Dual task measures in older adults with and without cognitive impairment: Response to simultaneous cognitive-exercise training and minimal clinically important difference estimates

BACKGROUND: Responsiveness and minimal clinically important difference (MCID) are critical indices to understand whether observed improvement represents a meaningful improvement after intervention. Although simultaneous cognitive-exercise training (SCET; e.g., performing memory tasks while cycling) has been suggested to enhance the cognitive function of older adults, responsiveness and MCID have not been established. Hence, we aimed to estimate responsiveness and MCIDs of two dual task performance involving cognition and hand function in older adults with and without cognitive impairment and to compare the differences in responsiveness and MCIDs of the two dual task performance between older adults with and without cognitive impairment. METHODS: A total of 106 older adults completed the Montreal Cognitive Assessment and two dual tasks before and after SCET. One dual task was a combination of Serial Sevens Test and Box and Block Test (BBT), and the other included frequency discrimination and BBT. We used effect size and standardized response mean to indicate responsiveness and used anchor- and distribution-based approaches to estimating MCID ranges. When conducting data analysis, all participants were classified into two cognitive groups, cognitively healthy (Montreal Cognitive Assessment ≥ 26) and cognitively impaired (Montreal Cognitive Assessment \u3c 26) groups, based on the scores of the Montreal Cognitive Assessment before SCET. RESULTS: In the cognitively healthy group, Serial Seven Test performance when tasked with BBT and BBT performance when tasked with Serial Seven Test were responsive to SCET (effect size = 0.18-0.29; standardized response mean = 0.25-0.37). MCIDs of Serial Seven Test performance when tasked with BBT ranged 2.09-2.36, and MCIDs of BBT performance when tasked with Serial Seven Test ranged 3.77-5.85. In the cognitively impaired group, only frequency discrimination performance when tasked with BBT was responsive to SCET (effect size = 0.37; standardized response mean = 0.47). MCIDs of frequency discrimination performance when tasked with BBT ranged 1.47-2.18, and MCIDs of BBT performance when tasked with frequency discrimination ranged 1.13-7.62. CONCLUSIONS: Current findings suggest that a change in Serial Seven Test performance when tasked with BBT between 2.09 and 2.36 corrected number (correct responses - incorrect responses) should be considered a meaningful change for older adults who are cognitively healthy, and a change in frequency discrimination performance when tasked with BBT between 1.47 and 2.18 corrected number (correct responses - incorrect responses) should be considered a meaningful change for older adults who are cognitively impaired. Clinical practitioners may use these established MCIDs of dual tasks involving cognition and hand function to interpret changes following SCET for older adults with and without cognitive impairment. TRIAL REGISTRATION: NCT04689776, 30/12/2020

Robust Spatial Sensing of Mating Pheromone Gradients by Yeast Cells

Projecting or moving up a chemical gradient is a universal behavior of living organisms. We tested the ability of S. cerevisiae a-cells to sense and respond to spatial gradients of the mating pheromone α-factor produced in a microfluidics chamber; the focus was on bar1Δ strains, which do not degrade the pheromone input. The yeast cells exhibited good accuracy with the mating projection typically pointing in the correct direction up the gradient (∼80% under certain conditions), excellent sensitivity to shallow gradients, and broad dynamic range so that gradient-sensing was relatively robust over a 1000-fold range of average α-factor concentrations. Optimal directional sensing occurred at lower concentrations (5 nM) close to the Kd of the receptor and with steeper gradient slopes. Pheromone supersensitive mutations (sst2Δ and ste2300Δ) that disrupt the down-regulation of heterotrimeric G-protein signaling caused defects in both sensing and response. Interestingly, yeast cells employed adaptive mechanisms to increase the robustness of the process including filamentous growth (i.e. directional distal budding) up the gradient at low pheromone concentrations, bending of the projection to be more aligned with the gradient, and forming a more accurate second projection when the first projection was in the wrong direction. Finally, the cells were able to amplify a shallow external gradient signal of α-factor to produce a dramatic polarization of signaling proteins at the front of the cell. Mathematical modeling revealed insights into the mechanism of this amplification and how the supersensitive mutants can disrupt accurate polarization. Together, these data help to specify and elucidate the abilities of yeast cells to sense and respond to spatial gradients of pheromone

Effects of human parvovirus B19 VP1 unique region protein on macrophage responses

