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Summary: The inter- and intraobserver agreement (K statistic) in reporting according to BI-RADS assessment categories was tested on 12 dedicated breast radiologists, with little prior working knowledge of BI-RADS, reading a set of 50 lesions (29 malignant, 21 benign). Intraobserver agreement (four categories: R2, R3, R4, R5) was fair (0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80) or almost perfect (>0.80) for one, two, five or four radiologists, or (six categories: R2, R3, R4a, R4b, R4c, R5) fair, moderate, substantial or almost perfect for three, three, three or three radiologists, respectively. Interobserver agreement (four categories) was fair, moderate or substantial for three, six, or three radiologists, or (six categories) slight, fair or moderate for one, six, or five radiologists. Major disagreement occurred for intermediate categories (R3=0.12, R4=0.25, R4a=0.08, R4b=0.07, R4c=0.10). We found insufficient intra- and interobserver consistency of breast radiologists in reporting BI-RADS assessment categories. Although training may improve these results, simpler alternative reporting methods (systems), focused on clinical decision-making, should be explored. [Copyright &y& Elsevier]

Background: Stroke patients often experience alterations in their subjective feeling of ownership for the affected limb, which can hinder motor function and interfere with rehabilitation. In this study, we aimed at disentangling the complex relationship between sensory impairment, body ownership (BO), and motor control in stroke patients., Methods: We recruited 20 stroke patients with unilateral upper limb sensory deficits and 35 age-matched controls. Participants performed a virtual reality reaching task with a varying displacement between their real unseen hand and a visible virtual hand. We measured reaching errors and subjective ownership ratings as indicators of hand ownership. Reaching errors were modeled using a probabilistic causal inference model, in which ownership for the virtual hand is inferred from the level of congruency between visual and proprioceptive inputs and used to weigh the amount of visual adjustment to reaching movements., Findings: Stroke patients were more likely to experience ownership over an incongruent virtual hand and integrate it into their motor plans. The model explained this tendency in terms of a decreased capability of detecting visuo-proprioceptive incongruences, proportionally to the amount of proprioceptive deficit. Lesion analysis further revealed that BO alterations, not fully explained by the proprioceptive deficit, are linked to frontoparietal network damage, suggesting a disruption in higher-level multisensory integration functions., Conclusions: Collectively, our results show that BO alterations in stroke patients can be quantitatively predicted and explained in a computational framework as the result of sensory loss and higher-level multisensory integration deficits., Funding: Swiss National Science Foundation (163951)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The acquisition of motor skills is a key element in many sports. A motor learning principle, which is frequently used to support skill acquisition is the application of different attentional foci. The effectiveness of different attentional foci on performance and the learning of motor skills has been investigated in various sports using randomised controlled trials. The aim of the present study was to investigate the effectiveness of different attentional foci (such as external (EFA) and internal attentional foci (IFA), but also holistic and switching foci) on the performance and learning of a sport-specific motor task in healthy individuals., Methods: This study was a systematic review with network meta-analysis. We followed the Prisma reporting guideline and the Cochrane handbook for systematic reviews. Cinahl, Embase, Medline and Cochrane Central were searched for eligible studies. Network meta-analyses were performed for the post-acquisition, retention and transfer test endpoints., Results: Twelve studies were included in the review. At post-acquisition an EFA was the most effective intervention compared to the control intervention (SMD: 0.9855; 95% CI [0.4-1.57]; p : 0.001). At the retention and transfer test endpoints, a holistic focus of attention had the highest effectiveness compared to an IFA (SMD 0.75; 95% CI [-0.1 to 1.6]; p : 0.09) and (SMD 1.16; 95% CI [0.47-1.86]; p : 0.001)., Discussion: For all three endpoints, we analysed a greater effectiveness of an EFA and holistic focus compared to an IFA. Several promising different attentional focus interventions were identified. The largest effects were analysed for a holistic focus. However, only one study used this intervention and therefore there remains uncertainty about the effectiveness. With regard to the inconsistency observed, the analysis at post-acquisition should be interpreted with caution. Modified versions of the EFA were the imagined and the dynamic EFA. Both were only explored in single studies and should therefore be investigated in further follow-up studies that directly compare them., Competing Interests: The authors declare that they have no competing interests., (© 2024 Favre-Bulle et al.)

