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The aim of the research is the laboratory study of a durable concrete, according to UNI-EN 206-1 and 11104, comparing four types of concrete by varying the type of binder to highlight some aspects of durability. For each type of concrete, to graph the correlations between: W/C ratio - resistance; cement dosage - strength; days of ripening-resistance; three mixes were packaged by varying the W/C ratio and the cement dosage. Three durable concretes were then designed, by way of example, with resistance class C30/37, exposure class XS1, workability class S5, maximum diameter 20 mm, by varying the type of binder to enhance some aspects of durability: - Type 1) With Portland II-A-LL 32.5 R cement - Type 2) With Portland II-A-LL 32.5 R cement + 11% silica fume - Type 3) With Portland II-A-LL 32.5 R cement + 22% fly ash. A cost analysis was then conducted for the concretes type 1), 2), 3), to highlight the incidence of additions in the concrete, and the benefits in terms of mechanical resistance to compression.

It has been shown that muscarinic acetylcholine receptors (mAChRs) located within the caudal nucleus tractus solitarii (cNTS) mediate a cholinergic inhibitory control mechanism of the cough reflex. Thus, identification of the involved mAChR subtypes could be of considerable interest for novel therapeutic strategies. In pentobarbital sodium-anesthetized, spontaneously breathing rabbits we investigated the contribution of different mAChR subtypes in the modulation of mechanically and chemically induced cough reflex. Bilateral microinjections of 1 mM muscarine into the cNTS increased respiratory frequency and decreased expiratory activity even to complete suppression. Interestingly, muscarine induced strong cough-suppressant effects up to the complete abolition of the reflex. Microinjections of specific mAChR subtype antagonists (M1–M5) into the cNTS were performed. Only microinjections of the M4 antagonist tropicamide (1 mM) prevented muscarine-induced changes in both respiratory activity and cough reflex. The results are discussed in light of the notion that cough involves the activation of the nociceptive system. They also suggest that M4 receptor agonists may have an important role in cough downregulation within the cNTS.

The Mediterranean mixed coniferous and broad-leaved forest of Moarda (Palermo) was affected by a large wildfire in summer 2020. In spring 2021, burned and unburned loam soil sites were sampled and the water drop penetration time (WDPT) and ethanol percentage (EP) tests applied to assess the influence of wetting-drying processes and soil water content on post-fire soil water repellency (SWR) as well as its vertical distribution. According to the WDPT test, the surface layer of the natural unburned soils was severely hydrophobic at intermediate soil water contents roughly corresponding to wilting point and SWR reduced either for very dry conditions (air- or oven-dried conditions) or wetter conditions close to field capacity. For these soils, EP test yielded results in agreement with WDPT. An influence of the wetting/drying cycle was detected as, for a given soil water content, WDPT was generally higher for the drying than the wetting process. The surface of burned soils was always wettable independently of the soil water content. The vertical distribution of SWR was modified by wildfire and the maximum hydrophobicity layer, that was located at the surface of the unburned soils, moved to a depth of 2–4 cm in the soils of burned sites. The results confirmed that wildfire can induce destruction of soil water repellency (SWR) naturally occurring at the surface of forest soils and create a shallow hydrophobic layer that may increase overland flow and erosion risk.

In the model-driven security domain, access control systems provide an application for handling access of persons through controlled gates. A gate, such as a door, can have a lock mechanism for securing the area from unauthorized access. Most commercial solutions for access control management offer pre-packaged software systems where customization of the authorization logic is either not allowed or subject to payment. Moreover, cross-platform development is a barrier for solution providers due to the high cost of development and maintenance that it implies. To overcome these limitations and further optimize the entire access control systems development process, we propose a model-driven approach that supports automatic code generation to enable communication between an IoT infrastructure and platforms for Facility Access Management. Specifically, the approach combines the benefits of Near-Field Communication (NFC) and Tinkerforge (i.e., an open-source hardware platform) with model-driven techniques. This allows the approach to exploit both behavioral and structural models for the modeling and the consequent code generation of part of the authorization mechanism, thus providing complete coverage of the code generated for the whole system. We implemented and evaluated our approach in a real-world case study within the premises of a fitness center with an IoT infrastructure consisting of several heterogeneous sensors by showing its practical applicability. Experimental results demonstrate the effectiveness of our approach in supporting abstraction and automation concerning traditional code-centric development through code generation features. Consequently, our approach makes the whole development process less time-consuming and error-prone, thus reducing the system’s time to market.

