Abasic and oxidized ribonucleotides embedded in DNA are processed by human APE1 and not by RNase H2

Ribonucleoside 5'-monophosphates (rNMPs) are the most common non-standard nucleotides found in DNA of eukaryotic cells, with over 100 million rNMPs transiently incorporated in the mammalian genome per cell cycle. Human ribonuclease (RNase) H2 is the principal enzyme able to cleave rNMPs in DNA. Whether RNase H2 may process abasic or oxidized rNMPs incorporated in DNA is unknown. The base excision repair (BER) pathway is mainly responsible for repairing oxidized and abasic sites into DNA. Here we show that human RNase H2 is unable to process an abasic rNMP (rAP site) or a ribose 8oxoG (r8oxoG) site embedded in DNA. On the contrary, we found that recombinant purified human apurinic/apyrimidinic endonuclease-1 (APE1) and APE1 from human cell extracts efficiently process an rAP site in DNA and have weak endoribonuclease and 3'-exonuclease activities on r8oxoG substrate. Using biochemical assays, our results provide evidence of a human enzyme able to recognize and process abasic and oxidized ribonucleotides embedded in DNA

Patient-Reported Outcomes After Swallowing (SWOARs)-Sparing IMRT in Head and Neck Cancers: Primary Results from a Prospective Study Endorsed by the Head and Neck Study Group (HNSG) of the Italian Association of Radiotherapy and Clinical Oncology (AIRO)

Objectives To prospectively investigate changes in M.D. Anderson Dysphagia Inventory (MDADI) scores in patients affected by naso- and oropharynx cancer after definitive radiochemotherapy (ChemoRT) using swallowing organs at risk (SWOARs)-sparing IMRT. Methods MDADI questionnaires were collected at baseline and at 6 and 12 months after treatment. MDADI scores were categorized as follows: >= 80 "optimal," 80-60 "adequate," < 60 "poor" deglutition-related quality of life (QoL) group, and dichotomized as "optimal" vs "adequate/poor" for the analysis. A mean MDADI composite (MDADI-C) change of 10 points was considered as minimal clinically important difference (MCID). Results Sixty-three patients were enrolled of which 47 were considered for the analysis. At baseline, 26 (55%) were "optimal" and 21 (45%) were "adequate/poor." The mean baseline MDADI-C score was 93.6 dropping to 81 at 6 months (p = 0.013) and slightly rising to 85.5 at 12 months (p = 0.321) for the "optimal" group. Indeed, the mean baseline MDADI-C score was 64.3 rising to 77.5 at 6 months (p = 0.006) and stabilizing at 76 at 12 months (p = 0.999) for the "adequate/poor" group. A statistically significant but not clinically relevant worsening of the MDADI-C score was reported for the "optimal" group, whereas both a statistically significant and clinically meaningful improvement of the MDADI-C score were reported for the "adequate/poor" group from before to post-treatment. Conclusion Our results suggest a doubly clinical benefit of dose optimization to SWOARs to minimize the RT sequalae in patients with a baseline "optimal" deglutition-related QoL and to recover from cancer dysphagia in those with a baseline "adequate/poor" deglutition-related QoL

Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

Myoglobin, encoded by MB, is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O-2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C>T ( p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O-2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.Peer reviewe

Bypass gastrico su ansa a Y alla Roux e Sleeve gastrectomy: meccanismi di remissione del diabete e ruolo degli ormoni intestinali.

RYGB e LSG hanno un impatto simile sulla remissione del diabete, nella quale la sensibilità basale delle cellule beta al glucosio e la restaurata sensibilità al GLP-1 sono parametri determinanti. Altre risposte ormonali sono conseguenze della anatomia gastrointestinale alterata

