Effects of Prefrontal Transcranial Direct Current Stimulation on Retention of Performance Gains on an Obstacle Negotiation Task in Older Adults.

OBJECTIVES: Complex walking in older adults can be improved with task practice and might be further enhanced by pairing transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex. We tested the hypothesis that a single session of practice of a complex obstacle negotiation task paired with active tDCS in older adults would produce greater within-session improvements in walking performance and retention of gains, compared to sham tDCS and no tDCS conditions. MATERIALS AND METHODS: A total of 50 older adults (mean age = 74.46 years ± 6.49) with self-reported walking difficulty were randomized to receive either active tDCS (active-tDCS group) or sham tDCS (sham-tDCS group) bilaterally to the dorsolateral prefrontal cortex or no tDCS (no-tDCS group). Each group performed ten practice trials of an obstacle negotiation task at their fastest safe speed. Retention of gains in walking performance was assessed with three trials conducted one week later. Within-session effects of practice and between-session retention effects on obstacle negotiation speed were examined. RESULTS: At the practice session, all three groups exhibited significant within-session gains in walking speed (p ≤ 0.005). However, the gains were significantly greater in the sham-tDCS group than in the active-tDCS and no-tDCS groups (p ≤ 0.03) and were comparable between the active-tDCS and no-tDCS groups (p = 0.89). At one-week follow-up, the active-tDCS group exhibited significant between-session retention of gains and continued "offline" improvement in walking speed (p = 0.005). The active-tDCS group showed significantly greater retention of gains than the no-tDCS (p = 0.02) but not the sham-tDCS group (p = 0.24). CONCLUSIONS: Pairing prefrontal active tDCS with a single session of obstacle negotiation practice may enhance one-week retention of gains in walking performance compared to no tDCS. However, the evidence is insufficient to suggest a benefit of active tDCS over sham tDCS for enhancing the gains in walking performance. Additional studies with a multisession intervention design and larger sample size are needed to further investigate these findings. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT03122236.

Rehabilitation with accurate adaptability walking tasks or steady state walking: A randomized clinical trial in adults post-stroke.

OBJECTIVE: To assess changes in walking function and walking-related prefrontal cortical activity following two post-stroke rehabilitation interventions: an accurate adaptability (ACC) walking intervention and a steady state (SS) walking intervention. DESIGN: Randomized, single blind, parallel group clinical trial. SETTING: Hospital research setting. SUBJECTS: Adults with chronic post-stroke hemiparesis and walking deficits. INTERVENTIONS: ACC emphasized stepping accuracy and walking adaptability, while SS emphasized steady state, symmetrical stepping. Both included 36 sessions led by a licensed physical therapist. ACC walking tasks recruit cortical regions that increase corticospinal tract activation, while SS walking activates the corticospinal tract less intensely. MAIN MEASURES: The primary functional outcome measure was preferred steady state walking speed. Prefrontal brain activity during walking was measured with functional near infrared spectroscopy to assess executive control demands. Assessments were conducted at baseline, post-intervention (three months), and follow-up (six months). RESULTS: Thirty-eight participants were randomized to the study interventions (mean age 59.6 ± 9.1 years; mean months post-stroke 18.0 ± 10.5). Preferred walking speed increased from baseline to post-intervention by 0.13 ± 0.11 m/s in the ACC group and by 0.14 ± 0.13 m/s in the SS group. The Time × Group interaction was not statistically significant (P = 0.86). Prefrontal fNIRS during walking decreased from baseline to post-intervention, with a marginally larger effect in the ACC group (P = 0.05). CONCLUSIONS: The ACC and SS interventions produced similar changes in walking function. fNIRS suggested a potential benefit of ACC training for reducing demand on prefrontal (executive) resources during walking.

Combining Frontal Transcranial Direct Current Stimulation With Walking Rehabilitation to Enhance Mobility and Executive Function: A Pilot Clinical Trial.

