Human foot outperforms the hand in mechanical pain discrimination

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterised. Here, we measured the capacity for mechanical pain discrimination using a two-alternative forced choice paradigm, with force-calibrated indentation stimuli (Semmes-Weinstein monofilaments) applied to the hand and foot dorsa of healthy human volunteers. In order to characterise the relationship between peripheral nociceptor activity and pain perception, we recorded single-unit activity from myelinated (A) and unmyelinated (C) mechanosensitive nociceptors in the skin using microneurography. At the perceptual level, we found that the foot was better at discriminating noxious forces than the hand, which stands in contrast to that for innocuous force discrimination, where the hand performed better than the foot. This observation of superior mechanical pain discrimination on the foot compared to the hand could not be explained by the responsiveness of individual nociceptors. We found no significant difference in the discrimination performance of either the myelinated or unmyelinated class of nociceptors between skin regions. This suggests the possibility that other factors such as skin biophysics, receptor density or central mechanisms may underlie these regional differences

E3 Ligase Activity of XIAP RING Domain Is Required for XIAP-Mediated Cancer Cell Migration, but Not for Its RhoGDI Binding Activity

Although an increased expression level of XIAP is associated with cancer cell metastasis, the underlying molecular mechanisms remain largely unexplored. To verify the specific structural basis of XIAP for regulation of cancer cell migration, we introduced different XIAP domains into XIAP−/− HCT116 cells, and found that reconstitutive expression of full length HA-XIAP and HA-XIAP ΔBIR, both of which have intact RING domain, restored β-Actin expression, actin polymerization and cancer cell motility. Whereas introduction of HA-XIAP ΔRING or H467A mutant, which abolished its E3 ligase function, did not show obvious restoration, demonstrating that E3 ligase activity of XIAP RING domain played a crucial role of XIAP in regulation of cancer cell motility. Moreover, RING domain rather than BIR domain was required for interaction with RhoGDI independent on its E3 ligase activity. To sum up, our present studies found that role of XIAP in regulating cellular motility was uncoupled from its caspase-inhibitory properties, but related to physical interaction between RhoGDI and its RING domain. Although E3 ligase activity of RING domain contributed to cell migration, it was not involved in RhoGDI binding nor its ubiquitinational modification

Interrogating and Predicting Tolerated Sequence Diversity in Protein Folds: Application to E. elaterium Trypsin Inhibitor-II Cystine-Knot Miniprotein

Cystine-knot miniproteins (knottins) are promising molecular scaffolds for protein engineering applications. Members of the knottin family have multiple loops capable of displaying conformationally constrained polypeptides for molecular recognition. While previous studies have illustrated the potential of engineering knottins with modified loop sequences, a thorough exploration into the tolerated loop lengths and sequence space of a knottin scaffold has not been performed. In this work, we used the Ecballium elaterium trypsin inhibitor II (EETI) as a model member of the knottin family and constructed libraries of EETI loop-substituted variants with diversity in both amino acid sequence and loop length. Using yeast surface display, we isolated properly folded EETI loop-substituted clones and applied sequence analysis tools to assess the tolerated diversity of both amino acid sequence and loop length. In addition, we used covariance analysis to study the relationships between individual positions in the substituted loops, based on the expectation that correlated amino acid substitutions will occur between interacting residue pairs. We then used the results of our sequence and covariance analyses to successfully predict loop sequences that facilitated proper folding of the knottin when substituted into EETI loop 3. The sequence trends we observed in properly folded EETI loop-substituted clones will be useful for guiding future protein engineering efforts with this knottin scaffold. Furthermore, our findings demonstrate that the combination of directed evolution with sequence and covariance analyses can be a powerful tool for rational protein engineering

Calibrating ADL-IADL scales to improve measurement accuracy and to extend the disability construct into the preclinical range: a systematic review

<p>Abstract</p> <p>Background</p> <p>Interest in measuring functional status among nondisabled older adults has increased in recent years. This is, in part, due to the notion that adults identified as 'high risk' for functional decline portray a state that is potentially easier to reverse than overt disability. Assessing relatively healthy older adults with traditional self-report measures (activities of daily living) has proven difficult because these instruments were initially developed for institutionalised older adults. Perhaps less evident, are problems associated with change scores and the potential for 'construct under-representation', which reflects the exclusion of important features of the construct (e.g., disability). Furthermore, establishing a formal hierarchy of functional status tells more than the typical simple summation of functional loss, and may have predictive value to the clinician monitoring older adults: if the sequence task difficulty is accelerated or out of order it may indicate the need for interventions.</p> <p>Methods</p> <p>This review identified studies that employed item response theory (IRT) to examine or revise functional status scales. IRT can be used to transform the ordinal nature of functional status scales to interval level data, which serves to increase diagnostic precision and sensitivity to clinical change. Furthermore, IRT can be used to rank items unequivocally along a hierarchy based on difficulty. It should be noted that this review is not concerned with contrasting IRT with more traditional classical test theory methodology.</p> <p>Results</p> <p>A systematic search of four databases (PubMed, Embase, CINAHL, and PsychInfo) resulted in the review of 2,192 manuscripts. Of these manuscripts, twelve met our inclusion/exclusion requirements and thus were targeted for further inspection.</p> <p>Conclusions</p> <p>Manuscripts presented in this review appear to summarise gerontology's best efforts to improve construct validity and content validity (i.e., ceiling effects) for scales measuring the early stages of activity restriction in community-dwelling older adults. Several scales in this review were exceptional at reducing ceiling effects, reducing gaps in coverage along the construct, as well as establishing a formal hierarchy of functional decline. These instrument modifications make it plausible to detect minor changes in difficulty for IADL items positioned at the edge of the disability continuum, which can be used to signal the onset of progressive type disability in older adults.</p

Innocuous pressure sensation requires A-type afferents but not functional ΡΙΕΖΟ2 channels in humans.

The sensation of pressure allows us to feel sustained compression and body strain. While our understanding of cutaneous touch has grown significantly in recent years, how deep tissue sensations are detected remains less clear. Here, we use quantitative sensory evaluations of patients with rare sensory disorders, as well as nerve blocks in typical individuals, to probe the neural and genetic mechanisms for detecting non-painful pressure. We show that the ability to perceive innocuous pressures is lost when myelinated fiber function is experimentally blocked in healthy volunteers and that two patients lacking Aβ fibers are strikingly unable to feel innocuous pressures at all. We find that seven individuals with inherited mutations in the mechanoreceptor PIEZO2 gene, who have major deficits in touch and proprioception, are nearly as good at sensing pressure as healthy control subjects. Together, these data support a role for Aβ afferents in pressure sensation and suggest the existence of an unknown molecular pathway for its detection

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Implementation of PID, bang-bang and backstep-ping controllers on 3D printed ambidextrous robot hand

Robot hands have attracted increasing research interest in recent years due to their high demand in industry and wide scope in number of applications. Almost all researches done on the robot hands were aimed at improving mechanical design, clever grasping at different angles, lifting and sensing of different objects. In this chapter, we presented the detail classification of control systems and reviewed the related work that has been done in the past. In particular, our focus was on control algorithms implemented on pneumatic systems using PID controller, Bang-bang controller and Backstepping controller. These controllers were tested on our uniquely designed ambidextrous robotic hand structure and results were compared to find the best controller to drive such devices. The five finger ambidextrous robot hand offers total of 13 degrees of freedom (DOFs) and it can bend its fingers in both ways left and right offering full ambidextrous functionality by using only 18 pneumatic artificial muscles (PAMs).Anthony Huynh, Luke Steele, Michal Simko, Luke Kavanagh and Alisdair Nimm