bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanohybrids as Protein-Polymer Conjugate Multimodal Therapeutics
Authors: Kiran Pallavi , Khan Amreen , Neekhra Suditi , Pallod Shubham , Srivastava Rohit
Published: September 2021

Protein therapeutic formulations are being widely explored as multifunctional nanotherapeutics. Challenges in ensuring susceptibility and efficacy of nanoformulation still prevail owing to various interactions with biological fluids before reaching the target site. Smart polymers with the capability of masking drugs, ease of chemical modification, and multi-stimuli responsiveness can assist controlled delivery. An active moiety like therapeutic protein has started to be known as an important biological formulation with a diverse medicinal prospect. The delivery of proteins and peptides with high target specificity has however been tedious, due to their tendency to aggregate formation in different environmental conditions. Proteins due to high chemical reactivity and poor bioavailability are being researched widely in the field of nanomedicine. Clinically, multiple nano-based formulations have been explored for delivering protein with different carrier systems. A biocompatible and non-toxic polymer-based delivery system serves to tailor the polymer or drug better. Polymers not only aid delivery to the target site but are also responsible for proper stearic orientation of proteins thus protecting them from internal hindrances. Polymers have been shown to conjugate with proteins through covalent linkage rendering stability and enhancing therapeutic efficacy prominently when dealing with the systemic route. Here, we present the recent developments in polymer-protein/drug-linked systems. We aim to address questions by assessing the properties of the conjugate system and optimized delivery approaches. Since thorough characterization is the key aspect for technology to enter into the market, correlating laboratory research with commercially available formulations will also be presented in this review. By examining characteristics including morphology, surface properties, and functionalization, we will expand different hybrid applications from a biomaterial stance applied in in vivo complex biological conditions. Further, we explore understanding related to design criteria and strategies for polymer-protein smart nanomedicines with their potential prophylactic theranostic applications. Overall, we intend to highlight protein-drug delivery through multifunctional smart polymers.
Characterization of Shiga Toxin 2a Encoding Bacteriophages Isolated From High-Virulent O145:H25 Shiga Toxin-Producing Escherichia coli
Authors: Ramstad Silje N. , Wasteson Yngvild , Lindstedt Bjørn-Arne , Taxt Arne M. , Bjørnholt Jørgen V. , Brandal Lin T. , Bohlin Jon
Published: September 2021

Shiga toxin-producing Escherichia coli (STEC) may cause severe disease mainly due to the ability to produce Shiga toxins (Stx) encoded on bacteriophages. In Norway, more than 30% of the reported cases with STEC O145:H25 develop hemolytic uremic syndrome (HUS), and most cases, with known travel history, acquired the infection domestically. To describe phage characteristics associated with high virulence, we extracted the Stx2a phage sequences from eight clinical Norwegian O145:H25 STEC to conduct in-depth molecular characterization using long and short read sequencing. The Stx2a phages were annotated, characterized, and compared with previously published Stx2a phages isolated from STEC of different serotypes. The Norwegian O145:H25 Stx2a phages showed high sequence identity (>99%) with 100% coverage. The Stx2a phages were located at the integration site yciD, were approximately 45 kbp long, and harbored several virulence-associated genes, in addition to stx2a, such as nanS and nleC. We observed high sequence identity (>98%) and coverage (≥94%) between Norwegian O145:H25 Stx2a phages and publicly available Stx2a phages from O145:H25 and O145:H28 STEC, isolated from HUS cases in the USA and a hemorrhagic diarrhea case from Japan, respectively. However, low similarity was seen when comparing the Norwegian O145:H25 Stx2a phage to Stx2a phages from STEC of other serotypes. In all the Norwegian O145:H25 STEC, we identified a second phage or remnants of a phage (a shadow phage, 61 kbp) inserted at the same integration site as the Stx2a phage. The shadow phage shared similarity with the Stx2a phage, but lacked stx2a and harbored effector genes not present in the Stx2a phage. We identified a conserved Stx2a phage among the Norwegian O145:H25 STEC that shared integration site with a shadow phage in all isolates. Both phage and shadow phage harbored several virulence-associated genes that may contribute to the increased pathogenicity of O145:H25 STEC.
Successful Treatment of Severe Post-craniotomy Meningitis Caused by an Escherichia coli Sequence Type 410 Strain Coharboring blaNDM–5 and blaCTX–M–65
Authors: Yang Qing , Zhang Piao-piao , Jiang Yan , Zheng Xiu-jue , Zheng Min , Qu Ting-ting
Published: September 2021