OBJECTIVES: This pilot study assessed whether frontal lobe transcranial direct current stimulation (tDCS) combined with complex walking rehabilitation is feasible, safe, and shows preliminary efficacy for improving walking and executive function. MATERIALS AND METHODS: Participants were randomized to one of the following 18-session interventions: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Active tDCS was delivered over F3 (cathode) and F4 (anode) scalp locations for 20 min at 2 mA intensity. Outcome measures included tests of walking function, executive function, and prefrontal activity measured by functional near infrared spectroscopy. RESULTS: Ninety percent of participants completed the intervention protocol successfully. tDCS side effects of tingling or burning sensations were low (average rating less than two out of 10). All groups demonstrated gains in walking performance based on within-group effect sizes (d ≥ 0.50) for one or more assessments. The Sham/Typical group showed the greatest gains for walking based on between-group effect sizes. For executive function, the Active/Complex group showed the greatest gains based on moderate to large between-group effect sizes (d = 0.52-1.11). Functional near-infrared spectroscopy (fNIRS) findings suggest improved prefrontal cortical activity during walking. CONCLUSIONS: Eighteen sessions of walking rehabilitation combined with tDCS is a feasible and safe intervention for older adults. Preliminary effects size data indicate a potential improvement in executive function by adding frontal tDCS to walking rehabilitation. This study justifies future larger clinical trials to better understand the benefits of combining tDCS with walking rehabilitation.

The structure-energy landscape of NMDA receptor gating.

N-Methyl-D-aspartate (NMDA) receptors are the main calcium-permeable excitatory receptors in the mammalian central nervous system. The NMDA receptor gating is complex, exhibiting multiple closed, open, and desensitized states; however, central questions regarding the conformations and energetics of the transmembrane domains as they relate to the gating states are still unanswered. Here, using single-molecule Förster resonance energy transfer (smFRET), we map the energy landscape of the first transmembrane segment of the Rattus norvegicus NMDA receptor under resting and various liganded conditions. These results show kinetically and structurally distinct changes associated with apo, agonist-bound, and inhibited receptors linked by a linear mechanism of gating at this site. Furthermore, the smFRET data suggest that allosteric inhibition by zinc occurs by an uncoupling of the agonist-induced changes at the extracellular domains from the gating motions leading to an apo-like state, while dizocilpine, a pore blocker, stabilizes multiple closely packed transmembrane states.

Patterns of care and outcomes for women with uterine cancer and ovarian metastases.

OBJECTIVE: For women with uterine cancer with metastases isolated to the adnexa (stage IIIA) optimal adjuvant therapy is unknown. We performed a population-based analysis to examine the use of chemotherapy, vaginal brachytherapy, and external beam therapy (in women with stage IIIA uterine cancer. METHODS: The National Cancer Database was used to identify women with stage IIIA uterine cancer with ovarian metastasis from 2004 to 2012. We explored the use of chemotherapy, vaginal brachytherapy, and external beam therapy over time. Multivariable models were developed to examine factors associated with survival. RESULTS: We identified 4088 women with uterine cancer and ovarian metastases. Overall, 56.2% of women received chemotherapy. Vaginal brachytherapy was used in 11.1%, while 36.6% received external beam therapy. Five-year survival was 64.7 % (95% CI, 62.9% to 66.5%). In a multivariable model, chemotherapy was associated with a 38% decrease in mortality (HR = 0.62; 95% CI, 0.54 to 0.71). Similarly, both external beam therapy (HR = 0.74; 95% CI, 0.65 to 0.85) and vaginal brachytherapy (HR = 0.67; 95% CI, 0.53 to 0.85) were associated with improved survival. When the cohort was limited to women who received chemotherapy, radiation was associated with improved overall survival (HR 0.74, 95% CI 0.61 to 0.90). There was no difference in survival between the use of external beam therapy and vaginal brachytherapy. CONCLUSIONS: Chemotherapy was associated with a decrease in mortality in women with endometrial cancer and ovarian metastases. The addition of radiation therapy was associated with improved overall survival, although there was no difference between external beam therapy and vaginal brachytherapy.