Inotersen is an antisense oligonucleotide used to treat hereditary transthyretin amyloidosis (ATTRv). The most common drug-related adverse effects (AEs) include thrombocytopenia and glomerulonephritis. Hepatic damage is rare, but liver enzyme monitoring is mandatory.A 70-year-old man with ATTRv (Val30Met) treated with inotersen developed a severe increase of transaminases, with normal bilirubin and cholinesterase levels, that forced us to stop therapy. At the same time, other causes of acquired hepatitis were excluded, and the hypothesis of an inotersen-related hepatic toxicity was supported by the normalization of liver enzymes after 40 days from the drug interruption.Our case showed that 1-year inotersen treatment can stabilize neurological impairment and even improve quality of life and suggests to carefully monitor liver enzymes in order to avoid an inotersen-related hepatic dysfunction.

Self-care performed by patients and the caregiver contribution to this self-care are essential for improving cardiovascular outcomes; however, so far, no studies have sufficiently investigated this field in Italy. This paper describes a research protocol of a multi-center longitudinal study designed to investigate the self-care of patients affected by coronary heart disease (CHD), the caregiver's contribution to this self-care, the predictors of patient and caregiver self-care, the mediating role of self-efficacy, and the self-care outcomes. Data collection will be performed across seven Italian inpatient settings at baseline and 3 and 6 months from enrollment. Multilevel modeling and actor partner interdependence models will be implemented on a sample of 330 patient-caregiver dyads to adjust for the interdependence of measurements. The study received approval from an ethics committee in Italy and was financed in January 2021 by a grant from the Solidal Foundation in Alessandria. This research will advance the knowledge about the self-care process in CHD. The results will guide research and clinical practice by identifying variables sensitive to educational interventions.

A major issue for many applications of blockchain technology is the tension between immutability and compliance to regulations. For instance, the GDPR in the EU requires to guarantee, under some circumstances, the right to be forgotten. This could imply that at some point one might be forced to delete some data from a locally stored blockchain, therefore irreparably hurting the security and transparency of such decentralized platforms. Motivated by such data protection and consistency issues, in this work we design and implement a mechanism for securely deleting data from Bitcoin blockchain. We use zero-knowledge proofs to allow any node to delete some data from Bitcoin transactions, still preserving the public verifiability of the correctness of the spent and spendable coins. Moreover, we specifically use STARK proofs to exploit the transparency that they provide. Our solution, unlike previous approaches, avoids the complications of asking nodes to reach consensus on the content to delete. In particular, our design allows every node to delete some specific data without coordinating this decision with others. In our implementation, data removal can be performed (resp., verified) in minutes (resp., seconds) on a standard laptop rather than in days as required in previous designs based on consensus.

Background and purpose Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID‐19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID‐19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID‐19 severity amongst PwMS. Methods Data were retrieved from an Italian web‐based platform (MuSC‐19) which includes PwMS with COVID‐19. PM2.5 2016–2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID‐19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID‐19 severity. Results In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID‐19 course (odds ratio 1.90; p = 0.009). Conclusions Even if several other factors explain the unfavourable course of COVID‐19 in PwMS, the role of air pollutants must be considered and further investigated., Air pollution, often assessed by particulate matter with diameter below 2.5 µg/m3, may contribute to severe COVID‐19 courses. 1087 patients were included, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died. Even if several other factors explain the unfavourable course of COVID‐19 in patients with multiple sclerosis, the role of air pollutants must be considered and further investigated.

Beerkan infiltration runs could provide an incomplete description of infiltration with reference to either the near steady-state or the transient stages. In particular, the process could still be in the transient stage at the end of the run or some transient infiltration data might be loss. The Wu1 method and the BEST-steady algorithm can be applied to derive soil hydrodynamic parameters even under these circumstances. Therefore, a soil dataset could be developed using two different data analysis methods. The hypothesis that the Wu1 method and BEST-steady yield similar predictions of the soil parameters when they are applied to the same infiltration curve was tested in this investigation. For a sandy-loam soil, BEST-steady yielded higher saturated soil hydraulic conductivity, Ks, microscopic pore radius, λm, and depth of the wetting front at the end of the run, dwf, and lower macroscopic capillary length, λc, as compared with the Wu1 method. Two corresponding means differed by 1.2–1.4 times, depending on the variable, and the differences appeared overall from moderate to relatively appreciable, that is neither too high nor negligible in any circumstance, according to some literature suggestions. Two estimates of Ks were similar (difference by < 25%) when the gravity-driven vertical flow and the lateral capillary components represented the 71–89% of total infiltration. In conclusion, the two methods of data analysis do not generally yield the same predictions of soil hydrodynamic parameters when they are applied to the same infiltration curve. However, it seems possible to establish what are the conditions making the two methods similar.

