and the mycorrhizal soil respiration component, so to determine the amount of carbon derived from GPP appearing as mycorrhizal mycelial respiration. Measurements of CO2 efflux were conducted in three different treatments – i) undisturbed, root and AMF-included (Rs), ii) root-excluded (Rbasal + myc) and iii) root- and AMF-excluded (Rbasal) plots – for three consecutive years in a Central-Hungarian dry sandy grassland between July 2011 and May 2014. GPP data were derived from eddy-covariance (EC) measurements, while an automated soil respiration system (SRS) consisting of ten chambers was used for continuous and long-term measurement of soil CO2 efflux. We analysed the relationship between mycorrhizal mycelial respiration and GPP by using cross-correlation and GAMs (generalized additive models). Besides, we used sine wave models to describe the diel pattern of basal and mycorrhizal fungi respiration in the soil together with the diel patterns of soil temperature and GPP.Considering the whole dataset correlation between GPP and mycorrhizal fungi respiration was highest at 13.5 hours time lag, while the average difference between peak timing of mycorrhizal fungi respiration and peak timing of GPP was 15 hours. However, the time lag and the peak timing difference varied from 10-24 hours. According to the results, carbon allocation to mycorrhizal fungi is a fast process in dry grasslands and the main driver of this respiration component is the GPP.

Quantifying greenhouse gas emissions has been a priority for climate scientists for decades. As a result, the spatial and temporal dynamics of emissions have been widely studied, but to date, we still do not fully understand the main drivers of the variation in patterns. The aim of our research is to quantify the spatio-temporal variability of these greenhouse gases under various nutrient supply conditions and different tillage practices (plow or cultivator) on sandy-clay and loam soils.Our measurements took place near Kartal on loam soil and near Gödöllő on sandy-clay soil, in Central Hungary, in 2022 on winter wheat. CO2 and N2O fluxes are analyzed with Li-cor gas analyzers (LI-870 CO2/H2O Analyzer and LI-7820 N2O/H2O Trace Gas Analyzer) connected to the 8200-01S Smart Chamber. We can track both modest changes brought on by natural factors (precipitation, temperature variations) and the impact of more significant artificial factors (fertilization, type of tillage) on the N2O and CO2 flux using these rather sensitive devices. In Kartal, 24, and in Gödöllő 40 KG-PVC rings with a diameter of 20 cm were placed in the study areas and measured on a weekly basis. In Kartal half of the collars received fertilizer, and the other half was covered during the application. In Gödöllő, 8 different treatments can be distinguished, resulting from a combination of 3 different fertilizer doses (0kg/ha, 75kg/ha, and 150kg/ha), 2 tillage methods (plow and cultivator), and soil conditioners. The collars protrude 4 cm from the soil and the inner soil surface has been cleared of vegetation. The gas exchange between soil and air is measured for 3 minutes on each collar, while simultaneously measuring soil moisture, temperature, and vegetation cover (LAI) near the collars. Soil samples were taken monthly to a depth of 15 cm, and 50 cm from the collars.Based on our observation, in the case of N2O emission, there are significant differences between the two study areas. On average N2O emissions in Gödöllő were higher than in Kartal. Cumulative N2O emissions were significantly higher in areas receiving higher doses of fertilizer. For 150kg/ha, the highest value was 42 g N m2, while for 0kg/ha and 75kg/ha, lower values of around 16-20 g N m2 were observed. With average emissions of 420–500 g C m2, there are no discernible variations in cumulative CO2 emission across treatments. However, the temporal variation of both GHG emissions shows differences due to the persistent drought in summer. During the rainy season, spring and autumn, a more intense N2O and CO2 flux were observed due to soil respiration.