Aim: To identify, synthesize, and interpret the scientific literature on the experience, perspectives, and feelings of transgender people during hospitalization., Design: A qualitative metasynthesis., Data Sources: PubMed, CINAHL and PSYCHINFO were consulted in March 2024., Methods: A literature review was conducted following Sandelowski and Barroso's four-step metasynthesis methodology. The article selection process was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were selected based on the objectives of the review, pre-established criteria and quality appraisal. A thematic analysis was conducted after extracting relevant quotations and a metasynthesis table was created to compare quotations and analyse overarching themes., Results: Twenty-two studies were included after screening titles and abstracts, full texts, and references. Three themes were identified: 'Perception of self-identity'; 'Misgendering' and 'Lack of staff training and awareness'., Conclusion: Transgender people's healthcare experiences during hospitalization were mainly negative, delayed or uncomfortable. Misgendering and lack of awareness of transgender issues among healthcare workers generated anxiety and frustration. Key aspects of care for transgender people need to be included in all training programs for health professionals., Implications for the Profession And/or Patient Care: There is a need to increase education and awareness among healthcare professionals towards transgender people's needs during hospitalization ensure high quality care., Impact: This study addressed the negative experience, perspectives and feelings of transgender people during hospitalization. Misgendering and unawareness of transgender peoples' issues create anxiety and frustration among nurses. Elements to improve care for transgender people need to be integrated into all nursing curricula and training programs., Reporting Method: The authors adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and the Critical Appraisal Skills Programme (CASP)., Patient or Public Contribution: Since this was a metasynthesis, no patient or public contribution was required., (© 2024 John Wiley & Sons Ltd.)

Multi-stable elements are commonly employed to design reconfigurable and adaptive structures, because they enable large and reversible shape changes in response to changing loads, while simultaneously allowing self-locking capabilities. However, existing multi-stable structures have properties that depend on their initial design and cannot be tailored post-fabrication. Here, a novel design approach is presented that combines multi-stable structures with two-way shape memory polymers. By leveraging both the one-way and two-way shape memory effect under bi-axial strain conditions, the structures can re-program their 3D shape, bear loads, and self-actuate. Results demonstrate that the structures' shape and stiffness can be tuned post-fabrication at the user's need and the multi-stability can be suppressed or activated on command. The control of multi-stability prevents undesired snapping of the structures and enables higher load-bearing capability, compared to conventional multi-stable systems. The proposed approach offers the possibility to augment the functionality of existing multi-stable concepts, showing potential for the realization of highly adaptable mechanical structures that can reversibly switch between being mono and multi-stable and that can undergo shape changes in response to a change in temperature., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

The perceptions of our own body (e.g., size and shape) do not always coincide with its real characteristics (e.g., dimension). To track the complexity of our perception, the concept of mental representations (model) of the body has been conceived. Body representations (BRs) are stored in the brain and are maintained and updated through multiple sensory information. Despite being altered in different clinical conditions and being tightly linked with self-consciousness, which is one of the most astonishing features of the human mind, the BRs and, especially, the underlying mechanisms and functions are still unclear. In this vein, here we suggest that (neuro)robotics can make an important contribution to the study of BRs. The first section of the study highlights the potential impact of robotics devices in investigating BRs. Far to be exhaustive, we illustrate major examples of its possible exploitation to further improve the assessment of motor, haptic, and multisensory information building up the BRs. In the second section, we review the main evidence showing the contribution of neurorobotics-based (multi)sensory stimulation in reducing BRs distortions in various clinical conditions (e.g., stroke, amputees). The present study illustrates an emergent multidisciplinary perspective combining the neuroscience of BRs and (neuro)robotics to understand and modulate the perception and experience of one's own body. We suggest that (neuro)robotics can enhance the study of BRs by improving experimental rigor and introducing new experimental conditions. Furthermore, it might pave the way for the rehabilitation of altered body perceptions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Risso and Bassolino.)