Intracranial infections caused by multidrug-resistant Gram-negative bacterium have led to considerable mortality due to extremely limited treatment options. Herein, we firstly reported a clinical carbapenem-resistant Escherichia coli isolate coharboring blaNDM–5 and blaCTX–M–65 from a patient with post-craniotomy meningitis. The carbapenem-resistant Escherichia coli strain CNEC001 belonging to Sequence Type 410 was only susceptible to amikacin and tigecycline, both of which have poor penetration through the blood-brain barrier (BBB). The blaCTX–M–65 gene was expressed on a 135,794 bp IncY plasmid. The blaNDM–5 gene was located on a genomic island region of an IncX3-type plasmid pNDM5-CNEC001. Based on the characteristics of the strain, we presented the successful treatment protocol of intravenous (IV) tigecycline and amikacin combined with intrathecal (ITH) amikacin in this study. Intracranial infection caused by Escherichia coli coharboring blaNDM–5 and blaCTX–M–65 is rare and fatal. Continuous surveillance and infection control measures for such strain need critical attention in clinical settings.
Characterization of MXene as a Cancer Photothermal Agent Under Physiological Conditions
Authors: Shurbaji Samar , Manaph Nimshitha P. Abdul , Ltaief Samia M. , Al-Shammari Abeer R. , Elzatahry Ahmed , Yalcin Huseyin C.
Published: September 2021

A growing interest has recently emerged in the use of nanomaterials in medical applications. Nanomaterials, such as MXene, have unique properties due to their 2D ultra-thin structure, which is potentially useful in cancer photothermal therapy. To be most effective, photothermal agents need to be internalized by the cancer cells. In this study, MXene was fabricated using chemical reactions and tested as a photothermal agent on MDA-231 breast cancer cells under static and physiological conditions. Fluid shear stress (∼0.1 Dyn/cm2) was applied using a perfusion system to mimic the physiological tumor microenvironment. The uptake of MXene was analyzed under fluid flow compared to static culture using confocal microscopy, scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), and transmission electron microscopy (TEM). Furthermore, a viability assay was used to assess cell’s survival after exposing the treated cells to photothermal laser at different power densities and durations. We showed that when incubated with cancer cells, 2D MXene nanoparticles were successfully internalized into the cells resulting in increased intracellular temperatures when exposed to NIR laser. Interestingly, dynamic culture alone did not result in a significant increase in uptake suggesting the need for surface modifications for enhanced cellular uptake under shear stress.
Intranasal Neuropeptide Y as a Potential Therapeutic for Depressive Behavior in the Rodent Single Prolonged Stress Model in Females
Authors: Nahvi Roxanna J. , Tanelian Arax , Nwokafor Chiso , Hollander Callie M. , Peacock Lauren , Sabban Esther L.
Published: September 2021