Soil respiration of grasslands is highly variable both in time and space reflecting the topographic characteristics, the changing environmental constrains and biological activity of the vegetation. The aim of this study was to describe the effect of gross primary productivity (GPP) and soil organic carbon content (SOC) on soil respiration under varying environmental conditions in a dry grassland site in Hungary. We made spatially explicit measurements of variables including soil respiration, aboveground biomass, green vegetation index, soil water content, and soil temperature during an 8-year study in the vegetation periods. Sampling was conducted 23 times in 80 x 60 m grids of 10 m resolution with 78 sampling points. Altitude, slope, and soil organic carbon were used as background factors at each sampling position. Site-level GPP data were derived from eddy-covariance measurements and used for the estimation of GPP at every sampling position as a weighted metric on the basis of the biomass and green vegetation index of the positions. Data were analyzed using generalized additive models (GAM). Spatially, soil respiration had negative correlation with soil temperature, altitude and slope, while it was positively correlated with soil water content, aboveground biomass, green vegetation index and SOC. Soil respiration was significantly different between SOC groups (low-medium-high carbon content), mean soil respiration increased with soil carbon content. According to the GAM analysis, the shape of the GPP response was almost linear in each SOC groups and GPP had a strong influence on soil respiration in all of the groups besides temperature and soil water content. The results suggest that GPP and the resulting belowground carbon allocation affecting mainly the autotrophic components of soil respiration have similar influence on soil respiration as the main environmental variables.

Background Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson’s disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification. Methods In this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn. Results We found the high-molecular weight fraction of CSF (> 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates. Conclusions Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts.

The ongoing COVID19 pandemic represents an unprecedented opportunity to test the feasibility of monoclonal antibody (mAb) therapies against respiratory viruses. While many hurdles were easily predictable (e.g. time to develop, scalability, and economic sustainability), mAb cocktails (i.e. the combination of two mAbs) were finally deployed in 2021, one year after the beginning of the pandemic. Of them, the REGN-COV-2 cocktail was likely the most successful experience and contributed at saving lives at the time of the wave sustained by the Delta variant of concern (VOC).Herein, the authors review the preclinical and clinical history of the casirivimab + imdevimab cocktail for the treatment of novel coronavirus infection. The authors furthermore provide the reader with their perspectives on this cocktail including its current place in the treatment armamentarium.Unfortunately, results from clinical trials highlighted a very limited efficacy in inpatients; furthermore, the current evidence with regards to its lack of effectiveness against the current dominant VOC (omicron) suggests a very limited use of these drugs in the future. In the authors' opinion, this story reminds us of the limitations of mAb therapies in pandemic settings, and of the inferiority of monoclonal versus polyclonal antibody-based therapeutics in such scenarios.

Background: Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson’s disease (PD) and other synucleinopathies. In these diseases, the extracellular spreading of misfolded α-syn significantly contributes to the cell-to-cell propagation of the α-syn misfolding pathology in a prion-like fashion. Therefore, extracellular α-syn aggregates are considered primary targets both for diagnostics and for novel disease modifying therapies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially sabotaging unoptimized α-syn SAAs and preventing seed quantification. Methods: In this study, we characterized the inhibitory effect of CSF on in vitro α-syn aggregation by means of CSF fractionation, mass spectrometry, dot-blot, Western blot, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn. Results: We found the high-molecular weight fraction of CSF (>100,000 Da) to be highly inhibitory and identified lipoproteins to be the main drivers of this effect. We evaluated direct interaction between lipoprotein and α-syn and observed lipoprotein-α-syn complexes by transmission electron microscopy. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, suggesting interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates instead. Lastly, we observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of a highly accurate diagnostic SAA. Conclusions: Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant biological and translational implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results so far obtained by the analysis of SAA-derived kinetic parameters. Furthermore, our data show that apolipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts.

Parkinson’s disease (PD) is a neurodegenerative disorder often associated with pre-motor symptoms involving both gastrointestinal and olfactory tissues. PD patients frequently suffer from hyposmia, hyposalivation, dysphagia and gastrointestinal dysfunctions. During the last few years it has been speculated that microbial agents could play a crucial role in PD. In particular, alterations of the microbiota composition (dysbiosis) might contribute to the formation of misfolded α-synuclein, which is believed to be the leading cause of PD. However, while several findings confirmed that there might be an important link between intestinal microbiota alterations and PD onset, little is known about the potential contribution of the nasal microbiota. Here, we describe the latest findings on this topic by considering that more than 80% of patients with PD develop remarkable olfactory deficits in their prodromal disease stage. Therefore, the nasal microbiota might contribute to PD, eventually boosting the gut microbiota in promoting disease onset. Finally, we present the applications of the seed amplification assays to the study of the gut and olfactory mucosa of PD patients, and how they could be exploited to investigate whether pathogenic bacteria present in the gut and the nose might promote α-synuclein misfolding and aggregation.