National Trends in Extended Procedures for Ovarian Cancer Debulking Surgery.

OBJECTIVE: Primary cytoreduction for ovarian cancer often requires extended radical procedures and is associated with significant morbidity. In 2010, neoadjuvant chemotherapy was shown to have similar survival to primary cytoreduction but with less need for radical surgery. We hypothesized that the increased use of neoadjuvant chemotherapy would decrease the use of radical cytoreductive procedures and thus examined trends in the performance of radical cytoreductive procedures. METHODS: We used the Nationwide Inpatient Sample to determine the annual number of extended procedures (colon, small intestine, liver, diaphragm, spleen, and gastric resection, ileostomy, colostomy) performed in women undergoing surgery for ovarian cancer from 1998 to 2013. Estimates were weighted to provide national averages. To account for changes in incidence over time, we used national incidence rates and report procedures performed per 1000 new cases of ovarian cancer. Trends were assessed using Cochrane-Armitage tests. RESULTS: We identified 274,639 ovarian cancer patients who underwent surgery, ranging from 15,720 to 18,714 procedures performed each year. We identified a significant increase in the use of extended procedures over this period. These differences were significant for absolute numbers of procedures, rate per 1000 new ovarian cancer cases, and percent per hysterectomy/bilateral salpingoophorectomy for rectosigmoid resection, diaphragm resection, splenectomy, ileostomy, and liver resection. Specifically, the use of these procedures rose from 1998 to 2010, declined in 2011, and rose again in 2012 and 2013. CONCLUSIONS: Although there was a transient decrease in the use of extended cytoreductive procedures from 2010 to 2011 after the publication of randomized neoadjuvant trial data, use of these procedures again rose in 2012 and 2013.

Mobility Function and Recovery After Stroke: Preliminary Insights From Sympathetic Nervous System Activity.

BACKGROUND AND PURPOSE: Poststroke hemiparesis increases the perceived challenge of walking. Perceived challenge is commonly measured by self-report, which is susceptible to measurement bias. A promising approach to objectively assess perceived challenge is measuring sympathetic nervous system (SNS) activity with skin conductance to detect the physiological stress response. We investigated the feasibility of using skin conductance measurements to detect task-related differences in the challenge posed by complex walking tasks in adults poststroke. METHODS: Adults poststroke (n = 31) and healthy young adults (n = 8) performed walking tasks including typical walking, walking in dim lighting, walking over obstacles, and dual-task walking. Measures of skin conductance and spatiotemporal gait parameters were recorded. Continuous decomposition analysis was conducted to assess changes in skin conductance level (ΔSCL) and skin conductance response (ΔSCR). A subset of participants poststroke also underwent a 12-week rehabilitation intervention. RESULTS: SNS activity measured by skin conductance (both ΔSCL and ΔSCR) was significantly greater for the obstacles task and dual-task walking than for typical walking in the stroke group. Participants also exhibited "cautious" gait behaviors of slower speed, shorter step length, and wider step width during the challenging tasks. Following the rehabilitation intervention, SNS activity decreased significantly for the obstacles task and dual-task walking. DISCUSSION AND CONCLUSIONS: SNS activity measured by skin conductance is a feasible approach for quantifying task-related differences in the perceived challenge of walking tasks in people poststroke. Furthermore, reduced SNS activity during walking following a rehabilitation intervention suggests a beneficial reduction in the physiological stress response evoked by complex walking tasks.Video Abstract available for more insights from the authors (See Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A234).

Solitomab, an epithelial cell adhesion molecule/CD3 bispecific antibody (BiTE), is highly active against primary chemotherapy-resistant ovarian cancer cell lines in vitro and fresh tumor cells ex vivo.