Shape transformation offers the possibility of realizing devices whose 3D shape can be altered to adapt to different environments. Many applications would profit from reversible and actively controllable shape transformation together with a self-locking capability. Solutions that combine such properties are rare. Here, a novel class of meta-structures that can tackle this challenge is presented thanks to multi-stability. Results demonstrate that the multi-stability of the meta-structure is strictly tied to the use of highly anisotropic materials. The design rules that enable large-shape transformation, programmability, and self-locking are derived, and it is proven that the shapes can be actively controlled and harnessed to realize inchworm-inspired locomotion by strategically actuating the meta-structure. This study provides routes toward novel shape adaptive lightweight structures where a metamaterial-inspired assembly of anisotropic components leads to an unforeseen combination of properties, with potential applications in reconfigurable space structures, building facades, antennas, lenses, and soft robots., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The multisensory integration of signals from different senses is crucial to develop an unambiguous percept of the environment and our body. Losing a limb causes drastic changes in the body, sometimes causing pain and distorted phantom limb perception. Despite the debate over why these phenomena arise, some researchers suggested that they might be linked to an impairment of multisensory signals inflow and integration. Therefore, reestablishing optimally integrated sensory feedback could be crucial. The related benefits on sensory performance and body self-representation are still to be demonstrated, particularly in lower-limb amputees. We present a multisensory framework combining Virtual reality and electro-cutaneous stimulation that allows the optimal integration of visuo-tactile stimuli in lower-limb amputees even if nonspatially matching. We also showed that this multisensory stimulation allowed faster sensory processing, higher embodiment, and reductions in phantom limb distortions. Our findings support the development of multisensory rehabilitation approaches, restoring a correct body representation., Competing Interests: S.R. holds shares of Sensars Neuroprosthetics Sarl, a company working to commercialize novel solutions for leg amputees. Other authors do not have anything to declare., (© 2022 The Authors.)

Objectives: The aim of the present study was to investigate "Proactive-Adjustment hypothesis" (PA) during the Stop Signal Task (SST). The PA is implied in the highly inconsistent literature, and it deals with the role of response inhibition (RI) in obsessive-compulsive disorder (OCD). This hypothesis assumed that participants would balance stopping and going by adjusting the response threshold (RT) in the go task. We verified whether the PA strategy was also implemented in our clinical group., Methods: To reach this goal, we analyzed SST performances in a group of 36 patients with OCD and 36 healthy controls (HCs). To identify different participants' behaviors during the task, without preconceived notions regarding the diagnosis, we performed a cluster analysis. Furthermore, we analyzed the influence of drug therapy and we investigated whether the rule and reversal acquisition investigated with the Intra-Extra Dimensional Set Shift, differed in the two clusters., Results: We did not find any difference relative to the number of patients with OCD and HCs included in the two clusters. Furthermore, we found that only Not Proactive participants performed the task as fast as possible, while Proactive participants consistently slowed down their RTs and showed a lower number of Direction Errors, higher Stop Signal Delay, and worse cognitive flexibility., Conclusions: Our results show that among patients with OCD the use of PA is changeable and does not differ from HCs. This finding supports the idea that the RI heterogeneity concerning patients with OCD could be related to PA. (JINS, 2018, 24, 703-714).

Planning ability (PA) is a key aspect of cognitive functioning and requires subjects to identify and organise the necessary steps to achieve a goal. Despite the central role of executive dysfunction in patients with obsessive-compulsive disorder (OCD), deficits in PA have been investigated leading to contrasting results. Given these inconsistencies, the main aim of our work is to give a deeper and clearer understanding of PA in OCD patients. Moreover, we are interested in investigating the relationship between PAs and impulsivity traits and other clinical variables. Sixty-eight OCD patients and 68 healthy controls (HCs) matched for sex and age were assessed through the Stocking of Cambridge (SoC), a computerised version of the Tower of London. We examined planning sub-components for each difficulty levels (from 2 to 5 minimum moves). Our results showed that OCD patients needed longer initial thinking time than HCs during the execution of low demanding tasks (i.e. 2 and 3 moves), while the accuracy level between the two groups did not significantly differ. OCD patients required longer initial thinking time also during high demanding tasks (i.e., 4 and 5 moves), but in this case their accuracy was significantly worse than HCs' one. We did not find any association between impulsivity and PAs. Our results supported the hypothesis that OCD patients were not able to retain in memory the planned sequence and they had to reschedule their movements during the execution. Thus, future studies should deepen the interrelation between working memory and PA to better understand the influence between these two cognitive functions and their interaction with clinical variables in OCD patients.

