Inflammageing and Cardiovascular System: Focus on Cardiokines and Cardiac-Specific Biomarkers

The term “inflammageing” was introduced in 2000, with the aim of describing the chronic inflammatory state typical of elderly individuals, which is characterized by a combination of elevated levels of inflammatory biomarkers, a high burden of comorbidities, an elevated risk of disability, frailty, and premature death. Inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and rapid progression to heart failure. The great experimental and clinical evidence accumulated in recent years has clearly demonstrated that early detection and counteraction of inflammageing is a promising strategy not only to prevent cardiovascular disease, but also to slow down the progressive decline of health that occurs with ageing. It is conceivable that beneficial effects of counteracting inflammageing should be most effective if implemented in the early stages, when the compensatory capacity of the organism is not completely exhausted. Early interventions and treatments require early diagnosis using reliable and cost-effective biomarkers. Indeed, recent clinical studies have demonstrated that cardiac-specific biomarkers (i.e., cardiac natriuretic peptides and cardiac troponins) are able to identify, even in the general population, the individuals at highest risk of progression to heart failure. However, further clinical studies are needed to better understand the usefulness and cost/benefit ratio of cardiac-specific biomarkers as potential targets in preventive and therapeutic strategies for early detection and counteraction of inflammageing mechanisms and in this way slowing the progressive decline of health that occurs with ageing.     

High IGKC-Expressing Intratumoral Plasma Cells Predict Response to Immune Checkpoint Blockade

Resistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes.     

Autonomous Vehicle Platoons In Urban Road Networks: A Joint Distributed Reinforcement Learning and Model Predictive Control Approach

In this paper, platoons of autonomous vehicles operating in urban road networks are considered. From a methodological point of view, the problem of interest consists of formally characterizing vehicle state trajectory tubes by means of routing decisions complying with traffic congestion criteria. To this end, a novel distributed control architecture is conceived by taking advantage of two methodologies: deep reinforcement learning and model predictive control. On one hand, the routing decisions are obtained by using a distributed reinforcement learning algorithm that exploits available traffic data at each road junction. On the other hand, a bank of model predictive controllers is in charge of computing the more adequate control action for each involved vehicle. Such tasks are here combined into a single framework: the deep reinforcement learning output (action) is translated into a set-point to be tracked by the model predictive controller; conversely, the current vehicle position, resulting from the application of the control move, is exploited by the deep reinforcement learning unit for improving its reliability. The main novelty of the proposed solution lies in its hybrid nature: on one hand it fully exploits deep reinforcement learning capabilities for decision-making purposes; on the other hand, time-varying hard constraints are always satisfied during the dynamical platoon evolution imposed by the computed routing decisions. To efficiently evaluate the performance of the proposed control architecture, a co-design procedure, involving the SUMO and MATLAB platforms, is implemented so that complex operating environments can be used, and the information coming from road maps (links, junctions, obstacles, semaphores, etc.) and vehicle state trajectories can be shared and exchanged. Finally by considering as operating scenario a real entire city block and a platoon of eleven vehicles described by double-integrator models, several simulations have been performed with the aim to put in light the main features of the proposed approach. Moreover, it is important to underline that in different operating scenarios the proposed reinforcement learning scheme is capable of significantly reducing traffic congestion phenomena when compared with well-reputed competitors.

     

Unusual crystallization behavior of isotactic polypropylene and propene/1-alkene copolymers at large undercoolings

During the investigation of the crystallization of metallocene isotactic polypropylene and copolymers with low amount of 1-butene and 1-hexene at large undercoolings, an unexpected behavior has been found. Random copolymers crystallize faster than the homopolymer between 80 and 40 °C, while at high temperatures the overall crystallization rates follow the expected trend. On the basis of structural and morphological evidences we suggest that the overall structuring kinetics of the homopolymer is slowed down by the concomitant formation of mesophase and monoclinic structures. This effect is absent in the copolymers because the branched counits retard the development of mesophase.     