The susceptibility to stress-elicited disorders is markedly influenced by sex. Women are twice as likely as men to develop posttraumatic stress disorder (PTSD), depression, anxiety disorders, and social impairments following exposure to traumatic stress. However, most of the studies in animal models examining putative therapeutics for stress-triggered impairments, including single prolonged stress (SPS), were performed predominantly with males. Previous studies in males demonstrated that intranasal neuropeptide Y (NPY) can provide therapeutic relief of many SPS-triggered behaviors, but is ineffective in females at the same dose. Thus, females may need a higher dose of exogenous NPY to attain a therapeutically significant concentration since the overwhelming majority of studies found that NPY levels in females in many brain regions are lower than in male rodents. Here, we examined SPS as an appropriate model to elicit many PTSD-associated symptoms in females and whether intranasal NPY at higher doses than with males is able to alter the development of SPS-triggered behavioral impairments. Sprague-Dawley female rats were exposed to SPS only, or in a separate cohort after SPS stressors were immediately infused intranasally with one of several doses of NPY, starting with 600 μg/rat—four times the dose effective in males. In the third cohort of animals, females were infused intranasally with either 600 μg NPY, omarigliptin [a dipeptidyl peptidase IV (DPP4) inhibitor], or both right after the SPS stressors. After 19 days they were tested on several behavioral tests. SPS elicited significant depressive/despair like behavior on the forced swim test (FST), anxiety behavior on the elevated plus maze (EPM), as well as impaired social interaction. On the FST, there was a dose-response effect of intranasal NPY, with 1,200 μg, but not 600 μg, preventing the development of the SPS-elicited depressive-like behavior. The omarigliptin and 600 μg NPY combined treatment, but neither alone, was also sufficient at preventing depressive-like behavior on the FST. The results demonstrate that: (1) SPS elicits several behavioral manifestations of PTSD in females; (2) early intervention with a high dose of intranasal NPY has therapeutic potential also for females; and (3) NPY cleavage by DPP4 may play a role in the higher dose requirement for females.
Mediation Role of Physical Fitness and Its Components on the Association Between Distribution-Related Fat Indicators and Adolescents’ Cognitive Performance: Exploring the Influence of School Vulnerability. The Cogni-Action Project
Authors: Hernández-Jaña Sam , Sanchez-Martinez Javier , Solis-Urra Patricio , Esteban-Cornejo Irene , Castro-Piñero Jose , Sadarangani Kabir P. , Aguilar-Farias Nicolas , Ferrari Gerson , Cristi-Montero Carlos
Published: September 2021

Background: Physical fitness and fatness converge simultaneously modulating cognitive skills, which in turn, are associated with children and adolescents’ socioeconomic background. However, both fitness components and fat mass localization are crucial for understanding its implication at the cognitive level.

Objective: This study aimed to determine the mediation role of a global physical fitness score and its components on the association between different fatness indicators related to fat distribution and adolescents’ cognitive performance, and simultaneously explore the influence of school vulnerability.

Methods: In this study, 1,196 Chilean adolescents participated (aged 10–14; 50.7% boys). Cardiorespiratory fitness (CRF), muscular fitness (MF), and speed-agility fitness (SAF) were evaluated, and a global fitness score (GFS) was computed adjusted for age and sex (CRF + MF + SAF z-scores). Body mass index z-score (BMIz), sum-of-4-skinfolds (4SKF), and waist-to-height ratio (WHtR) were used as non-specific, peripheral, and central adiposity indicators, respectively. A global cognitive score was computed based on eight tasks, and the school vulnerability index (SVI) was registered as high, mid or low. A total of 24 mediation analyses were performed according to two models, adjusted for sex and peak high velocity (Model 1), and adding the school vulnerability index (SVI) in Model 2. The significance level was set at p < 0.05.

Results: The fitness mediation role was different concerning the fatness indicators related to fat distribution analyzed. Even after controlling for SVI, CRF (22%), and SAF (29%), but not MF, mediated the association between BMIz and cognitive performance. Likewise, CRF, SAF and GFS, but not MF, mediated the association between WHtR and cognitive performance (38.6%, 31.9%, and 54.8%, respectively). No mediations were observed for 4SKF.

Conclusion: The negative association between fatness and cognitive performance is mitigated by the level of adolescents’ physical fitness, mainly CRF and SAF. This mediation role seems to be more consistent with a central fat indicator even in the presence of school vulnerability. Strategies promoting physical fitness would reduce the cognitive gap in children and adolescents related to obesity and school vulnerability.
Association of Regular Thrombus Surface Phenotype With Complete Recanalization in First-Line Contact Aspiration Thrombectomy for Basilar Artery Occlusion
Authors: Kaiser Daniel , Krukowski Pawel , Hädrich Kevin , Winzer Robert , Pallesen Lars-Peder , Gawlitza Matthias , Linn Jennifer , Puetz Volker , Gerber Johannes C.
Published: September 2021

Objective: To assess whether angiographic thrombus surface phenotype has an impact on efficacy of contact aspiration (CA) thrombectomy in patients with basilar artery occlusion (BAO).