Aging is a progressive and multifaceted event, which involves all the cells and organs of the human body. In this chapter we will try to analyze how the senses of smell and taste change with age. Anatomical and physiological modifications of the nose and salivary glands will be described, as well as changes in structures of the Central Nervous System and neurochemical processes that underlie these two senses. Finally, we will discuss the effect of many senile age drugs and chemo- radiotherapy on the perception of smell and taste, as well as the impact of chronical diseases on these senses.

Long term flux measurements are needed to improve our understanding of the carbon balance of arable lands. The objective of our study was to determine the seasonal dynamics of carbon cycling in a Hungarian cropland and to examine the effect of crop rotation on net ecosystem exchange of CO2 (NEE), furthermore to assess the influences of C outputs and inputs derived from lateral fluxes on soil organic carbon (SOC) stock. In this study we update the results presented in our poster of last year’s conference (EGU21-10977).The experiment began in 2017 and crop rotation of the measured field consisted of winter wheat (2017-2018 and 2019-2020), rapeseed (2018), sorghum (2019) and sunflower (2021). CO2 fluxes and annual net ecosystem exchange (NEE) of CO2 were measured by a field-scale eddy covariance (EC) station at a Central Hungarian cropland site. Both vertical and lateral C fluxes were taken into account when calculating the net ecosystem carbon budget (NECB).As presented in our previous study the largest sink activity was observed in the sorghum season (-277 g C m-2 from sowing to harvest). The cropland acted as a source of CO2 during the rapeseed season (140 g C m-2) due to incomplete germination caused by extreme autumnal drought.We found that during the study period both meteorological variables and lateral carbon fluxes such as C inputs derived from seed and crop residues and outputs (harvest) had significant influence on the C dynamics. The higher temperatures and precipitation amount that characterised the fall of 2019 caused large differences in NEE dynamics for winter wheat when compared to 2017. The impact of climatic factors could be seen in the sunflower period since lack of precipitation in 2021 led to remarkably low carbon uptake.Fallow periods in total covered a relatively long period of time (approximately 1 year out of the 4 year long study period). These fallow periods had a significant effect on NECB values due to immense C loss. During the four years of our experiment cumulative NEE was -222 g C m-2 and NECB was 726 g C m-2 as carbon loss during fallow periods (437 g C m-2 in total) and carbon export through harvest (964 g C m-2 in total) counterbalanced the crop’s CO2 uptake.We can conclude that while this Hungarian cropland was a sink of carbon it could not maintain the soil organic carbon content as it was not able to sequester enough carbon to do so. Cover plants and crop residue retention could be a solution to reduce the risk of soil carbon stock depletion but further studies are needed in the field of soil management practices.

Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder caused by the conformational conversion of the prion protein (PrPC) into an abnormally folded form, named prion (or PrPSc). The combination of the polymorphism at codon 129 of the PrP gene (coding either methionine or valine) with the biochemical feature of the proteinase-K resistant PrP (generating either PrPSc type 1 or 2) gives rise to different PrPSc strains, which cause variable phenotypes of sCJD. The definitive diagnosis of sCJD and its classification can be achieved only post-mortem after PrPSc identification and characterization in the brain. By exploiting the Real-Time Quaking-Induced Conversion (RT-QuIC) assay, traces of PrPSc were found in the olfactory mucosa (OM) of sCJD patients, thus demonstrating that PrPSc is not confined to the brain. Here, we have optimized another technique, named protein misfolding cyclic amplification (PMCA) for detecting PrPSc in OM samples of sCJD patients. OM samples were collected from 27 sCJD and 2 genetic CJD patients (E200K). Samples from 34 patients with other neurodegenerative disorders were included as controls. Brains were collected from 26 sCJD patients and 16 of them underwent OM collection. Brain and OM samples were subjected to PMCA using the brains of transgenic mice expressing human PrPC with methionine at codon 129 as reaction substrates. The amplified products were analyzed by Western blot after proteinase K digestion. Quantitative PMCA was performed to estimate PrPSc concentration in OM. PMCA enabled the detection of prions in OM samples with 79.3% sensitivity and 100% specificity. Except for a few cases, a predominant type 1 PrPSc was generated, regardless of the tissues analyzed. Notably, all amplified PrPSc were less resistant to PK compared to the original strain. In conclusion, although the optimized PMCA did not consent to recognize sCJD subtypes from the analysis of OM collected from living patients, it enabled us to estimate for the first time the amount of prions accumulating in this biological tissue. Further assay optimizations are needed to faithfully amplify peripheral prions whose recognition could lead to a better diagnosis and selection of patients for future clinical trials.