New evidence of functional interactions within the hand motor system

Humans developed the ability to use their hands as tools to actively interact with the surrounding world. On a daily basis, without effort or a conscious will to act, we can manipulate dozens of objects placed in the environment to achieve different purposes. This, at first glance simple, ability relies on a network of cerebral areas computing a series of complex neural processes. The core cerebral regions involved in transforming visual inputs into hand actions have been identified within two distinct pareto-frontal networks, the dorsomedial and dorsolateral pathways. These pathways have been traditionally considered to process different types of information independently. The dual-route model of the hand motor system represents a milestone within the literature exploring the neural correlates of motor control. Nevertheless, following the recent improvement of the technical and analytical approaches adopted to investigate brain’s functioning, this initial description has been considered reductive. Nowadays, it is clear that the neural processes needed to produce a hand action require the integration of different information (e.g. spatial location of the object, spatial location of the arm, grip aperture, goal to pursue, etc.) that imply the exchange of information between anatomically distant, but functionally interconnected, cerebral areas. In light of the most recent neuroscientific advance in the field of motor control, we investigated the specific role of the cerebral areas of the motor system and their functional interactions during the planning and execution of hand actions. In the present thesis, we adopted several methodologies (TMS, fMRI) and analysis approaches (univariate, MVPA, DCM), to explore the involvement of defined areas in specific motor tasks, their representational content and their connectivity profiles. In the three neuroimaging studies here presented, we first considered the functional dynamics that occur within the hand network (Chapter 2). Secondly, we described a broader and integrated hand motor system including also the ventral stream, always considered as specialized in perceiving visual inputs (Chapter 3). Finally, we focused on the often neglected homologous regions within the right hemisphere (Chapter 4), providing a pan of the hand motor system in its entirety. The first study (Chapter 2) adopted a combined TMS-fMRI approach, and focused on understanding the interactions between the dorsomedial and dorsolateral pathways of the hand motor system. We adopted a delayed-reach-and-grasp task, performed under different perceptual conditions (eyes opened or closed), and we perturbed the activity of SPOC in the dorsomedial pathway of the left hemisphere by means of rTMS. We used univariate and multivariate analysis to investigate the modifications occurring during the planning phase of the action within areas functionally connected with the region stimulated with TMS. We found that when the normal activity of SPOC is altered, changes in encoding grasping action information occur within the dorsolateral pathway. This study showed a causal interaction between the dorsomedial and dorsolateral pathway of the hand motor network, which are traditionally considered to be specialized and independent. In the second study (Chapter 3), we adopted fMRI to explore the possible communication between dorsal and ventral stream, verifying the possible complementary and supportive role of the temporal cortex in motor control. To this aim, we adopted a delayed tool-pantomiming task known to recruit the ventral stream. Our delayed pantomiming task allowed us to consider the planning phase of the movement together with the execution of the pantomime. With multivariate analysis, we explored where in the dorsal and in the ventral streams different abstract goals of an action, i.e. independent from the tool identity, are represented in respect to more concrete aspects, related to the tool considered in the pantomime. In addition, we investigated the possible functional interactions between temporal and fronto-parietal regions, showing an exchange of information between the two pathways both with MVPA and connectivity analysis (DCM). Overall, these results point out a hand motor system that not only relies on the specialized-for-action dorsal network, but also on temporal lobe areas. In the third study of the thesis (Chapter 4), we combined data from Chapter 3 with a complementary fMRI session. In the second session we changed instruction modality and effector used to perform the pantomime, while experimental design and the task requirement were unchanged. This approach allowed focusing on understanding: (i) changes in the encoding of concrete and abstract representation based on task requirements (i.e. different instruction modality and effector) and (ii) the possible encoding of tool pantomimes’ information also outside the classically-defined left-lateralized tool network, in homologous regions within the right hemisphere. Overall, we found task-dependent changes in the representational content of the considered areas both in the left and in the right hemisphere. These results provided novel insights into the neural correlates of tool pantomime, pointing towards the supportive role of the temporal cortices and of the right hemisphere when planning and pantomiming this type of action. Overall, our studies contributed delineating a novel view on the organization of the hand motor system describing (i) the functional specialization of its different cerebral areas and (ii) the interactions occurring between these regions. Our research highlighted how the hand motor system has a functionally interconnected organization in which, to different degrees, various areas located in three main cerebral routes (ventral stream, dorsolateral and dorsomedial pathways) communicate to build a meaningful motor output

Functional assessment of dysphagia in head and neck tumors and correlation with perceived quality of life