Methods: From January 2016 to December 2019, consecutive stroke patients with a BAO and first-line CA were analyzed in this retrospective study. We assessed baseline and imaging characteristics and treatment and clinical outcomes. We rated thrombus surface phenotype on pre-treatment digital subtraction angiography in a three-reader-consensus setting. Primary outcome was complete recanalization (modified treatment in cerebral ischemia [mTICI] 3 and arterial occlusive lesion [AOL] 3) after first-line CA without additionally stent retriever passes. Data analysis was stratified according to thrombus surface phenotype and complete first-line recanalization.

Results: Seventy-eight patients met the inclusion criteria. Median age was 74 years (IQR 64–80), 64% were male, and median baseline NIHSS score was 24 (IQR 7–32). Thirty patients had a regular and 16 patients had an irregular thrombus phenotype. Thrombus surface was not assessable in 32 patients. In patients with a regular phenotype, complete recanalization was more often achieved compared to irregular and non-ratable phenotypes (50 vs. 18.8% and 21.9%; p = 0.027). Patients with a regular phenotype [odds ratio [OR] 8.3; 95% confidence interval [CI]: 1.9–35.8; p = 0.005], cardioembolic stroke (OR 12.1, 95% CI: 2.0–72.8; p = 0.007), and proximal end of the thrombus in the middle basilar artery segment (OR 5.2, 95% CI: 1.0–26.6; p = 0.046) were more likely to achieve complete recanalization after first-line CA without rescue therapy.

Conclusion: The efficacy of CA may differ according to the angiographic thrombus surface phenotype in patients with BAO. A regular phenotype is associated with higher rates of complete recanalization in first-line CA. However, assessment of thrombus phenotype is frequently not feasible in BAO.
Impact of COVID-19 on Acute Stroke Presentation in a Designated COVID-19 Hospital
Authors: Tan Qing , Liu Qing-Jun , Fan Wen-Hui , Du Xiao-Yan , Wu Lin , Gong Hong-Min , Wei Jing , Zhao Rui , Lei Ming , Zhao Li-Bo
Published: September 2021

Objectives: Thousands of designated COVID-19 hospitals have been set up in China to fight the ongoing COVID-19 pandemic. Anecdotal reports indicate a falling rate of acute stroke diagnoses in these hospitals during the COVID-19 period. We conducted an exploratory single-center analysis to estimate the change in acute stroke presentation at the designated COVID-19 hospitals.

Methods: This retrospective observational study included all patients admitted to Yongchuan Hospital Affiliated to Chongqing Medical University with acute stroke between January 24 and March 10, 2020. Patient demographics, characteristics of the stroke, treatment details, and clinical outcomes were compared with those of patients admitted in the corresponding period in the year before (2019, “the pre-COVID-19 period”). Subgroup analysis was performed in the ischemic and hemorrhagic stroke groups.

Results: A total of 110 patients presented with acute stroke symptoms during the COVID-19 pandemic, compared with 173 patients in the pre-COVID-19 period. A higher proportion of stroke patients presented to the hospital via emergency medical services during the pandemic (48.2 vs. 31.8%, p = 0.006). There was a lower proportion of ischemic stroke patients (50.9 vs. 65.3%, p = 0.016) than in the preceding year. There were significantly fewer patients with 90-day modified Rankin Scale score ≥3 in the COVID-19 period compared with the pre-COVID-19 period (17.3 vs. 30.6%, p = 0.012). Among patients with ischemic stroke, the mean time from patient arrival to vessel puncture for emergency endovascular therapy in the COVID-19 period was shorter than that in the pre-COVID-19 period (109.18 ± 71.39 vs. 270.50 ± 161.51 min, p = 0.002). Among patients with hemorrhagic stroke, the rate of emergency surgical operation in the COVID-19 period was higher than that in the pre-COVID-19 period (48.1 vs. 30.0%, p = 0.047). The mean time from patient arrival to emergency surgical operation (15.31 ± 22.89 vs. 51.72 ± 40.47 min, p = 0.002) was shorter in the COVID-19 period than in the pre-COVID-19 period.