BACKGROUND: Solitomab is a novel, bispecific, single-chain antibody that targets epithelial cell adhesion molecule (EpCAM) on tumor cells and also contains a cluster of differentiation 3 (CD3) (T-cell coreceptor) binding region. The authors evaluated the in vitro activity of solitomab against primary chemotherapy-resistant epithelial ovarian carcinoma cell lines as well as malignant cells in ascites. METHODS: EpCAM expression was evaluated by flow cytometry in 5 primary ovarian cancer cell lines and in 42 fresh ovarian tumor cell cultures in ascites from patients with mainly advanced or recurrent, chemotherapy-resistant disease. The potential activity of solitomab against EpCAM-positive tumor cells was evaluated by flow cytometry, proliferation, and 4-hour chromium-release, cell-mediated cytotoxicity assays. RESULTS: EpCAM expression was detected by flow cytometry in approximately 80% of the fresh ovarian tumors and primary ovarian tumor cell lines tested. EpCAM-positive, chemotherapy-resistant cell lines were identified as resistant to natural killer cell-mediated or T-cell-mediated killing after exposure to peripheral blood lymphocytes in 4-hour chromium-release assays (mean±standard error of the mean, 3.6%±0.7% of cells killed after incubation of EpCAM-positive cell lines with control bispecific antibody). In contrast, after incubation with solitomab, EpCAM-positive, chemotherapy-resistant cells became highly sensitive to T-cell cytotoxicity (mean±standard error of the mean, 28.2%±2.05% of cells killed; P<.0001) after exposure to peripheral blood lymphocytes. Ex vivo incubation of autologous tumor-associated lymphocytes with EpCAM-expressing malignant cells in ascites with solitomab resulted in a significant increase in T-cell activation markers and a reduction in the number of viable ovarian tumor cells in ascites (P<.001). CONCLUSIONS: Solitomab may represent a novel, potentially effective agent for the treatment of chemotherapy-resistant ovarian cancers that overexpress EpCAM.

Prefrontal cortical activity during uneven terrain walking in younger and older adults.

Introduction: Walking in complex environments increases the cognitive demand of locomotor control; however, our understanding of the neural mechanisms contributing to walking on uneven terrain is limited. We used a novel method for altering terrain unevenness on a treadmill to investigate the association between terrain unevenness and cortical activity in the prefrontal cortex, a region known to be involved in various cognitive functions. Methods: Prefrontal cortical activity was measured with functional near infrared spectroscopy while participants walked on a novel custom-made terrain treadmill surface across four different terrains: flat, low, medium, and high levels of unevenness. The assessments were conducted in younger adults, older adults with better mobility function and older adults with worse mobility function. Mobility function was assessed using the Short Physical Performance Battery. The primary hypothesis was that increasing the unevenness of the terrain would result in greater prefrontal cortical activation in all groups. Secondary hypotheses were that heightened prefrontal cortical activation would be observed in the older groups relative to the younger group, and that prefrontal cortical activation would plateau at higher levels of terrain unevenness for the older adults with worse mobility function, as predicted by the Compensation Related Utilization of Neural Circuits Hypothesis. Results: The results revealed a significant main effect of terrain, indicating a significant increase in prefrontal cortical activation with increasing terrain unevenness during walking in all groups. A significant main effect of group revealed that prefrontal cortical activation was higher in older adults with better mobility function compared to younger adults and older adults with worse mobility function in all pooled terrains, but there was no significant difference in prefrontal cortical activation between older adults with worse mobility function and younger adults. Contrary to our hypothesis, the older group with better mobility function displayed a sustained increase in activation but the other groups did not, suggestive of neural compensation. Additional findings were that task-related increases in prefrontal cortical activation during walking were lateralized to the right hemisphere in older adults with better mobility function but were bilateral in older adults with worse mobility function and younger adults. Discussion: These findings support that compared to walking on a flat surface, walking on uneven terrain surfaces increases demand on cognitive control resources as measured by prefrontal cortical activation.

Visuospatial cognition predicts performance on an obstructed vision obstacle walking task in older adults.