Parkinson’s disease (PD) and multiple system atrophy (MSA) are caused by two distinct strains of disease-associated α-synuclein (αSynD). Recently, we have shown that olfactory mucosa (OM) samples of patients with PD and MSA can seed the aggregation of recombinant α-synuclein by means of Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC). Remarkably, the biochemical and morphological properties of the final α-synuclein aggregates significantly differed between PD and MSA seeded samples. Here, these aggregates were given to neuron-like differentiated SH-SY5Y cells and distinct inflammatory responses were observed. To deepen whether the morphological features of α-synuclein aggregates were responsible for this variable SH-SY5Y inflammatory response, we generated three biochemically and morphologically distinct α-synuclein aggregates starting from recombinant α-synuclein that were used to seed αSyn_RT-QuIC reaction; the final reaction products were used to stimulate SH-SY5Y cells. Our study showed that, in contrast to OM samples of PD and MSA patients, the artificial aggregates did not transfer their distinctive features to the αSyn_RT-QuIC products and the latter induced analogous inflammatory responses in cells. Thus, the natural composition of the αSynD strains but also other specific factors in OM tissue can substantially modulate the biochemical, morphological and inflammatory features of the αSyn_RT-QuIC products.

Background Detection of the pathological and disease-associated alpha-synuclein (αSynD) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson’s disease (PD). We recently showed that αSynD can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes. Methods OM samples were prospectively collected from patients with a probable diagnosis of MSA-P (n = 20, mean disease duration 4.4 years), MSA-C (n = 10, mean disease duration 4 years), PD (n = 13, mean disease duration 8 years), and healthy control subjects (HS) (n = 11). Each sample was analyzed by αSyn_RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn_RT-QuIC analytical procedures. Results were correlated with demographic and clinical data. Results The αSyn_RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83–1.00). In particular, αSyn_RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn_RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn_RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability. Conclusions Our study provides evidence that OM-αSynD may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn_RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials.

Background Working memory (WM) abilities are frequently impaired in neurological disorders affecting fronto-parietal cortical/sub-cortical structures. WM deficits negatively influence interventional outcomes and everyday functioning. This study thus aimed at the following: (a) developing and standardizing an ecologically valid task for WM assessment ( Ice Cream Test, ICT); (b) validating and norming a novel WM test (Digit Ordering Test, DOT), as well as providing updated norms for digit span (DS) tasks, in an Italian population sample; (c) introducing a novel scoring procedure for measuring WM. Methods One-hundred and sixty-eight Italian healthy participants—73 male, 95 females; age: 48.4 ± 19.1 (18–86); education: 12.1 ± 4.8 (4–21)—underwent a thorough WM assessment—DOT, ICT, and both forward and backward DS tasks (FDS, BDS). The ICT requires participants to act as waiters who have to keep track of customers’ orders. For each task, WM and total (T) outcomes were computed, i.e., the number of elements in the longest sequence and that of recalled sequences, respectively. Norms were derived via the equivalent score (ES) method. Results DS ratios (DSRs) were computed for both WM/S and T outcomes on raw DS measures (BDS divided by FDS). Age and education significantly predicted all WM tasks; sex affected FDS and DSR-T scores (males > females). WM measures were highly internally related. Discussion The present work provides Italian practitioners with a normatively updated, multi-component, adaptive battery for WM assessment (WoMAB) as well as with novel outcomes which capture different WM facets—WM capacity and attentive monitoring abilities.