Background Hereditary transthyretin amyloidosis (ATTRv) is a rare, debilitating and fatal disease, mostly characterized by progressive axonal peripheral neuropathy. Diagnosis is still challenging and diagnostic delay in non-endemic area is about 3–4 years. The aim of this study was to arrange a clinical and electrophysiological score to select patients with axonal neuropathy that deserve screening for TTR mutation. Methods Thirty-five ATTRv patients and 55 patients with chronic idiopathic axonal polyneuropathy (CIAP) were retrospectively analyzed. Clinical and electrophysiological findings at first evaluation were collected. Based on significant results between the two groups, a compound (clinical and electrophysiological) score was arranged, and ROC analysis was performed to identify the ideal cut-off able to discriminate between the two groups. Results ATTRv patients presented a later age at onset, more frequent muscle weakness and carpal tunnel syndrome history. On the other hand, electrophysiological analysis showed that ATTRv patients had lower CMAP and SAP amplitude in all examined nerves. We arranged a compound score constituted by 7 total items, ranging from 0 to 12. ROC analysis showed an Area Under the Curve = 0.8655 and we set the cut-off ≥ 5 points to discriminate ATTRv patients with a sensitivity of 96.6% and a specificity of 63.6%. Conclusion Our study demonstrated that our compound score with cut-off ≥ 5 allows to discriminate ATTRv patients among subject affected by axonal polyneuropathy with a sensitivity > 95%. Thus, our compound score is a quick, easy and effective screening tool.

Background: In the first section of this review, we examined the neuroanatomical and neurochemical data on hunger and satiety centers, glucose receptors, sensorial influences on eating behavior, and regulation of energy requirements. The second section is devoted to orexigenic and anorexigenic hormones. Objective: This paper aimed to overview and summarize data regarding the role of neuroendocrine regulation of food intake and eating behavior. Methods: Appropriate keywords and MeSH terms were identified and searched in MEDLINE/PubMed. References of original articles and reviews were examined. Discussion and conclusion: Hunger and satiety center are located in the lateral (LH) and ventromedial hypothalamus (VMH). Lasting aphagia has been observed following a lesion of LH, while hyperphagia is induced by LH stimulation. On the other hand, increased food intake after VMH lesion and aphagia following VMH stimulation in hungry animals has also been reported. Intracellular glucopenia triggers food intake by reducing neuronal activity at the satiety center level. Moreover, sensory influences are regulated by food palatability as the positive hedonic evaluation of food and energy requirement indicates the average amount of food energy needed to balance energy expenditure. Orexigenic and anorexigenic hormones secreted from the gastrointestinal tract and adipose tissue regulate brain areas involved in eating behavior via gastric afferent vagal nerve, circumventricular organ area postrema, or transporter system. Finally, oxytocin (OT) plays a role in reward-related eating by inhibiting sugar intake and decreasing palatable food intake by suppressing the reward circuitry in the brain. Moreover, the anorectic effect of nesfatin-1 is abolished by an OT antagonist.

Wind stress and turbulent heat fluxes are the major driving forces that modify the ocean dynamics and thermodynamics. In the Nucleus for European Modelling of the Ocean (NEMO) ocean general circulation model, these turbulent air–sea fluxes (TASFs) can critically impact the simulated ocean characteristics. This paper investigates how the various bulk parameterizations used to calculate turbulent air-sea fluxes in NEMOv4 can lead to substantial differences in the estimation of sea surface temperatures (SSTs). Specifically, we study the contributions of different aspects and assumptions of the bulk parameterizations in driving the SST differences in the NEMO global model configuration at 1/4∘ of horizontal resolution. These aspects include the use of the skin temperature instead of the bulk SST in the computation of turbulent heat flux components and the estimation of wind stress and turbulent heat flux components, which vary in each parameterization due to different bulk transfer coefficients. The analysis of a set of short-term sensitivity experiments where the only change is related to one of the aspects of the bulk parameterizations shows that parameterization-related SST differences are primarily sensitive to wind stress differences and to the implementation of skin temperature in the computation of turbulent heat flux components. In addition, in order to highlight the role of SST–turbulent heat flux negative feedback at play in ocean simulations, we compare the TASF differences obtained using the NEMO ocean model with the estimations by Brodeau et al. (2017), who compared the different bulk parameterizations using prescribed SSTs. Our estimations of turbulent heat flux differences between bulk parameterizations are weaker than those found by Brodeau et al. (2017).

Background and purpose: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. Method: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. Results: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p=0.005) and more in smoker patients (OR 1.39; p=0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p=0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p=0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p=0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p=0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p=0.024), joint or muscle pain (G2, p=0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. Conclusion: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

The effect on seismic demand of the soil-foundation compliance is investigated for a reinforced concrete frame building representative of Italian constructions from the 1970s. Design accounts for regulations, materials, preferred structure and foundation layouts and analysis methods of the period. Inelastic response history analysis for multiple motions at three intensities is carried out. For the compliant-base case, each foundation is replaced with a nonlinear inertial macro-element. Results suggest that the effect of interaction is minor, lower than expected from similar analysis on a new building, due to the larger degree of conservatism associated with foundation design in the considered period and the corresponding lower strength and stiffness of the superstructure.