Pre-mRNA splicing is catalyzed by the spliceosome, a multi-megadalton ribonucleoprotein machine. Previous work from our laboratory revealed the splicing factor SRSF1 as a regulator of the SUMO pathway, leading us to explore a connection between this pathway and the splicing machinery. We show here that addition of a recombinant SUMO-protease decreases the efficiency of pre-mRNA splicing in vitro. By mass spectrometry analysis of anti-SUMO immunoprecipitated proteins obtained from purified splicing complexes formed along the splicing reaction, we identified spliceosome-associated SUMO substrates. After corroborating SUMOylation of Prp3 in cultured cells, we defined Lys 289 and Lys 559 as bona fide SUMO attachment sites within this spliceosomal protein. We further demonstrated that a Prp3 SUMOylation-deficient mutant while still capable of interacting with U4/U6 snRNP components, is unable to co-precipitate U2 and U5 snRNA and the spliceosomal proteins U2-SF3a120 and U5-Snu114. This SUMOylation-deficient mutant fails to restore the splicing of different pre-mRNAs to the levels achieved by the wild type protein, when transfected into Prp3-depleted cultured cells. This mutant also shows a diminished recruitment to active spliceosomes, compared to the wild type protein. These findings indicate that SUMO conjugation plays a role during the splicing process and suggest the involvement of Prp3 SUMOylation in U4/U6•U5 tri-snRNP formation and/or recruitment., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Dengue virus NS5 protein plays multiple functions in the cytoplasm of infected cells, enabling viral RNA replication and counteracting host antiviral responses. Here, we demonstrate a novel function of NS5 in the nucleus where it interferes with cellular splicing. Using global proteomic analysis of infected cells together with functional studies, we found that NS5 binds spliceosome complexes and modulates endogenous splicing as well as minigene-derived alternative splicing patterns. In particular, we show that NS5 alone, or in the context of viral infection, interacts with core components of the U5 snRNP particle, CD2BP2 and DDX23, alters the inclusion/exclusion ratio of alternative splicing events, and changes mRNA isoform abundance of known antiviral factors. Interestingly, a genome wide transcriptome analysis, using recently developed bioinformatics tools, revealed an increase of intron retention upon dengue virus infection, and viral replication was improved by silencing specific U5 components. Different mechanistic studies indicate that binding of NS5 to the spliceosome reduces the efficiency of pre-mRNA processing, independently of NS5 enzymatic activities. We propose that NS5 binding to U5 snRNP proteins hijacks the splicing machinery resulting in a less restrictive environment for viral replication., Competing Interests: The authors have declared that no competing interests exist.

Akt/PKB, a serine/threonine kinase member of the AGC family of proteins, is involved in the regulation of a plethora of cellular processes triggered by a wide diversity of extracellular signals and is thus considered a key signalling molecule in higher eukaryotes. Deregulation of Akt signalling is associated with a variety of human diseases, revealing Akt-dependent pathways as an attractive target for therapeutic intervention. Since its discovery in the early 1990s, a large body of work has focused on Akt phosphorylation of two residues, Thr308 and Ser473, and modification of these two sites has been established as being equivalent to Akt activation. More recently, Akt has been identified as a substrate for many different post-translational modifications, including not only phosphorylation of other residues, but also acetylation, glycosylation, oxidation, ubiquitination and SUMOylation. These modifications could provide additional regulatory steps for fine-tuning Akt function, Akt trafficking within the cell and/or for determining the substrate specificity of this signalling molecule. In the present review, we provide an overview of these different post-translational modifications identified for Akt, focusing on their consequences for this kinase activity.

Akt/PKB is a key signaling molecule in higher eukaryotes and a crucial protein kinase in human health and disease. Phosphorylation, acetylation, and ubiquitylation have been reported as important regulatory post-translational modifications of this kinase. We describe here that Akt is modified by SUMO conjugation, and show that lysine residues 276 and 301 are the major SUMO attachment sites within this protein. We found that phosphorylation and SUMOylation of Akt appear as independent events. However, decreasing Akt SUMOylation levels severely affects the role of this kinase as a regulator of fibronectin and Bcl-x alternative splicing. Moreover, we observed that the Akt mutant (Akt E17K) found in several human tumors displays increased levels of SUMOylation and also an enhanced capacity to regulate fibronectin splicing patterns. This splicing regulatory activity is completely abolished by decreasing Akt E17K SUMO conjugation levels. Additionally, we found that SUMOylation controls Akt regulatory function at G₁/S transition during cell cycle progression. These findings reveal SUMO conjugation as a novel level of regulation for Akt activity, opening new areas of exploration related to the molecular mechanisms involved in the diverse cellular functions of this kinase.