Conclusions: Although fewer acute stroke patients sought medical care in this designated COVID-19 hospital during the COVID-19 pandemic, this type of hospital was more efficient for timely treatment of acute stroke. Recognizing how acute strokes presented in designated COVID-19 hospitals will contribute to appropriate adjustments in strategy for dealing with acute stroke during COVID-19 and future pandemics.
Korean Model for Post-acute Comprehensive rehabilitation (KOMPACT): The Study Protocol for a Pragmatic Multicenter Randomized Controlled Study on Early Supported Discharge
Authors: Chang Won Kee , Kim Won-Seok , Sohn Min Kyun , Jee Sungju , Shin Yong-Il , Ko Sung-Hwa , Ock Minsu , Kim Hyun Joo , Paik Nam-Jong
Published: September 2021

Introduction: Early supported discharge (ESD) is a transitional care model aimed at facilitating post-acute stroke patients' discharge to home. Previous studies have demonstrated that ESD provides equivalent patient and caregiver outcomes with superior cost-effectiveness compared to conventional rehabilitation (CR). This study intends to examine the feasibility of ESD in Korea.

Methods and Analysis: This study is designed as a multicenter assessor-blinded, randomized controlled trial. Ninety post-acute stroke patients with mild to moderate disability (modified Rankin Scale 1–3) will be recruited from three university hospitals (30 patients per hospital) in Korea and allocated to either the ESD group or the CR group in a 1:1 ratio. Patients in the ESD group will receive individualized discharge planning and goal setting, a 4-week home-based rehabilitation program, and liaison service to community-based resources by a multidisciplinary team. Patients in the CR group will receive rehabilitation practices according to their current hospital policy.

Outcomes: The primary outcome is the Korean version of the modified Barthel Index, and the primary endpoint was post-onset 3 months. Clinical outcomes, patient/caregiver reported outcomes, and socioeconomic outcomes will be measured at baseline, 1 month after discharge, 2 months after discharge, and 3 months after onset.

Discussion: The efficacy and cost-effectiveness of ESD can vary according to the healthcare system and sociocultural aspects. To establish ESD as an alternative transitional care model for post-acute stroke patients in Korea, its feasibility needs to be examined in prior. This study will add evidence on the applicability of ESD in Korea.

Ethical Considerations: The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Bundang Hospital (IRB number B-2012/654-308). The study protocol was registered at ClinicalTrials.gov (Identifier NCT04720820). Disseminations will include submission to peer-reviewed journals and presentations at conferences.
Case Report:
Good Prognosis of Mixed Alien Hand Syndrome by Verbal-Cue Rehabilitation Exercise
Authors: Qu Kang , Gan Lin , Jiang Wei , Yu Peng , Dong Ming
Published: September 2021

Mixed alien hand syndrome is a rare disease reported in the literature. The mixed callosal–frontal variant of alien hand syndrome is associated with uncoordinated hand movements, and patients may present with an involuntary grasp reflex and intermanual conflict. There are few videos in the existing literature on the comparison of patients' condition before and after recovery of the symptoms of mixed alien hand syndrome. We presented the prognosis of mixed alien hand syndrome in the form of a video. In addition, we have included some videos on the comparison of the condition of patients before and after recovery of the symptoms of mixed alien hand syndrome. A 57-year-old woman presented with left-handed intermanual conflict and right-handed involuntary grasp reflex due to infarction of the frontal lobe and corpus callosum. She was diagnosed with a mixed callosal–frontal variant of alien hand syndrome. Her left hand counteracted the purposeful movements of the right hand. However, the intermanual conflict disappeared after 3 months of therapy, including drug treatment and verbal-cue rehabilitation, and she regained normal coordination of her hand movements. Her prognosis was good despite the large corpus callosum lesions. The uncoordinated hand movements of the patient affected her daily life and caused psychological problems. Initiating rehabilitation early was important and necessary for her to regain coordination. It is possible that the verbal-cue training method played an important role in the recovery of the patient. Therefore, this method of rehabilitation deserves consideration and can be adopted in larger cohort studies as we presented only a single case. The possible mechanisms behind the verbal-cue exercise require further studies, and this patient had a good prognosis despite severe corpus callosum injury, which may merit further investigation.
Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease
Authors: Santoro Jonathan D. , Lee Sarah , Wang Anthony C. , Ho Eugenia , Nagesh Deepti , Khoshnood Mellad , Tanna Runi , Durazo-Arvizu Ramon A. , Manning Melanie A. , Skotko Brian G. , Steinberg Gary K. , Rafii Michael S.
Published: September 2021

Objective: To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population.