Although characteristics of the carbon balance and the organic carbon stock changes of arable lands have been the primary research focus of numerous studies, uncertainity is still a major factor in this area of research. Our aim is to determine the dynamics of carbon cycling in croplands in regards to a crop rotation consisting of different crop types and to clarify the factors driving the carbon fluxes between its main components.A field-scale eddy covariance (EC) station was established in 2017 at a cropland site in Central Hungary in order to obtain the cropland’s annual net ecosystem exchange of CO2 (NEE). Net ecosystem carbon budget (NECB) was calculated considering vertical and lateral C fluxes as well. Soil management is a conventional management with yearly deep ploughing and mineral fertilizer application.During the three years of our experiment the crop rotation included winter wheat, winter rapeseed, sorghum and winter wheat. The largest net CO2 uptake was observed during the sorghum season (from sowing to harvest, -309 g C m-2 yr-1). However, extreme autumnal drought resulted in the incomplete germination of rapeseed in 2018, which led to carbon loss (108 g C m-2 yr-1) during this vegetation period. Results show a significant difference between the two winter wheat seasons – sown in 2017 and 2019 – which can be explained by the differing precipitation of the two periods. Despite the strong CO2 uptake of winter wheat and sorghum, NECB ranged between negligible C gain (-18.26 g C m-2 year-1, sorghum) to C losses of up to 108 g C m-2 year-1 (rapeseed). During three years the C loss was 420 g C m-2 as C export through harvest and fallow periods counterbalanced the crops’ CO2 uptake.As a conclusion we can state this cropland could not sequester enough carbon to maintain the soil organic carbon pool and in order to reduce the risk of the depletion of soil carbon stock further efforts are needed in the field of soil management practices.

As substantial constituents of the multiple myeloma (MM) microenvironment, pro-inflammatory macrophages have emerged as key promoters of disease progression, bone destruction, and immune impairment. We identify beta-2-microglobulin (β2m) as a driver in initiating inflammation in myeloma-associated macrophages (MAMs). Lysosomal accumulation of phagocytosed β2m promotes β2m amyloid aggregation in MAMs, resulting in lysosomal rupture and ultimately production of active interleukin-1β (IL-1β) and IL-18. This process depends on activation of the NLRP3 inflammasome after β2m accumulation, as macrophages from NLRP3-deficient mice lack efficient β2m-induced IL-1β production. Moreover, depletion or silencing of β2m in MM cells abrogates inflammasome activation in a murine MM model. Finally, we demonstrate that disruption of NLRP3 or IL-18 diminishes tumor growth and osteolytic bone destruction normally promoted by β2m-induced inflammasome signaling. Our results provide mechanistic evidence for β2m's role as an NLRP3 inflammasome activator during MM pathogenesis. Moreover, inhibition of NLRP3 represents a potential therapeutic approach in MM.

The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation; therapy was maintained until the platelet count was ≥50x109 /L. In case of concomitant anticancer treatment and hemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135:104/135 were on anticancer therapy. We did not observe either thrombotic or major hemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non major (CRNM) in 2 patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent hemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs. This article is protected by copyright. All rights reserved.

Spatial variability of ecosystem processes constitutes significant uncertainty source in greenhouse gas flux measurements and estimations. The major disadvantage of the chamber-based flux measurements is the poor spatial representativeness, but eddy-covariance measurements also have an uncertainty due to the unequal and not constant footprint area. One way to overcome these difficulties is the spatial sampling improving the field-scale data coverage.The aim of this study was to describe the spatial variability of grassland soil CO2 efflux under varying environmental conditions. For this reason, we conducted spatial measurements on a range of variables including soil respiration, above-ground biomass, greenness index of the vegetation, soil water content and soil temperature during a seven-year study in a dry grassland site in Hungary. Altitude and soil organic carbon (SOC) content of the measuring positions were also used as background factors. Measurements were repeated 19 times at 78 positions during the study, in the main phenological stages of the grassland vegetation: spring growth, summer drought, autumn regrowth. The sampling scheme was based on 80×60 m grid of 10 m resolution. SOC content was highly variable among the positions due to the exposure differences and their environmental constrains. We analyzed the effect of the drivers on soil respiration grouping the measuring positions by the SOC content of the soil.

Anti-CD19 chimeric antigen receptor (CAR) T cells represent the first approved third-line therapy associated with long-term remissions in patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). Eligibility criteria to identify patients who can successfully receive CAR-T are still debated. For this reason, the aim of this study was to identify factors influencing eligibility and define a realistic patient estimate. Of 1100 DLBCL patients, 137 were included. Based on the Juliet trial inclusion criteria, only 64 patients (46.7%) would be eligible. Median overall survival (OS) was 8.04 months in eligible

Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic phase chronic myeloid leukemia (CP-CML) patients has become a reality. Treatment-free remission (TFR) defines the rate of success aft...

Lymphomatoid granulomatosis (LYG) is a rare Epstein–Barr Virus (EBV)-associated B-cell chronic lymphoproliferative disorder [1]. In 1972, Liebow et al. [2] described LYG as a disease that was in a ...

