Ca2+ waves coordinate purinergic receptor–evoked integrin activation and polarization

The integrin GPIIb/IIIa is highly abundant on the surface of platelets and can be activated by intracellular Ca2+ signaling in an “inside-out” manner to bind to the adhesive ligand fibrinogen. Bye et al. imaged intracellular Ca2+ signaling and fibrinogen binding events in primary rat megakaryocytes activated through the ADP-stimulated receptors P2Y1 and P2Y12. The authors found that signaling by both receptors was required for full integrin activation, which depended on P2Y1-stimulated Ca2+ signaling and P2Y12-stimulated activation of the kinase PI3K. In addition, fibrinogen binding became polarized in these cells in a manner dependent on the direction of ADP-stimulated Ca2+ waves

Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction

The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy

Platelet signaling: a complex interplay between inhibitory and activatory networks

The role of platelets in hemostasis and thrombosis is dependent on a complex balance of activatory and inhibitory signaling pathways. Inhibitory signals released from the healthy vasculature suppress platelet activation in the absence of platelet receptor agonists. Activatory signals present at a site of injury initiate platelet activation and thrombus formation; subsequently, endogenous negative signaling regulators dampen activatory signals to control thrombus growth. Understanding the complex interplay between activatory and inhibitory signaling networks is an emerging challenge in the study of platelet biology and necessitates a systematic approach to utilize experimental data effectively. In this review, we will explore the key points of platelet regulation and signaling that maintain platelets in a resting state, mediate activation to elicit thrombus formation or provide negative feedback. Platelet signaling will be described in terms of key signaling molecules that are common to the pathways activated by platelet agonists and can be described as regulatory nodes for both positive and negative regulators. This article is protected by copyright. All rights reserved

Validation of Different Combination of Three Reversing Half-Hitches Alternating Posts (RHAPs) Effects on Arthroscopic Knot Integrity

Introduction. With arthroscopic techniques being used, the importanceof knot tying has been examined. Previous literaturehas examined the use of reversing half-hitches on alternatingposts (RHAPs) on knot security. Separately, there has been researchregarding different suture materials commonly used inthe operating room. The specific aim of this study was to validatethe effect of different stacked half-hitch configuration anddifferent braided suture materials on arthroscopic knot integrity. Methods. Three different suture materials tied withfive different RHAPs in arthroscopic knots were compared.A single load-to-failure test was performed andthe mean ultimate clinical failure load was obtained. Results. Significant knot holding strength improvement wasfound when one half-hitch was reversed as compared to baselineknot. When two of the half-hitches were reversed, therewas a greater improvement with all knots having a mean ultimateclinical failure load greater than 150 newtons (N). Comparisonof the suture materials demonstrated a higher meanultimate clinical failure load when Force Fiber® was used andat least one half-hitch was reversed. Knots tied with eitherForce Fiber® or Orthocord® showed 0% chance of knot slippagewhile knots tied with FiberWire® or braided fishing linehad about 10 and 30% knot slippage chances, respectively. Conclusion. A significant effect was observed in regards to bothstacked half-hitch configuration and suture materials used onknot loop and knot security. Caution should be used with tyingthree RHAPs in arthroscopic surgery, particularly witha standard knot pusher and arthroscopic cannulas. The findingsof this study indicated the importance of three RHAPsin performing arthroscopic knot tying and provided evidenceregarding discrepancies of maximum clinical failure loads observedbetween orthopaedic surgeons, thereby leading to bettersurgical outcomes in the future. KS J Med 2017;10(2):35-39

Advances in Organic Solvent Nanofiltration Rely on Physical Chemistry and Polymer Chemistry

The vast majority of industrial chemical synthesis occurs in organic solution. Solute concentration and solvent recovery consume ~50% of the energy required to produce chemicals and pose problems that are as relevant as the synthesis process itself. Separation and purification processes often involve a phase change and, as such, they are highly energy-intensive. However, novel, energy-efficient technologies based on polymer membranes are emerging as a viable alternative to thermal processes. Despite organic solvent nanofiltration (OSN) could revolutionize the chemical, petrochemical, food and pharmaceutical industry, its development is still in its infancy for two reasons: (i) the lack of fundamental knowledge of elemental transport phenomena in OSN membranes, and (ii) the instability of traditional polymer materials in chemically challenging environments. While the latter issue has been partially solved, the former was not addressed at all. Moreover, the few data available about solute and solvent transport in OSN membranes are often interpreted using inappropriate theoretical tools, which contributes to the spread of misleading conclusions in the literature. In this review we provide the state of the art of organic solvent nanofiltration using polymeric membranes. First, theoretical models useful to interpret experimental data are discussed and some misleading conclusions commonly reported in the literature are highlighted. Then, currently available materials are reviewed. Finally, materials that could revolutionize OSN in the future are identified. Among the possible applications of OSN, isomers separation could open a new era in chemical engineering and polymer science in the years to come

Performance of parental genotypes and inheritance of Angular Leaf Spot (Phaeosariopsis griseola) resistance in the common bean (Phaseolus vulgaris)