In head and neck cancer (HNC) patients, radiation induced dysphagia (RID) is a very common side effect and has a significant impact on patient’s quality of life (QoF). The aim of this study is to evaluate the functional assessment of RID and correlation with perceived QoF. We evaluate a coort of 56 HNC patients treated with chemoradiotherapy on nasopharynx and oropharynx districts, between August 2015 and October 2021. All patients underwent to MD Anderson Dysphagia Inventory (MDADI) test for the evaluation of swallowing related QoL, FEES and videofluoroscopy (VFS) at t0 (time 0), t6 (after 6 months) and t12 (after 12 month). MDADI test is a written, 20 item self-amministred questionnaire; we mainly use a summary score called composite (MDADI-C) at time 0, and then after 6 and 12 months after chemo-radiotherapy. We correlate the MDADI – C score at t0, t6 and t12 to the results of FEES and VFS at the same time and their variation during the study to establish a link between patient’s self-perception of dysphagia links and FEES or VFS. We find that FEES is probably linked with MDADI-C variation (even though this results is not statistically significative) whereas VFS does not

Neural encoding and functional interactions underlying pantomimed movements

none2: Pantomimes are a unique movement category which can convey complex information about our intentions in the absence of any interaction with real objects. Indeed, we can pretend to use the same tool to perform different actions or to achieve the same goal adopting different tools. Nevertheless, how our brain implements pantomimed movements is still poorly understood. In our study, we explored the neural encoding and functional interactions underlying pantomimes adopting multivariate pattern analysis (MVPA) and connectivity analysis of fMRI data. Participants performed pantomimed movements, either grasp-to-move or grasp-to-use, as if they were interacting with two different tools (scissors or axe). These tools share the possibility to achieve the same goal. We adopted MVPA to investigate two levels of representation during the planning and execution of pantomimes: (1) distinguishing different actions performed with the same tool, (2) representing the same final goal irrespective of the adopted tool. We described widespread encoding of action information within regions of the so-called "tool" network. Several nodes of the network-comprising regions within the ventral and the dorsal stream-also represented goal information. The spatial distribution of goal information changed from planning-comprising posterior regions (i.e. parietal and temporal)-to execution-including also anterior regions (i.e. premotor cortex). Moreover, connectivity analysis provided evidence for task-specific bidirectional coupling between the ventral stream and parieto-frontal motor networks. Overall, we showed that pantomimes were characterized by specific patterns of action and goal encoding and by task-dependent cortical interactions.noneMalfatti, Giulia; Turella, LucaMalfatti, Giulia; Turella, Luc

Decoding motor imagery and action planning in the early visual cortex: Overlapping but distinct neural mechanisms

Recent evidence points to a role of the primary visual cortex that goes beyond visual processing into high-level cognitive and motor-related functions, including action planning, even in absence of feedforward visual information. It has been proposed that, at the neural level, motor imagery is a simulation based on motor representations, and neuroimaging studies have shown overlapping and shared activity patterns for motor imagery and action execution in frontal and parietal cortices. Yet, the role of the early visual cortex in motor imagery remains unclear. Here we used multivoxel pattern analyses on functional magnetic resonance imaging (fMRI) data to examine whether the content of motor imagery and action intention can be reliably decoded from the activity patterns in the retinotopic location of the target object in the early visual cortex. Further, we investigated whether the discrimination between specific actions generalizes across imagined and intended movements. Eighteen right-handed human participants (11 females) imagined or performed delayed hand actions towards a centrally located object composed of a small shape attached on a large shape. Actions consisted of grasping the large or small shape, and reaching to the center of the object. We found that despite comparable fMRI signal amplitude for different planned and imagined movements, activity patterns in the early visual cortex, as well as dorsal premotor and anterior intraparietal cortex, accurately represented action plans and action imagery. However, movement content is similar irrespective of whether actions are actively planned or covertly imagined in parietal but not early visual or premotor cortex, suggesting a generalized motor representation only in regions that are highly specialized in object directed grasping actions and movement goals. In sum, action planning and imagery have overlapping but non identical neural mechanisms in the cortical action network