BACKGROUND. Patients (pts) with diffuse large B-cell lymphoma (DLBCL) refractory to second-line therapy or relapsed after an autologous stem cell transplant (ASCT) have a very poor clinical outcome with a median overall survival (OS) of 5 and 8-10 months, respectively. Autologous anti-CD19 chimeric antigen receptor (CD19 CAR) T cells have been associated with sustained complete remissions and long-term survivals in a large proportion of pts with R/R DLBCL by the two pivotal clinical trials Zuma1 and Juliet. This has led to the rapid approval by FDA and then by EMA of CAR-T cells for the third-line treatment of R/R DLBCL. Despite being a potentially revolutionary treatment for pts with advanced disease, the costs are much greater than any previously approved cancer therapy and this may become a substantial economic challenge for the health care system. The definition of inclusion and exclusion criteria capable of identifying more precisely pts who can successfully undergo CAR-T cell therapy, minimizing the severity of the toxicity, still remains a matter of discussion. Moreover, some eligible pts run the risk of becoming ineligible because of poor disease control. Indeed, one of the major obstacles to the successful use of CAR-T cells is the 4-5 week period so far required for the manufacturing and transfer of CAR-T cells. To address this issue, we have examined data of R/R DLBCL pts managed between 2010 and 2018 at our Center in order to: 1) better identify the characteristics and outcome of a cohort of R/R DLBCL pts potentially eligible, according to the approval criteria, for CAR-T cell therapy; 2) define factors influencing CAR-T cell eligibility; 3) make a realistic estimate of pts eligible for CAR-T cells. METHODS. All DLBCL pts treated at our Center with R-CHOP were recorded and those who then subsequently underwent a second or subsequent line of therapy were included in our analysis. This cohort of R/R DLBCL was reviewed under IRB approval to determinate the potential eligibility to CAR-T cell therapy by applying the Juliet clinical trial inclusion/exclusion criteria. OS was defined as the time of interval from the second relapse until death from any cause or last follow-up. OS curves were estimated according to the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariable analyses were performed using the Cox proportional hazard model. Model selection was performed in a stepwise fashion. Conditional survival at the threshold of 28 days was predicted using the final multivariate Cox regression model after estimation of the baseline hazard through a Nelson-Aalen estimator. OS curves were estimated with the Kaplan-Meier method and compared using the log-rank test. RESULTS. We have analyzed 116/480 (24%) pts with R/R DLBCL after R-CHOP managed between January 2010 and May 2018. Of these, 82/116 (71%) had received at least two lines of treatment and were further investigated. Median age was 64 years (21-87), 13 had relapsed after an ASCT, 7 within 1 year. Thirty of the 82 pts (37%) were defined as ineligible for CAR-T cell therapy by restrospective review, for reasons reported in Table 1. The median OS was 7 months in eligible vs 2 months in non-eligible pts (p=0.3). The 1-year OS was 27% in the overall pts population. In univariate analysis, OS was significantly reduced in pts with: B symptoms (p=.026), ECOG ≥2 (p= CONCLUSIONS. In this retrospective real-life cohort of R/R DLBCLs, 82/480 pts (17%) were R/R tosecond-line treatment including ASCT. Considering Juliet's inclusion/exclusion criteria for CAR-T cell therapy, only 50 pts (10.4%) would be eligible for CAR-T cells. Our analysis suggests that elevated LDH plus ECOG ≥2 have to be considered the two most significant features of very rapid disease progression. These variables should be taken in account in order to better select DLBCL pts potentially eligible to CAR-T therapy. Disclosures Di Rocco: Roche: Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Sandoz: Consultancy. Martelli:Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria. Foà:Roche: Consultancy, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.