Walking performance and cognitive function demonstrate strong associations in older adults, with both declining with advancing age. Walking requires the use of cognitive resources, particularly in complex environments like stepping over obstacles. A commonly implemented approach for measuring the cognitive control of walking is a dual-task walking assessment, in which walking is combined with a second task. However, dual-task assessments have shortcomings, including issues with scaling the task difficulty and controlling for task prioritization. Here we present a new assessment designed to be less susceptible to these shortcomings while still challenging cognitive control of walking: the Obstructed Vision Obstacle (OBVIO) task. During the task, participants hold a lightweight tray at waist level obstructing their view of upcoming foam blocks, which are intermittently spaced along a 10 m walkway. This forces the participants to use cognitive resources (e.g., attention and working memory) to remember the exact placement of upcoming obstacles to facilitate successful crossing. The results demonstrate that adding the obstructed vision board significantly slowed walking speed by an average of 0.26 m/s and increased the number of obstacle strikes by 8-fold in healthy older adults (n = 74). Additionally, OBVIO walking performance (a score based on both speed and number of obstacle strikes) significantly correlated with computer-based assessments of visuospatial working memory, attention, and verbal working memory. These results provide initial support that the OBVIO task is a feasible walking test that demands cognitive resources. This study lays the groundwork for using the OBVIO task in future assessment and intervention studies.

Mo(vi) complexes of amide-imine conjugates for tuning the selectivity of fluorescence recognition of Y(iii) vs. Pb(ii).

Two amide-imine conjugates, viz. 3-methyl-benzoic acid (4-diethylamino-2-hydroxy-benzylidene)-hydrazide (L1) and 3-methyl-benzoic acid (2-hydroxy-naphthalen-1-ylmethylene)-hydrazide (L2), have been prepared and used for a further synthesis of Mo(vi) complexes (M1 and M2, respectively). Single crystal X-ray diffraction analysis confirmed their structures. Interestingly, M1 selectively recognizes Y3+ and Pb2+ at two different wavelengths, whereas M2 selectively interacts with Y3+ with a significantly high binding constant, 1.3 × 105 M-1. The proposed sensing mechanism involves the displacement of Mo(vi) by Y3+/Pb2+ from respective Mo(vi) complexes. The TCSPC experiment also substantiates the "turn-on" fluorescence process. A logic gate has been constructed utilizing the fluorescence recognition of cations by M1. DFT studies corroborated the cation-probe interactions and allowed exploring the orbital energy parameters.

Somatosensory impairment of the feet is associated with higher activation of prefrontal cortex during walking in older adults.

BACKGROUND: Over-activation of prefrontal cortex during walking has been reported in older adults versus young adults. Heighted activity in prefrontal cortex suggests a shift toward an executive control strategy to control walking. A potential contributing factor is degraded functioning of pattern-generating locomotor circuits in the central nervous system that are important to walking coordination. Somatosensory information is a crucial input to these circuits, so age-related impairment of somatosensation would be expected to compromise the neural control of walking. The present study tested the hypothesis that poorer somatosensation in the feet of older adults will be associated with greater recruitment of the prefrontal cortex during walking. This study also examines the extent to which somatosensory function and prefrontal activity are associated with performance on walking and balance assessments. METHODS: Forty seven older adults (age 74.6 ± 6.8 years; 32 female) participated in walking assessments (typical walking and obstacle negotiation) and Berg Balance Test. During walking, prefrontal activity was measured with functional near infrared spectroscopy (fNIRS). Participants also underwent somatosensory testing with Semmes-Weinstein monofilaments. RESULTS: The primary findings is that worse somatosensory monofilament level was associated with greater prefrontal cortical activity during typical walking (r = 0.38, p = 0.008) and obstacle negotiation (r = 0.40, p = 0.006). For the obstacle negotiation task, greater prefrontal activity was associated with faster walking speed (p = 0.004). Poorer somatosensation was associated with slower typical walking speed (p = 0.07) and obstacles walking speed (p < 0.001), as well as poorer balance scores (p = 0.03). CONCLUSIONS: The study findings are consistent with a compensation strategy of recruiting prefrontal/executive control resources to overcome loss of somatosensory input to the central nervous system. Future research should further establish the mechanisms by which somatosensory impairments are linked to the neural control and performance of walking tasks, as well as develop intervention approaches.