Background Migraine affects more than a billion people all over the world and requires critical employment of healthcare resources. Telemedicine could be a reasonable tool to manage people suffering from headaches, and it received a big push from the COVID-19 pandemic. Objective This review aims to propose a practical approach for the virtual management of these patients. Methods To do this, we conducted a literature search, including 32 articles relevant to the topic treated in this review. Results The most challenging step in telemedicine applied to practical neurology remains the clinical assessment, but through a careful headache history and a recently proposed entirely virtual neurological assessment, this hitch can be easily overcome. Electronic diary compilations and virtual administration of disability-measuring scales, conversely, are the key features of effective long-term follow-up although we do not have apps that met the criteria of scientific reliability. Furthermore, tele-rehabilitation seems to be effective and has demonstrated to be a solution to alternatively treat chronic patients at home, and can be considered part of the remote management of headache patients. Moreover, virtual management of headaches finds an application in specific communities of patients, as pediatric patients and for rural communities of low- and middle-income countries suffer from health disparities, with inadequate resources and knowledge gaps. Conclusion Telemedicine could be promising for patients with no regular or convenient access to headache specialists and seems to be a priority in managing migraine patients to avoid non-urgent hospitalizations

Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

Aims Provide an overview of remote motivational interviewing (MI) interventions for chronically ill patients, and understand their degree of effectiveness on different health outcomes. Methods and results A systematic review with meta-analysis was conducted using the following databases: PubMed, CINAHL, PsychInfo, and Web of Science. Eligibility criteria included studies that administered remote MI alone or in combination with other remote approaches. A narrative synthesis and two meta-analyses were performed. Fifteen studies met the inclusion criteria. MI administration almost exclusively occurred by telephone and individual sessions. Eight studies reported treatment fidelity aspects, and four declared adopting a theoretical framework. Most targeted outcomes were therapeutic adherence, physical activity, depression, quality of life, and mortality. Risk of bias varied markedly, with the largest source resulting from selection process and intervention performance. The two meta-analyses indicated a significant effect of MI on depression [standardized mean difference = –0.20, 95% confidence interval (CI): –0.34, –0.05, Z = 2.73, P = 0.006, I2 = 0%], and no effect of MI on glycosylated haemoglobin (mean difference = –0.02, 95% CI: –0.48, 0.45, P = 0.94, I2 = 84%). Conclusion Remote MI can be a promising approach for improving depression in chronic disease patients. However, studies are inconclusive due to risks of bias, heterogeneity, and lack of reporting of interventionist’s training, treatment fidelity, and theoretical frameworks’ use. More studies with solid designs are needed to inform clinical decision-making and research. Registration PROSPERO: CRD42021241516.

Research conducted to date has highlighted barriers to initial adoption of universal behavior screening in schools. However, little is known regarding the experiences of those implementing these procedures and there have been no studies conducted examining the experiences of educators in different stages of implementing various tiered systems of supports. Universal screening is foundational to a successful Comprehensive, Integrated Three-Tiered (Ci3T) model of prevention-an integrated tiered system addressing academics, behavior, and social and emotional well-being. Therefore, the perspectives of Ci3T Leadership Team members at different stages of Ci3T implementation were solicited through an online survey that sought to understand (1) current school-based screening practices and (2) individual beliefs regarding those practices. A total of 165 Ci3T Leadership Team members representing five school districts from three geographic regions across the United States, all of whom were participating in an Institute of Education Sciences Network grant examining integrated tiered systems, reported the screening procedures were generally well-understood and feasible to implement. At the same time, results highlighted continuing professional learning may be beneficial in the areas of: (1) integrating multiple sources of data (e.g., screening data with other data collected as regular school practices) and (2) using those multiple data sources to determine next steps for intervention. We discuss educational implications, limitations, and directions for future inquiry.

Cytopenias are important but less studied adverse events following chimeric antigen receptor-engineered T cell (CAR-T) therapy. In our analysis of patients with large cell lymphoma who received axicabtagene ciloleucel (axi-cel), we sought to determine the rate and risk factors of clinically significant short term cytopenias defined as grade ≥3 neutropenia, anemia, or thrombocytopenia, or treatment with growth factors or blood product transfusions between days 20-30 after axi-cel. Fifty-three pts received axi-cel during the study period and severe cytopenias were observed in 32 (60%) pts. Significant cytopenias were more common in non-responders (stable or progressive disease) vs. responders (partial or complete response) (100% vs. 70%