Satellite cells are mitotically quiescent myogenic stem cells resident beneath the basal lamina surrounding adult muscle myofibers. In response to injury, multiple extrinsic signals drive the entry of satellite cells into the cell cycle and then to proliferation, differentiation, and self-renewal of their downstream progeny. Because satellite cells must endure for a lifetime, their cell cycle activity must be carefully controlled to coordinate proliferative expansion and self-renewal with the onset of the differentiation program. In this study, we find that cyclin D3, a member of the family of mitogen-activated D-type cyclins, is critically required for proper developmental progression of myogenic progenitors. Using a cyclin D3-knockout mouse we determined that cyclin D3 deficiency leads to reduced myofiber size and impaired establishment of the satellite cell population within the adult muscle. Cyclin D3-null myogenic progenitors, studied ex vivo on isolated myofibers and in vitro, displayed impaired cell cycle progression, increased differentiation potential, and reduced self-renewal capability. Similarly, silencing of cyclin D3 in C2 myoblasts caused anticipated exit from the cell cycle and precocious onset of terminal differentiation. After induced muscle damage, cyclin D3-null myogenic progenitors exhibited proliferation deficits, a precocious ability to form newly generated myofibers and a reduced capability to repopulate the satellite cell niche at later stages of the regeneration process. These results indicate that cyclin D3 plays a cell-autonomous and nonredundant function in regulating the dynamic balance between proliferation, differentiation, and self-renewal that normally establishes an appropriate pool size of adult satellite cells.

HIV-infected patients appear to have a significantly greater risk of non-AIDS comorbidities such as osteoporosis and atherosclerosis. Subjects with osteoporosis are at a higher risk of developing cardiovascular disease than those with normal bone mass, therefore a possible relation between these two conditions can be hypothesized. In the setting of HIV infection, several factors might contribute to bone disease and endothelial dysfunction. The aim of our study was to evaluate the relationship between bone and cardiovascular disease and to investigate the role of traditional factors, T-cell phenotype and osteoprotegerin in HIV positive subjects on effective antiretroviral therapy. We included 94 HIV positive subjects on antiretroviral therapy with virological suppression and 41 healthy subjects matched for age and gender as a control group. Carotid-Intima Media Thickness (c-IMT) and bone mineral density (BMD) were performed by ultrasound and DEXA, respectively. CD4+/CD8+ T-cell activation, senescence and osteoprotegerin plasma levels were measured by flow-cytometry and ELISA, respectively. Among HIV positive patients, 56.4% had osteopenia/osteoporosis and 45.7% had pathological c-IMT (>0.9 mm). Subjects with pathological c-IMT and BMD exhibited higher CD4+ and CD8+ activated, CD8+ senescent and osteoprotegerin than subjects with normal c-IMT and BMD. HIV positive subjects with osteopenia/osteoporosis had higher c-IMT than subjects with normal BMD, and linear regression analysis showed a negative correlation between BMD and c-IMT. Several factors are implicated in the pathogenesis of non-AIDS comorbidities in HIV positive patients. Osteoprotegerin together with inflammation and immunosenescence in HIV positive patients could affect bone and vascular system and could be considered as a possible common link between these two diseases.

HIV-infected patients have a significantly greater risk of cardiovascular disease. Several markers including osteoprotegerin have been shown to be involved in the development and progression of atherosclerosis. We investigated the relationship between T-cell phenotype, osteoprotegerin, and atherosclerosis evaluated by carotid intima-media thickness (c-IMT) in 94 HIV+ patients on suppressive antiretroviral therapy with Framingham score

The 4DMPET project aims to develop PET detector modules compatible with operations inside a MRI scanner. PET/MRI hybrid imaging will improve the diagnostic capabilities in soft tissues like the human brain, providing functional and morphological information within the same device. The block detector, designed to provide a measurement of the Depth of Interaction and the Time Of Flight, will feature Silicon Photomultipliers (SiPM) coupled to LYSO scintillator slabs. The Monte Carlo simulations presented here are validated by the comparison with experimental data obtained with 4 × 4 and 8 × 8 SiPM matrices coupled to a LYSO scintillator. The proposed block layout is based on a 48 mm × 48 mm × 10 mm LYSO slab, read out by two 16 × 16 identical SiPM matrices on both sides. The preliminary results of the simulation of the proposed detector are presented, showing good performance in terms of energy, spatial and time resolution.

Nine hours after ethionine administration, an inhibition of RNA synthesis in vivo is detectable (about 80%). In vitro , purified nuclei have a decreased capacity for incorporating labeled precursor into acid-insoluble material, and both RNA polymerase I + III and RNA polymerase II activities are inhibited, thus confirming the effects of ethionine on RNA synthesis (for a review, see Farber, E. (1971) Annu. Rev. Pharmacol. 11 , 71–96). It is further reported that solubilized RNA polymerases from liver nuclei of ethionine-treated rats have decreased activities with respect to polymerases from control animals. Chromatin but not deproteinized chromatin from livers of treated rats had a reduced template activity when assayed with partially purified RNA polymerase II from normal rat liver.