Exploring a new dinuclear Fe(iii) complex for the fixation of atmospheric CO2 and optical recognition of nano-molar levels of Zn2+ ions.

A dinuclear Fe(iii) complex (F1) of an imine derivative (L1) derived from 3-ethoxy-2-hydroxy-benzaldehyde and hydrazine, structurally characterised via single crystal X-ray studies, is employed for the catalytic conversion of epoxides to cyclic carbonates utilizing carbon dioxide. In addition, F1 is employed for the selective optical recognition of nano-molar levels of Zn2+ (42.23 nM) via a metal displacement approach. The Job plot reveals interactions between F1 and Zn2+ at a 1 : 3 molar ratio with an association constant of 7.71 × 104 M-1. Studies on the catecholase-like activity of F1 reveal a k cat value of 4.42 × 103 h-1.

Imaging Switchable Protein Interactions with an Active Porous Polymer Support.

Mechanistic details about how local physicochemistry of porous interfaces drives protein transport mechanisms are necessary to optimize biomaterial applications. Cross-linked hydrogels made of stimuli-responsive polymers have potential for active protein capture and release through tunable steric and chemical transformations. Simultaneous monitoring of dynamic changes in both protein transport and interfacial polymer structure is an experimental challenge. We use single-particle tracking (SPT) and fluorescence correlation spectroscopy Super-resolution Optical Fluctuation Imaging (fcsSOFI) to relate the switchable changes in size and structure of a pH-responsive hydrogel to the interfacial transport properties of a model protein, lysozyme. SPT analysis reveals the reversible switching of protein transport dynamics in and at the hydrogel polymer in response to pH changes. fcsSOFI allows us to relate tunable heterogeneity of the hydrogels and pores to reversible changes in the distribution of confined diffusion and adsorption/desorption. We find that physicochemical heterogeneity of the hydrogels dictates protein confinement and desorption dynamics, particularly at pH conditions in which the hydrogels are swollen.

Obstacle Negotiation in Older Adults: Prefrontal Activation Interpreted Through Conceptual Models of Brain Aging.

BACKGROUND AND OBJECTIVES: The influence of interindividual differences on brain activation during obstacle negotiation and the implications for walking performance are poorly understood in older adults. This study investigated the extent to which prefrontal recruitment during obstacle negotiation is explained by differences in age, executive function, and sex. These data were interpreted according to the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH) framework of brain aging. We also tested the association between prefrontal recruitment and walking performance. RESEARCH DESIGN AND METHODS: Prefrontal oxygenated hemoglobin concentration (O2Hb) was measured during typical walking (Typical) and obstacle negotiation (Obstacles) tasks in 50 adults aged 65 years and older using functional near-infrared spectroscopy. The primary outcome was the change in prefrontal recruitment (∆PFR), measured as Obstacles ∆O2Hb minus Typical ∆O2Hb. Multiple regression was used to test the relationship between ∆PFR and age, executive function measured by the Trail Making Test, and sex. Pearson's correlation coefficient was used to investigate the association between ∆PFR and the cost of Obstacles walking speed relative to Typical walking. RESULTS: Age, executive function, and their interaction significantly predicted greater ∆PFR (R 2 = 0.34, p = .01). Participants were subgrouped according to age and executive function to examine the interaction effects. Adults of lower age and with lower executive function exhibited greater ∆PFR during Obstacles compared to their peers with higher executive function (p = .03). Adults of advanced age exhibited a ceiling of prefrontal recruitment during obstacle negotiation, regardless of executive function level (p = .87). Greater ∆PFR was significantly associated with a smaller cost of Obstacles (r = 0.3, p = .03). DISCUSSION AND IMPLICATIONS: These findings are consistent with the CRUNCH framework: neural inefficiency where a greater amount of brain activation is needed for task performance at a similar level, compensatory overactivation to prevent a steeper decline in task performance, and capacity limitation with a recruitment ceiling effect.