Purpose: To study interocular asymmetry in distribution of leaks in central serous chorioretinopathy (CSC). Material and methods: Patients with unilateral CSC were included in this retrospective multicenter study. All patients received multimodal imaging. The prevalence of leaks within 1 disk diameter (DD) peripapillary area and the mean shortest distance between a leak and the optic disk edge was analyzed for the right and left eyes separately based on FA images. Clinical and morphological characteristics were collected and compared between eyes with a peripapillary leak and eyes with a leak elsewhere. Results: In total, 152 eyes (77 right eyes and 75 left eyes) of 152 patients (128 males and 24 females) with a mean age of 45.2 ± 9.8years were included. The mean distance from the leak to the edge of the optic disk was statistically significantly lower (p = 0.0003), and the prevalence of the leaks within the 1 DD-peripapillary area was higher in the left eye than in the right eye (32.1% versus 10.7%, respectively, p = 0.0017). The eyes with a peripapillary leak had a longer duration of the disease (p < 0.05), a wider area of retinal pigment epithelium alteration (p < 0.001), and a higher prevalence of outer retinal atrophy (p < 0.001) compared to the eyes with a leak elsewhere. Conclusion: The left eye showed closer location of the leak to the optic disk edge and higher prevalence of leaks within the peripapillary area. The cases with peripapillary leak commonly demonstrated characteristics of chronic CSC despite relative preservation of visual acuity.

Despite of the many progresses with alignment algorithms, aligning divergent protein sequences including those sharing less than 20-35% pairwise identity (so called “twilight zone”) remains a difficult problem. Many alignment algorithms have been using substitution matrices since their creation in the 1970’s to generate alignments. These matrices however do not work well within the twilight zone. We developed PEbA for Protein Embedding based Alignments. Similar to the traditional Smith-Waterman algorithm, PEbA uses a dynamic programming algorithm but the matching score of amino acids is based on their embeddings from a protein language model. We tested PEbA on benchmark alignments and the results showed that PEbA greatly outperformed BLOSUM substitution matrix-based pairwise alignments, achieving different levels of improvements of the alignment quality for pairs of sequences with different levels of similarity (over five times as well for pairs of sequences with <10% identity). We compared PEbA with embeddings generated by different protein language models (ProtT5 and ESM-2) and found that ProtT5-XL-U50 produced the most useful embeddings for aligning protein sequences. PEbA even outperformed DEDAL, a recently developed deep learning model that was created specifically for aligning protein sequences, particularly on longer alignments and sequences with low pairwise identity. Our results suggested that general purpose protein language models provide useful contextual information for accurate protein alignments.

The variability of the South Atlantic meridional overturning circulation and meridional heat transport measured across 34.5°S during 2013–2017 differs significantly between observational and ocean reanalysis estimates. Variability in an ocean reanalysis ensemble and an eddy-resolving reanalysis is similar to an altimeter-based estimate, but smaller than energy-budget and mooring-based estimates. Over 1993–2020, there is no long-term trend in the ensemble-mean overturning and heat transport, although there are inter-model differences, whereas the altimeter-based and energy-budget estimate transports increase over this period. Time-mean overturning volume transport (and the depth of maximum overturning) across 34.5°S in the ensemble and observations are similar, whereas the corresponding mean heat transports differ by up to 0.3 PW. The seasonal cycle of these transports varies between estimates, due to differences in the methods for estimating the geostrophic flow and the sampling characteristics of the observational approaches. The baroclinic, barotropic and Ekman MOC components tend to augment each other in mooring-based estimates, whereas in other estimates they tend to oppose each other so the monthly-mean, inter-annual and seasonal MOC anomalies have a greater magnitude in the mooring-based estimates. Thus, the mean and variation of real world South Atlantic transports, and the amplitude of their fluctuations, are still uncertain. Ocean reanalyses may be useful tools to understand these differences and the mechanisms that control volume and heat transport variability in the South Atlantic, a region critical for determining the global overturning pathways and inter-basin transports.

The ocean mixed layer is the interface between the ocean interior and the atmosphere or sea ice, and plays a key role in climate variability. Numerical models used in climate studies should therefore have a good representation of the mixed layer, especially its depth (MLD). Here we use simulations from the Ocean Model Intercomparison Project (OMIP), which have been forced by a common atmospheric state, to assess the realism of the simulated MLDs. For model validation, an updated MLD dataset has been computed from observations using the fixed density threshold recommended by the OMIP protocol. We evaluate the influence of horizontal resolution by using six pairs of simulations, non-eddying (typically 1° resolution) and eddy-rich (1/10° to 1/16° resolution). In winter, low resolution models exhibit large biases in the deep water formation regions. These biases are reduced in eddy-rich models but not uniformly across models and regions. The improvement is most noticeable in the mode water formation regions of the northern hemisphere, where the eddy-rich models produce a more robust MLD and deep biases are reduced. The Southern Ocean offers a more contrasted view, with biases of either sign remaining at high resolution. In eddy-rich models, mesoscale eddies control the spatial variability of MLD in winter. Contrary to an hypothesis that the deepening of the MLD in anticyclones would make the MLD deeper globally, eddy-rich models tend to have a shallower MLD in the zonal mean. In summer, a deep MLD bias is found in all the non-eddying models north of the equator; this bias is greatly reduced at high resolution. In addition, our study highlights the sensitivity of the MLD computation to choice of a reference level and the spatio-temporal sampling, which motivates new recommendations for MLD computation in future model intercomparison projects.