The unfolded protein response (UPR) and the Akt signaling pathway share several regulatory functions and have the capacity to determine cell outcome under specific conditions. However, both pathways have largely been studied independently. Here, we asked whether the Akt pathway regulates the UPR. To this end, we used a series of chemical compounds that modulate PI3K/Akt pathway and monitored the activity of the three UPR branches: PERK, IRE1 and ATF6. The antiproliferative and antiviral drug Akt-IV strongly and persistently activated all three branches of the UPR. We present evidence that activation of PERK/eIF2α requires Akt and that PERK is a direct Akt target. Chemical activation of this novel Akt/PERK pathway by Akt-IV leads to cell death, which was largely dependent on the presence of PERK and IRE1. Finally, we show that hypoxia-induced activation of eIF2α requires Akt, providing a physiologically relevant condition for the interaction between Akt and the PERK branch of the UPR. These data suggest the UPR and the Akt pathway signal to one another as a means of controlling cell fate.

Alternative splicing and post-translational modifications are key events for the generation of proteome diversity in eukaryotes. The study of the molecular mechanisms governing these processes, and every other step of gene expression, has underscored the existing interconnectedness among them. Therefore, molecules that could concertedly regulate different stages from transcription to pre-mRNA processing, translation and even protein activity have called our attention. Serine/arginine-rich proteins, initially identified as splicing regulators, are involved in diverse aspects of gene expression. Although most of the roles exerted by members of this family are related to mRNA biogenesis and metabolism, few recently uncovered ones link these proteins to other regulatory steps along gene expression, particularly the regulation of post-translational modification by conjugation of the small ubiquitin-related modifier. This along with the established link between ubiquitin, transcription and pre-mRNA processing points to a general mechanism of interaction between different cellular machineries, such as ubiquitin/ubiquitin-like conjugation pathways, transcription apparatus and the spliceosome.

Serine/arginine-rich (SR) proteins are among the most studied splicing regulators. They constitute a family of evolutionarily conserved proteins that, apart from their initially identified and deeply studied role in splicing regulation, have been implicated in genome stability, chromatin binding, transcription elongation, mRNA stability, mRNA export and mRNA translation. Remarkably, this list of SR protein activities seems far from complete, as unexpected functions keep being unraveled. An intriguing aspect that awaits further investigation is how the multiple tasks of SR proteins are concertedly regulated within mammalian cells. In this article, we first discuss recent findings regarding the regulation of SR protein expression, activity and accessibility. We dive into recent studies describing SR protein auto-regulatory feedback loops involving different molecular mechanisms such asunproductive splicing, microRNA-mediated regulation and translational repression. In addition, we take into account another step of regulation of SR proteins, presenting new findings about a variety of post-translational modifications by proteomics approaches and how some of these modifications can regulate SR protein sub-cellular localization or stability. Towards the end, we focus in two recently revealed functions of SR proteins beyond mRNA biogenesis and metabolism, the regulation of micro-RNA processing and the regulation of small ubiquitin-like modifier (SUMO) conjugation., (Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.)

Heterogeneous nuclear ribonucleoprotein (hnRNP) K is a nucleocytoplasmic shuttling protein that is a key player in the p53-triggered DNA damage response, acting as a cofactor for p53 in response to DNA damage. hnRNP K is a substrate of the ubiquitin E3 ligase MDM2 and, upon DNA damage, is de-ubiquitylated. In sharp contrast with the role and consequences of the other post-translational modifications, nothing is known about the role of SUMO conjugation to hnRNP K in p53 transcriptional co-activation. In the present work, we show that hnRNP K is modified by SUMO in lysine 422 within its KH3 domain, and sumoylation is regulated by the E3 ligase Pc2/CBX4. Most interestingly, DNA damage stimulates hnRNP K sumoylation through Pc2 E3 activity, and this modification is required for p53 transcriptional activation. Abrogation of hnRNP K sumoylation leads to an aberrant regulation of the p53 target gene p21. Our findings link the DNA damage-induced Pc2 activation to the p53 transcriptional co-activation through hnRNP K sumoylation.