Hydrogen production by two-step thermochemical cycles based on commercial nickel ferrite: Kinetic and structural study

One of the promising routes for hydrogen production consists of the dissociation of the water molecule through two-step thermochemical cycles based on iron oxides, i.e., ferrites. In a previous work, our group evaluated the activity of five commercial ferrites for this purpose, being Ni ferrite the one that exhibits the highest hydrogen production. In this work, the results obtained after a more exhaustive study of the thermochemical cycle based on a commercially available Ni ferrite are presented. Structural characterization of NiFe₂O₄ after each step of the thermochemical cycle is shown, as well as oxygen and hydrogen production over several cycles. In addition, kinetic parameters of this cycle are also studied, fitting the experimental data obtained under isothermal conditions to the most appropriate model among those ascribed to gas–solid non-catalytic multistep reaction systems.     

Computers and classical myths

This paper is a qualitative review of a series of classical myths which are or could be used as interpretative metaphors or similes for people, settings, and situations relating to the Computer World. It will look at basic, widely accepted terms like Trojan or Trojan horse, cyberphobia, or Project Athena. It will also infer others through an exercise in hermeneutical mythopoeia. Examples include Tantalus, representing the controlled obsolescence of technological resources, turning the user into a revived Sisyphus, or Theseus as a powerful anti-virus. Not forgetting the clumsy navigator, Odysseus or Ulysses, representing disperse, inefficient Internet users, and especially the great myth of the teacher Mentor, representing the power of information available on the Internet and searchable via Google.     

The Logic of Knowledge and the Flow of Information

In this paper I look at Fred Dretske’s account of information and knowledge as developed in Knowledge and The Flow of Information. In particular, I translate Dretske’s probabilistic definition of information to a modal logical framework and subsequently use this to explicate the conception of information and its flow which is central to his account, including the notions of channel conditions and relevant alternatives. Some key products of this task are an analysis of the issue of information closure and an investigation into some of the logical properties of Dretske’s account of information flow.     

Identification of a pathogenicity island required for Salmonella enteropathogenicity

Salmonella spp. interact with ileal mucosa and disrupt normal intestinal function, which results in an acute inflammatory cell influx, fluid secretion and enteritis. We have recently characterized SopB, a novel secreted effector protein of Salmonella dublin, and presented evidence that SopB is translocated into eukaryotic cells via a sip-dependent pathway to promote fluid secretion and inflammatory responses. Here, we show that sopB is located on a large DNA fragment unique to the Salmonella chromosome. This locus is conserved in Salmonella and maps at approximately 20 centisome of the S. typhimurium chromosome. Sequence analysis revealed that this Salmonella-specific DNA fragment is flanked by DNA sequences with significant sequence similarity to the Escherichia coli K-12 genes, tRNA1ser (serT) on one side and copS/copR on the other. Thus, this Salmonella-specific DNA fragment has features characteristic of 'pathogenicity islands' and, therefore, it was denoted SPI-5 (Salmonella pathogenicity island-5). SPI-5 was sequenced and was found to contain five novel genes, pipA, pipB, pipC, pipD (pathogenicity island-encoded proteins) and orf, in addition to sopB. The effect of mutations in pipA, pipB and pipD on the induction of fluid secretion and an acute inflammatory cell influx was assessed in bovine ligated ileal loops. The effect of mutations in SPI-5-encoded genes on systemic salmonellosis was assessed in mice. The results of these experiments suggest that SPI-5-encoded genes contribute to enteric but not to systemic salmonellosis.     

Focal dilation and paradoxical collapse of cortical fissures and sulci in patients with normal-pressure hydrocephalus

OBJECT: The authors describe a subgroup of patients with shunt-proven normal-pressure hydrocephalus (NPH) who presented with focal fissural and sulcal dilation on imaging studies. The specific radiological features and methods of differentiating this condition from cortical atrophy are delineated. METHODS: Normal-pressure hydrocephalus has been described as dilation of the ventricles that is out of proportion to the sulci. Sulcal dilation has been taken as evidence of cortical atrophy and has even been used as a criterion to exclude patients from undergoing a shunting procedure. The authors describe five cases of patients with shunt-proven NPH who presented with focal dilation of cortical fissures and sulci. In three of the cases, there was a paradoxical decrease in the size of the dilated fissures and sulci that paralleled the decrease in the size of the lateral ventricles following successful shunting. CONCLUSIONS: This study demonstrates that focal fissural and sulcal dilation may represent reservoirs of cerebrospinal fluid analogous to the ventricular system. Patients should not be denied a shunting procedure solely on the basis of focally dilated fissures of sulci.