Mechanistic Understanding of the Phosphorylation-Induced Conformational Rigidity at the AMPA Receptor C-terminal Domain.

Phosphorylation at the intracellular C-terminal domain (CTD) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces conformational rigidity. Such intracellular alterations to the AMPA receptor influence its functional responses, which are involved in multiple synaptic processes and neuronal signaling. The structure of the CTD still remains unresolved, which poses challenges toward providing a mechanism for the process of phosphorylation and deciphering the role of each phosphorylation step in causing the resultant conformational behavior. Herein, we utilize smFRET spectroscopy to understand the mechanism of phosphorylation, with the help of strategic point mutations that mimic phosphorylation. Our results reveal that first, phosphorylation at three target sites (S818, S831, and T840) is necessary for the change in the secondary structure of the existing disordered native sequence. Also, the results suggest that the formation of the tertiary structure through electrostatic interaction involving one specific phosphorylation site (S831) stabilizes the structure and renders conformational rigidity.

Subtle structural variation in azine/imine derivatives controls Zn2+ sensitivity: ESIPT-CHEF combination for nano-molar detection of Zn2+ with DFT support.

Excited-state intra-molecular proton transfer (ESIPT)-active imine and azine derivatives, structurally characterised by XRD, and denoted L1, L2, L3 and L4, possess weak fluorescence. The interaction of these probes with Zn2+ turns ON the fluorescence to allow its nano-molar detection. Among the four ESIPT-active molecules, L2, L3 and L4 are bis-imine derivatives while L1 is a mono-imine derivative. Among the three bis-imine derivatives, one is symmetric (L3) while L2 and L4 are unsymmetrical. The lowest detection limits (DL) of L1, L2, L3 and L4 for Zn2+ are 32.66 nM, 36.16 nM, 15.20 nM and 33.50 nM respectively. All the probes bind Zn2+ (105 M-1 order) strongly. Computational studies explore the orbital level interactions responsible for the associated photo-physical processes.

Phosphorylation Induces Conformational Rigidity at the C-Terminal Domain of AMPA Receptors.

The intracellular C-terminal domain (CTD) of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor undergoes phosphorylation at specific locations during long-term potentiation. This modification enhances conductance through the AMPA receptor ion channel and thus potentially plays a crucial role in modulating receptor trafficking and signaling. However, because the CTD structure is largely unresolved, it is difficult to establish if phosphorylation induces conformational changes that might play a role in enhancing channel conductance. Herein, we utilize single-molecule Förster resonance energy transfer (smFRET) spectroscopy to probe the conformational changes of a section of the AMPA receptor CTD, under the conditions of point-mutated phosphomimicry. Multiple analysis algorithms fail to identify stable conformational states within the smFRET distributions, consistent with a lack of well-defined secondary structure. Instead, our results show that phosphomimicry induces conformational rigidity to the CTD, and such rigidity is electrostatically tunable.

A Perspective on Objective Measurement of the Perceived Challenge of Walking.

Perceived challenge of walking is a broad term that we use to encompass walking-related anxiety, balance self-efficacy/confidence, and fear of falling. Evidence shows that even after accounting for physical performance capabilities, a higher perceived challenge can cause individuals to self-impose restrictions in walking-related activities. Perceived challenge is typically measured by self-report, which is susceptible to subjective measurement bias and error. We assert that measurement of perceived challenge can be enhanced by augmenting self-report with objective, physiologically based measures. A promising approach that has emerged in the literature is measurement of sympathetic nervous system (SNS) activity by recording skin conductance. Heightened SNS activity is a physiological stress response to conditions that are cognitively, emotionally, or physically challenging. In the present article, we explain the rationale and physiological basis for measuring SNS activity to assess perceived challenge of walking. We also present existing and new evidence supporting the feasibility of this approach for assessing perceived challenge in lab-based and real-world walking environments. Future research directions are also discussed.