Arctic sea-ice area and volume have dramatically decreased since the beginning of the satellite era. This alarming rate of ice decline raises a key scientific question: how soon will the Arctic meet the first “ice-free” summer? Coupled climate models are the primary tools to provide projections of future sea ice conditions. Increasing the horizontal resolution of general circulation models is a widely recognized way to improve the representation of the complex processes at high latitudes, and to obtain trustworthy predictions of ice variability. Here, we investigate the past and future changes of sea ice cover at hemispheric and regional scales using model outputs from the High Resolution Model Intercomparison Project (HighResMIP, Haarsma et al. 2016) of the sixth phase of the Coupled Model Intercomparison Project (CMIP6). The main objective is to investigate the impact of ocean/atmosphere model resolution on the representation of Arctic sea ice area (SIA) and volume (SIV) and their seasonal, interannual variability, and trends in the recent past. Model results over the period 1950–2014 are compared to a set of observational datasets. All models project substantial sea ice shrinking: from 1950 to 2050 the Arctic loses nearly 92% of SIV from 1950 to 2050. The individual models simulate the first summer ice-free Arctic as early as 2019 and as late as 2050. The ensemble mean of the three best performing models suggests the event to happen by 2044. Along with the overall reduction of sea ice cover, there are changes in the structure of sea ice cover: the marginal ice zone (MIZ) dominates the ice cover by the mid-XXI which implies the shift to a new sea ice regime closest to the Antarctic conditions. The MIZ-dominated Arctic might suggest to adapt and modify model physics parameterizations and sea ice rheology.Our analysis does not present a strong relationship between ocean/atmosphere spatial resolution and sea ice cover representation: the impact of horizontal resolution rather depends on the model used and the examined variables. However, the refinement of the ocean mesh has a more prominent effect compared to the atmospheric one, mainly due to a more realistic representation of the sea ice edges as a result of better simulated ocean currents and heat transports in the Northern Atlantic Ocean.

The simulated North Atlantic atmosphere­–ocean variability is assessed in a subset of models from HighResMIP that have either low-resolution (LR) or high-resolution (HR) in their atmosphere and ocean model components. In general, the LR models overestimate the low-frequency variability of subpolar sea-surface temperature (SST) anomalies and underestimate their correlation with the NAO compared to ERA5 reanalysis. These biases are substantially reduced in the HR models, and it is shown that the improvements are related to a reduction of intrinsic (non-NAO-driven) variability of the subpolar ocean circulation.To understand the mechanisms behind the overestimated intrinsic subpolar ocean variability in the LR models, a link is demonstrated between the biases in subpolar ocean variability and known biases in the mean state of the Labrador-Irminger seas. Supporting previous studies, the Labrador-Irminger seas are found to be too cold and too fresh in the LR models compared to observations from EN4 and the HR models. This causes upper-ocean density and hence convection anomalies in this region to be more salinity-controlled in the LR models versus more temperature-controlled in the HR models. It is hypothesized that this may cause the excessive subpolar ocean variability in the LR models by 1) promoting a positive feedback between subpolar upper-ocean salinity, convection and Atlantic Meridional Overturning Circulation (AMOC) anomalies, and 2) weakening the negative feedback between subpolar upper-ocean temperature, convection and AMOC anomalies that is apparent in the HR models. The results overall suggest that mean ocean biases play an important role in the simulation of the variability of the extratropical ocean.

The rapid decline of the Arctic sea ice cover is a primary indicator of Earth’s changing climate. The variability of ice-covered area plays a crucial role in the modulating the ocean-atmosphere exchange. Knowledge of ice properties and their variability is necessary for an adequate simulation of those fluxes. Yet the response of September sea ice area or extent (SIA/SIE) is underestimated compared to observations in many global climate models.Global ocean reanalyses provide consistent and comprehensive records of sea ice variables and are of pivotal significance for climate studies also in polar regions. We present the temporal and spatial variability of Arctic sea ice area in the CMEMS ensemble of global ocean reanalyses (GREP), from 1993 onward. We assess the accuracy of GREP in reproducing the evolution in time and space of total sea ice and discriminating between the marginal ice zone (MIZ) from consolidated pack ice. The MIZ properties markedly differ from the thicker, quasi-continuous ice cover of the inner pack, strongly influencing various atmosphere–ocean fluxes, especially the heat flux. The MIZ has become a significant component of contemporary Arctic sea ice cover, with a summer area comparable to that occupied by pack ice. The trend towards the MIZ is set to accelerate.Compared to satellite products (OSISAF and CDR), GREP provides consistent estimates of recent changes in the Arctic sea ice area and properly reproduces observed interannual and seasonal variability, linear trend, as well as record highs and lows. For sea ice classes, the ensemble spread is comparable to the spread among observational estimates that is as large as the ensemble spread. GREP is shown to properly represent the variability of MIZ area during the growing and melting seasons, as well as their minima and maxima. More evident discrepancies between GREP and satellite products occur during summer, when the MIZ amount increases, causing a spread widening among individual reanalyses.Our analysis suggests that GREP can be used to get a robust estimate of current Arctic sea ice state and recent trends in sea ice properties.

New and updated physics and parameterizations implemented in the NEMO ocean model from version 4 onwards are tested in a global eddying ocean/sea ice configuration, specifically the GLOB16 system. Such configuration is at the base of the operational short-term Global Ocean Forecast System (GOFS) adopted at the Euro-Mediterranean Center on Climate Change (CMCC) and uses a nonuniform tripolar grid with 1/16° horizontal resolution (corresponding to 6.9 km at the Equator) and 98 vertical levels. We performed a set of short-term simulations forced by the ECMWF operational atmospheric fields at 1/10° spatial resolution.Among all the recent functionalities of the NEMO model, this work focuses on the new features that could impact the ocean energy budget. The new formulation of tides, the parameterization of the mixing induced by breaking internal waves and the formulation of the surface wave-induced mixing are selected. Test simulations are compared against a control run employing a set of metrics computed on the global domain and regional ocean sectors. Additionally, model results are evaluated against available satellite estimates to provide a first validation of the variability of upper ocean energy budget.In the simulation in which the surface wave-induced mixing is included, external input forcings are needed to provide an accurate representation of the surface wave processes. Here, integrated wave parameters from WAVEWATCH III model feed the NEMO ocean model, in the forced mode.Our analysis shows that all new ocean implementations impact global and regional patterns of sea surface salinity and sea surface height; conversely, only enhanced surface mixing affects the sea surface temperature and the mixed layer depth. However, all experiments showed the tendency to reduce the surface and basin-averaged ocean energy with updated mixing processes.

Antarctic sea ice prediction has garnered increasing attention in recent years, particularly in the context of the recent record lows of February 2022 and 2023. As Antarctica becomes a climate change hotspot, as polar tourism booms, and as scientific expeditions continue to explore this remote continent, the capacity to anticipate sea ice conditions weeks to months in advance is in increasing demand. Spurred by recent studies that uncovered physical mechanisms of Antarctic sea ice predictability and by the intriguing large variations of the observed sea ice extent in recent years, the Sea Ice Prediction Network South (SIPN South) project was initiated in 2017, building upon the Arctic Sea Ice Prediction Network. The SIPN South project annually coordinates spring-to-summer predictions of Antarctic sea ice conditions, to allow robust evaluation and intercomparison, and to guide future development in polar prediction systems. In this paper, we present and discuss the initial SIPN South results collected over six summer seasons (December-February 2017-2018 to 2022-2023). We use data from 22 unique contributors spanning five continents that have together delivered more than 3000 individual forecasts of sea ice area and concentration. The SIPN South median forecast of the circumpolar sea ice area captures the sign of the recent negative anomalies, and the verifying observations are systematically included in the 10-90% range of the forecast distribution. These statements also hold at the regional level except in the Ross Sea where the systematic biases and the ensemble spread are the largest. A notable finding is that the group forecast, constructed by aggregating the data provided by each contributor, outperforms most of the individual forecasts, both at the circumpolar and regional levels. This indicates the value of combining predictions to average out model-specific errors. Finally, we find that dynamical model predictions (i.e., based on process-based general circulation models) generally perform worse than statistical model predictions (i.e., data-driven empirical models including machine learning) in representing the regional variability of sea ice concentration in summer. SIPN South is a collaborative community project that is hosted on a shared public repository. The forecast and verification data used in SIPN South are publicly available in near-real time for further use by the polar research community, and eventually, policymakers.