Two studies, one on performance of six common bean parental genotypes and another on inheritance of resistance to Phaeosariopsis griseola (Pg) in the common bean were carried out in Malawi. Common bean entries namely; Chimbamba, Nasaka, RC 15, CAL 143 and Mexico 54 were evaluated on station in the 2004/2005 growing season at Bunda, Dedza, Ng'onga and Ntchenachena sites. The second study started by generating F1s and then F2 and F3 seeds in greenhouse at Bunda College. CAL 143 and Mexico 54 were sources of Pg resistance genes while Chimbamba, Nasaka and RC 15 were susceptible recipient parents. Following green house trials, Pg resistance was evaluated on station in the samesites. CAL 143 was highest yielding but unstable across sites. RC 15 was stable and gave the highest yield at the dry-spell-stricken Ng’onga whereas Mexico 54 was superior at Ntchenachena but highly unstable across sites. Yield was strongly correlated to number of effective pods per plant in all genotypes. The inheritance study showed that resistance to Pg in the common bean is controlled by one gene using both CAL 143 and Mexico 54 as resistant parents.&#160

Efficacy of cognitive remediation on activities of daily living in individuals with mild cognitive impairment or early-stage dementia : a systematic review and meta-analysis

Introduction: Instrumental activities of daily living are essential for ageing well and independent living. Little is known about the effectiveness of cognitive remediation on instrumental activities of daily living performance for individuals with mild cognitive impairment or early-stage dementia. The objective of this study was to evaluate the immediate and long-term carryover effects of cognitive remediation on improving or maintaining instrumental activities of daily living performance in older adults with mild cognitive impairment and early-stage dementia. Methods: Randomized controlled trials published from 2009 to 2022 were identified in OvidSP versions of MEDLINE and Embase, EBSCO versions of CINAHL and PsycINFO, and the Cochrane Central Register of Controlled Trials. A narrative synthesis of the findings was reported on the outcomes of the included studies. Relevant data was extracted and analysed using R software’s ‘metafor’ package with a random effect model with 95% CI. Results: Thirteen studies, totalling 1414 participants, were identified in the narrative analysis. The results of meta-analysis, inclusive of 11 studies, showed that cognitive remediation elicited a significant improvement in the instrumental activities of daily living performance (SMD: 0.17, 95% CI 0.03–0.31). There was insufficient evidence of any lasting effect. Discussion: Cognitive remediation is effective in improving instrumental activities of daily living performance immediately post-intervention in older adults with mild cognitive impairment and early-stage dementia. It appears that individualized interventions with a short duration, such as 10 hours, might be beneficial. Systematic review registration: PROSPERO CRD4201604236

A semantic-based cognitive training programme on everyday activities : a feasibility and acceptability study among cognitively healthy older adults

Background. During the normal ageing process, a person’s cognitive functions and memory gradually decline, which can affect their ability to perform everyday activities including cooking, cleaning, managing finances, and shopping. Semantic memory encoding strategies benefit older adults’ cognitive and functional performance. Such strategies can be taught by an accessible, cost-effective, and flexible app-based programme. Currently, no studies examine such an app-based programme focussed on everyday activities. Objectives. To determine if an app-based programme constructed on the principles of semantic memory encoding strategies, targeted towards older adults, called Enhancing Memory in Daily Life (E-MinD Life) is (1) feasible by examining acceptance, engagement, and attendance and (2) acceptable by examining the perceived effectiveness, relevancy, clarity, and convenience. Methods. Eleven participants were recruited to a nine-week (18 sessions) programme using E-MinD Life. Feasibility was measured by collecting data on recruitment and retention rates, attendance, and duration of sessions. Acceptability was measured via a Likert scale questionnaire and free comments. Likert scale responses were analysed using descriptive statistics; open-ended responses were categorised qualitatively via constant comparative approach. Results. Nine participants completed the programme. Overall, most participants found the programme relevant, convenient, logical, and easy to understand and perceived it to be effective to address functional cognitive problems impacting performance of everyday activities. The results from the qualitative analysis showed that participants found the programme enjoyable and the interaction with the research team throughout the intervention beneficial. Conclusion. E-MinD Life shows promise as the focus of further research to determine the effectiveness of the programme and sematic-based cognitive strategies in maintaining cognition and performance in everyday activities among older adults with and without cognitive impairment

PPARγ agonists negatively regulate αIIbβ3 integrin outside-in signalling and platelet function through upregulation of protein kinase A activity

BACKGROUND: Agonists for the peroxisome proliferator activated receptor PPARγ, have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. OBJECTIVES: Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signalling. Both GPVI and GPCR signalling pathways lead to αIIbβ3 activation, and signalling through αIIbβ3 plays a critical role in platelet function and normal haemostasis. METHODS: The effects of PPARγ agonists on the regulation of αIIbβ3 outside-in signalling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signalling components downstream of αIIbβ3 activation were also determined following adhesion to fibrinogen by western blotting. RESULTS: Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbβ3 signalling, including the integrin β3 subunit, Syk, PLCγ2, FAK and Akt was also observed as a result of reduced interaction of the integrin β3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was a due to an increase in PKA activity following treatment with PPARγ receptor agonists. CONCLUSIONS: This study provides further evidence for anti-platelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbβ3 outside-in signalling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation