Variable force and visual feedback effects on teleoperator man/machine performance

An experimental study was conducted to determine the effects of various forms of visual and force feedback on human performance for several telemanipulation tasks. Experiments were conducted with varying frame rates and subtended visual angles, with and without force feedback

Apparatus for providing sensory substitution of force feedback

A feedback apparatus for an operator to control an effector that is remote from the operator to interact with a remote environment has a local input device to be manipulated by the operator. Sensors in the effector's environment are capable of sensing the amplitude of forces arising between the effector and its environment, the direction of application of such forces, or both amplitude and direction. A feedback signal corresponding to such a component of the force, is generated and transmitted to the environment of the operator. The signal is transduced into an auditory sensory substitution signal to which the operator is sensitive. Sound production apparatus present the auditory signal to the operator. The full range of the force amplitude may be represented by a single, audio speaker. Auditory display elements may be stereo headphones or free standing audio speakers, numbering from one to many more than two. The location of the application of the force may also be specified by the location of audio speakers that generate signals corresponding to specific forces. Alternatively, the location may be specified by the frequency of an audio signal, or by the apparent location of an audio signal, as simulated by a combination of signals originating at different locations

Apparatus for providing vibrotactile sensory substitution of force feedback

A feedback apparatus for an operator to control an effector that is remote from the operator to interact with a remote environment has a local input device to be manipulated by the operator. Sensors in the effector's environment are capable of sensing the amplitude of forces arising between the effector and its environment, the direction of application of such forces, or both amplitude and direction. A feedback signal corresponding to such a component of the force, is generated and transmitted to the environment of the operator. The signal is transduced into a vibrotactile sensory substitution signal to which the operator is sensitive. Vibration producing apparatus present the vibrotactile signal to the operator. The full range of the force amplitude may be represented by a single, mechanical vibrator. Vibrotactile display elements can be located on the operator's limbs, such as on the hand, fingers, arms, legs, feet, etc. The location of the application of the force may also be specified by the location of a vibrotactile display on the operator's body. Alternatively, the location may be specified by the frequency of a vibrotactile signal

The undesired fellow traveller

n/

BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein

Patients with chronic myeloid leukemia in whom tyrosine kinase inhibitors (TKIs) fail often present mutations in the BCR-ABL catalytic domain. We noticed a lack of substitutions involving 4 amino acids (E286, M318, I360, and D381) that form hydrogen bonds with ponatinib. We therefore introduced mutations in each of these residues, either preserving or altering their physicochemical properties. We found that E286, M318, I360, and D381 are dispensable for ABL and BCR-ABL protein stability but are critical for preserving catalytic activity. Indeed, only a "conservative" I360T substitution retained kinase proficiency and transforming potential. Molecular dynamics simulations of BCR-ABLI360T revealed differences in both helix αC dynamics and protein-correlated motions, consistent with a modified ATP-binding pocket. Nevertheless, this mutant remained sensitive to ponatinib, imatinib, and dasatinib. These results suggest that changes in the 4 BCR-ABL residues described here would be selected against by a lack of kinase activity or by maintained responsiveness to TKIs. Notably, amino acids equivalent to those identified in BCR-ABL are conserved in 51% of human tyrosine kinases. Hence, these residues may represent an appealing target for the design of pharmacological compounds that would inhibit additional oncogenic tyrosine kinases while avoiding the emergence of resistance due to point mutations.This work was supported by an investigator grant to P.V. from Associazione Italiana per la Ricerca sul Cancro (AIRC) and by funding from the Biotechnology and Biological Sciences Research Council (BB/I023291/1 and BB/H018409/1 to AP and FF). P.B. is the recipient of an AIRC - Marie Curie fellowship

BCR-ABL1 doubling-times and halving-times may predict CML response to tyrosine kinase inhibitors

In Chronic Myeloid Leukemia (CML), successful treatment requires accurate molecular monitoring to evaluate disease response and provide timely interventions for patients failing to achieve the desired outcomes. We wanted to determine whether measuring BCR-ABL1 mRNA doubling-times (DTs) could distinguish inconsequential rises in the oncogene’s expression from resistance to tyrosine kinase inhibitors (TKIs). Thus, we retrospectively examined BCR-ABL1 evolution in 305 chronic-phase CML patients receiving imatinib mesylate (IM) as a first line treatment. Patients were subdivided in two groups: those with a confirmed rise in BCR-ABL1 transcripts without MR3.0 loss and those failing IM. We found that the DTs of the former patients were significantly longer than those of patients developing IM resistance (57.80 vs. 41.45 days, p = 0.0114). Interestingly, the DT values of individuals failing second-generation (2G) TKIs after developing IM resistance were considerably shorter than those observed at the time of IM failure (27.20 vs. 41.45 days; p = 0.0035). We next wanted to establish if decreases in BCR-ABL1 transcripts would identify subjects likely to obtain deep molecular responses. We therefore analyzed the BCR-ABL1 halving-times (HTs) of a different cohort comprising 174 individuals receiving IM in first line and observed that, regardless of the time point selected for our analyses (6, 12, or 18 months), HTs were significantly shorter in subjects achieving superior molecular responses (p = 0.002 at 6 months; p < 0.001 at 12 months; p = 0.0099 at 18 months). Moreover, 50 patients receiving 2G TKIs as first line therapy and obtaining an MR3.0 (after 6 months; p = 0.003) or an MR4.0 (after 12 months; p = 0.019) displayed significantly shorter HTs than individuals lacking these molecular responses. Our findings suggest that BCR-ABL1 DTs and HTs are reliable tools to, respectively, identify subjects in MR3.0 that are failing their assigned TKI or to recognize patients likely to achieve deep molecular responses that should be considered for treatment discontinuation

Clinical implications of discordant early molecular responses in CML patients treated with imatinib

A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3-and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points

Spatially targeted nature-based solutions can mitigate climate change and nature loss but require a systems approach

Funding Information: This study was funded by the Royal Society for the Protection of Birds (RSPB) and Natural England (project code ECM 58632). The Breeding Bird Survey is a Partnership between the BTO, RSPB, and Joint Nature Conservation Committee (on behalf of Natural Resources Wales, Natural England, Council for Nature Conservation and Countryside, and NatureScot) and relies on volunteer surveyors. Simon Gillings provided tetrad-level predictions of relative abundance for wading birds. We are grateful to members of the RSPB steering group, who contributed to the development of our scenarios, and Profs. Tim Benton and Andrew Balmford who commented on an earlier version of this manuscript. Conceptualization, T.F. R.B.B. T.B.-L. G.M.B. W.J.P. and R.H.F.; methodology, T.F. T.B.-L. J.P.C. D.M. P.S. and R.H.F.; software, T.F.; formal analysis, T.F.; resources, D.M.; data curation, T.F.; writing – original draft, T.F.; writing – review & editing, R.B.B. T.B.-L. G.M.B. J.P.C. D.M. P.S. W.J.P. and R.H.F.; visualization, T.F.; supervision, W.J.P. The authors declare no competing interests. Publisher Copyright: © 2023 The AuthorsPeer reviewedPublisher PD

A large de novo 9p21.3 deletion in a girl affected by astrocytoma and multiple melanoma.

BACKGROUND: Association of melanoma, neural system tumors and germ line mutations at the 9p21 region in the CDKN2A, CDKN2B and CDKN2BAS genes has been reported in a small number of families worldwide and described as a discrete syndrome in melanoma families registered as a rare disease, the melanoma–astrocytoma syndrome. CASE PRESENTATION: We here studied two young patients developing melanoma after radiotherapy for astrocytoma, both reporting lack of family history for melanoma or neural system tumors at genetic counselling. Patient A is a girl treated for anaplastic astrocytoma at 10 years and for multiple melanomas on the scalp associated to dysplastic nevi two years later. Her monozygotic twin sister carried dysplastic nevi and a slow growing, untreated cerebral lesion. Direct sequencing analysis showed no alterations in melanoma susceptibility genes including CDKN2A, CDK4, MC1R and MITF or in TP53. By microsatellite analysis, multiplex ligation-dependent probe amplification, and array comparative genomic hybridization a deletion including the CDKN2A, CDKN2B and CDKN2BAS gene cluster was detected in both twin sisters, encompassing a large region at 9p21.3 and occurring de novo after the loss of one paternal allele. Patient B is a boy of 7 years when treated for astrocytoma then developing melanoma associated to congenital nevi on the head 10 years later: sequencing and multiplex ligation-dependent probe amplification revealed a normal profile of the CDKN2A/CDKN2B/CDKN2BAS region. Array comparative genomic hybridization confirmed the absence of deletions at 9p21.3 and failed to reveal known pathogenic copy number variations. CONCLUSIONS: By comparison with the other germ line deletions at the CDKN2A, CDKN2B and CDKN2BAS gene cluster reported in melanoma susceptible families, the deletion detected in the two sisters is peculiar for its de novo origin and for its extension, as it represents the largest constitutive deletion at 9p21.3 region identified so far. In addition, the two studied cases add to other evidence indicating association of melanoma with exposure to ionizing radiation and with second neoplasm after childhood cancer. Melanoma should be considered in the monitoring of pigmented lesions in young cancer patients

Mobile application development exploiting science gateway technologies

Nowadays, collaborative applications are valuable tools for scientists to share their studies and experiences, for example, by interacting simultaneously with their data and outcomes giving feedback to other colleagues on how the data are processed. This paper presents a mobile application connected to a workflow-enabled framework to perform visualization and data analysis of large-scale, multi-dimensional datasets on distributed computing infrastructures. In particular, the usage of workflow-driven applications, through science gateway technologies, allows the scientist to share heavy data exploration tasks as workflows and the relative results in a transparent and user-friendly way