<p>Abstract</p> <p>Background</p> <p>Activity of secreted phospholipase A (sPLA2) has been implicated in a wide range of cellular responses. However, little is known about the function of human parvovirus B19-VP1 unique region (VP1u) with sPLA2 activity on macrophage.</p> <p>Methods</p> <p>To investigate the roles of B19-VP1u in response to macrophage, phospholipase A2 activity, cell migration assay, phagocytosis activity, metalloproteinase assay, RT-PCR and immunoblotting were performed.</p> <p>Results</p> <p>In the present study, we report that migration, phagocytosis, IL-6, IL-1β mRNA, and MMP9 activity are significantly increased in RAW264.7 cells by B19-VP1u protein with sPLA2 activity, but not by B19-VP1uD175A protein that is mutated and lacks sPLA2 activity. Additionally, significant increases of phosphorylated ERK1/2 and JNK proteins were detected in macrophages that were treated with B19-VP1u protein, but not when they were treated with B19-VP1uD175A protein.</p> <p>Conclusion</p> <p>Taken together, our experimental results suggest that B19-VP1u with sPLA2 activity affects production of IL-6, IL-1β mRNA, and MMP9 activity, possibly through the involvement of ERK1/2 and JNK signaling pathways. These findings could provide clues in understanding the role of B19-VP1u and its sPLA2 enzymatic activity in B19 infection and B19-related diseases.</p

Epilepsy and Neurodevelopmental Outcomes in Children With Etiologically Diagnosed Central Nervous System Infections: A Retrospective Cohort Study

Background: Central nervous system (CNS) infection in childhood can lead to neurological sequelae, including epilepsy, and neurodevelopmental disorders, such as attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). This study investigated the association of etiologically diagnosed childhood brain infections with the subsequent risks of epilepsy and neurodevelopmental disorders.Objectives: We retrospectively analyzed the data of children aged &lt;18 years who had definite brain infections with positive cerebrospinal fluid cultures from January 1, 2005, to December 31, 2017. These patients were followed to evaluate the risks of epilepsy and neurodevelopmental disease (ADHD and ASD) after brain infections (group 1) in comparison with the risks in those without brain infections (group 2).Results: A total of 145 patients with an average age of 41.2 months were included in group 1. Enterovirus accounted for the majority of infections, followed by group B Streptococcus, S. pneumoniae, and herpes simplex virus. A total of 292 patients with an average age of 44.8 months were included in group 2. The 12-year risk of epilepsy in group 1 was 10.7 (95% confidence interval [CI], 2.30–49; p &lt; 0.01). Compared with group 2 (reference), the risk of ASD in the age interval of 2–5 years in group 1 was 21.3 (95% CI, 1.33–341.4; p = 0.03). The incidence of ADHD in group 1 was not significantly higher than that in group 2.Conclusions: This study identified the common etiological causes of brain infections in Taiwanese children. The highest-risk neurodevelopmental sequelae associated with brain infections was epilepsy. Children who had a diagnosis of brain infection (specially Enterovirus) should be followed since they are at greater risk of developing epilepsy and ASD

Periodic counter-current chromatography for continuous purification of monoclonal antibody

Integrated and continuous processing of antibody drugs offers several advantages over traditional batch processing in the biotechnology industry. The flexibility of periodic counter-current (PCC) design is performed in the selection of residence time and column numbers on the capture process. In this study, we investigate the association of residence time and product recovery in the downstream PCC purification. A practical operation of PCC as a continuous capture purification step has been applied to 50L feed-bath culture, 5L perfusion culture and 5L concentrated feed-batch culture. Protein breakthrough curve was determined for the appropriate column switching strategy. Using an empirical model for the protein breakthrough curve, residence time (RT) was evaluated and the loading flow rate was adjusted to achieve a target RT of 2.25 minutes for monoclonal antibody (mAb). The sample load volume for each column switching was set on 50-58% breakthrough curves, mAb recovery was 83-92%, and buffer consumption was decreased to under half that of the batch process. Overall, 1.0 to 1.5 gram mAb was obtained for per milliliter resin in 24 hours using a PCC purification system. We used size exclusion-high performance liquid chromatography to confirm composition and masses of our fragment samples. Comparison of qualities of mAb analyzed by UPLC and reverse phase chromatography show that glycan profiles and purity are quite similar between PCC and Avant purification, whereas that for acidic variants are different, the acidic variants of mAb purified by PCC is higher than that purified by Avant. The advantages of a continuous downstream capture step are highlighted for our case study in comparison with the existing batch chromatography processes. The use of PCC improves the higher resin capacity utilization and lower buffer consumption