2.AbstractBackgroundParkinson’s disease is a progressive neurodegenerative disorder mainly distinguished by sporadic aetiology, although a genetic component is also well established. Variants in theLRRK2gene are associated with both familiar and sporadic disease. We have previously shown that PAK6 and 14-3-3γ protein interact with and regulate the activity of LRRK2.ObjectivesThe aim of this study is to quantify PAK6 and 14-3-3γ in plasma as a reliable biomarker strategy for the diagnosis of both sporadic and LRRK2-linked Parkinson’s disease.MethodsAfter an initial quantification of PAK6 and 14-3-3γ expression by means of Western blot in post-mortem human brains, we verified the presence of the two proteins in plasma by using quantitative ELISA tests. We analysed samples obtained from 39 healthy subjects, 40 patients with sporadic Parkinson’s disease, 50 LRRK2-G2019S non-manifesting carriers and 31 patients with LRRK2-G2019S Parkinson’s disease.ResultsThe amount of PAK6 and 14-3-3γ is significantly different in patients with Parkinson’s disease compared to healthy subjects. Moreover, the amount of PAK6 also varies with the presence of the G2019S mutation in the LRRK2 gene. Although the generalized linear models show a low association between the presence of PD and PAK6, the kinase can be added in a broader panel of biomarkers for the diagnosis of Parkinson’s disease.ConclusionsChanges of PAK6 and 14-3-3γ amount in plasma represent a shared readout for patients affected by sporadic and LRRK2-linked Parkinson’s disease. Overall, they can contribute to the establishment of an extended panel of biomarkers for the diagnosis of Parkinson’s disease.

Background: Eosinophilic esophagitis (EoE) is increasingly diagnosed in patients with dysphagia and upper gastroenteric symptoms. Elimination diets and/or pharmacologic agents may accomplish temporary remission, but long-term control is challenging. Type-2 immunity to ingested antigens can induce EoE histopathology via non-IgE-dependent mechanisms, possibly involving IgG4 and IL-10 production. To elucidate the contribution of IgG4- and IL-10-producing cells to EoE pathogenesis, we examined their frequencies and association with clinical and histologic endpoints in adult EoE patients given a two-food elimination diet (TFED). Methods: Sixteen patients with EoE were prescribed a TFED. Biopsies collected at baseline and follow-up were used for immunofluorescent detection of IgG4- and IL-10-expressing cells and serum food-specific IgG4 were measured. All variables were correlated with established histologic measures of disease activity. Results: Patients exhibited significant clinical improvement and significant reduction in esophageal eosinophilia and overall histology. A significant decrease in the frequencies of IL-10-expressing cells was also observed, which correlated with histologic changes. In contrast, a concomitant decline in serum and esophageal IgG4, while substantial, did not correlate with IL-10 -cell frequencies or any histologic parameter of EoE activity. Conclusions: The close association of esophageal IL-10 expression with histologic features and their changes after a TFED suggests a critical role of this cytokine in EoE pathogenesis. Conversely, IgG4 serum and mucosal expression, while reflecting the level of exposure to relevant food antigens, is not obviously related to EoE histopathology or IL-10 expression. Studies are needed to characterize IL-10 cellular sources and their functions in EoE progression and treatment response.

Zygotic genome activation (ZGA) is a crucial step of embryonic development. So far, little is known about the role of chromatin factors during this process. Here, we used an in vivo RNA interference reverse genetic screen to identify chromatin factors necessary for embryonic development in Drosophila melanogaster . Our screen reveals that histone acetyltransferases (HATs) and histone deacetylases are crucial ZGA regulators. We demonstrate that Nejire (CBP/EP300 ortholog) is essential for the acetylation of histone H3 lysine-18 and lysine-27, whereas Gcn5 (GCN5/PCAF ortholog) for lysine-9 of H3 at ZGA, with these marks being enriched at all actively transcribed genes. Nonetheless, these HATs activate distinct sets of genes. Unexpectedly, individual catalytic dead mutants of either Nejire or Gcn5 can activate zygotic transcription (ZGA) and transactivate a reporter gene in vitro. Together, our data identify Nejire and Gcn5 as key regulators of ZGA.

Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood.Experimental Design and Results: Using gene expression analysis, we define a core set of six genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. MYC, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through SP1 or MIZ1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials.Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way toward personalized therapies. Clin Cancer Res; 23(10); 2542–55. ©2016 AACR.

SAHA effects in different cell lines.

Supplementary Table S2 from Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells

This file contains the legends to all Supplementary Figures

The demonstration that the small synthetic molecule reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of committed cells into multipotent progenitor-type cells has raised hopes on the exploitation of this small chemical tool for the generation of stem cells. Here, we show that reversine causes a failure in cytokinesis and induces polyploidization. These effects of reversine are due to the inhibition of Aurora A and B, two related kinases that are implicated in several aspects of mitosis and that are frequently amplified and overexpressed in human tumors. Reversine inhibits the phosphorylation of histone H3, a direct downstream target of Aurora kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently entered phase II clinical trials for cancer treatment, reversine inhibited colony formation of leukemic cells from patients with acute myeloid leukemia but was significantly less toxic than VX-680 on cells from healthy donors. The crystal structure of the reversine-Aurora B kinase complex shows that reversine is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our studies raise serious doubts on the application of reversine in regenerative medicine, they support the paradigm that reversine might be a useful agent in cancer chemotherapy. [Mol Cancer Ther 2008;7(5):1140–9]