Methods: A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression.

Results: The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively (p < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times (p < 0.001, 95% CI: 1.82–5.58) higher than the idiopathic moyamoya group and 1.5 times (p = 0.002, 95% CI: 1.17–1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder (p = 0.05, 95%CI: 1.08–6.08).

Interpretation: This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.
Parietal Cortex Connectivity as a Marker of Shift in Spatial Attention Following Continuous Theta Burst Stimulation
Authors: Mariner Jessica , Loetscher Tobias , Hordacre Brenton
Published: September 2021

Non-invasive brain stimulation is a useful tool to probe brain function and provide therapeutic treatments in disease. When applied to the right posterior parietal cortex (PPC) of healthy participants, it is possible to temporarily shift spatial attention and mimic symptoms of spatial neglect. However, the field of brain stimulation is plagued by issues of high response variability. The aim of this study was to investigate baseline functional connectivity as a predictor of response to an inhibitory brain stimulation paradigm applied to the right PPC. In fourteen healthy adults (9 female, aged 24.8 ± 4.0 years) we applied continuous theta burst stimulation (cTBS) to suppress activity in the right PPC. Resting state functional connectivity was quantified by recording electroencephalography and assessing phase consistency. Spatial attention was assessed before and after cTBS with the Landmark Task. Finally, known determinants of response to brain stimulation were controlled for to enable robust investigation of the influence of resting state connectivity on cTBS response. We observed significant inter-individual variability in the behavioral response to cTBS with 53.8% of participants demonstrating the expected rightward shift in spatial attention. Baseline high beta connectivity between the right PPC, dorsomedial pre-motor region and left temporal-parietal region was strongly associated with cTBS response (R2 = 0.51). Regression analysis combining known cTBS determinants (age, sex, motor threshold, physical activity, stress) found connectivity between the right PPC and left temporal-parietal region was the only significant variable (p = 0.011). These results suggest baseline resting state functional connectivity is a strong predictor of a shift in spatial attention following cTBS. Findings from this study help further understand the mechanism by which cTBS modifies cortical function and could be used to improve the reliability of brain stimulation protocols.
The Role of Electrode-Site Placement in the Long-Term Stability of Intracortical Microstimulation
Authors: Saldanha Ramya L. , Urdaneta Morgan E. , Otto Kevin J.
Published: September 2021

Intracortical microelectrodes are neuroprosthetic devices used in brain-machine interfaces to both record and stimulate neural activity in the brain. These technologies have been improved by advances in microfabrication, which have led to the creation of subcellular and high-density microelectrodes. The greater number of independent stimulation channels in these devices allows for improved neuromodulation selectivity, compared to single-site microelectrodes. Elements of electrode design such as electrode-site placement can influence the long-term performance of neuroprostheses. Previous studies have shown that electrode-sites placed on the edge of a planar microelectrode have greater chronic recording functionality than sites placed in the center. However, the effect of electrode-site placement on long-term intracortical microstimulation (ICMS) is still unknown. Here, we show that, in rats chronically implanted with custom-made planar silicon microelectrodes, electrode-sites on the tip of the device outperformed those on both the edge and center in terms of the effect per charge delivered, though there is still a slight advantage to using edge sites over center sites for ICMS. Longitudinal analysis of ICMS detection thresholds over a 16-week period revealed that while all sites followed a similar trend over time, the tip and edge sites consistently elicited the behavioral response with less charge compared to center sites. Furthermore, we quantified channel activity over time and found that edge sites remained more active than center sites over time, though the rate of decay of active sites for center and edge sites was comparable. Our results demonstrate that electrode-site placement plays an important role in the long-term stability of intracortical microstimulation and could be a potential factor to consider in the design of future intracortical electrodes.
Mapping Visual Field Defects With fMRI – Impact of Approach and Experimental Conditions
Authors: Prabhakaran Gokulraj T. , Al-Nosairy Khaldoon O. , Tempelmann Claus , Thieme Hagen , Hoffmann Michael B.
Published: September 2021

Current initiatives to restore vision emphasize the need for objective assessments of visual field (VF) defects as pursued with functional magnetic resonance imaging (fMRI) approaches. Here, we compared population receptive field (pRF) mapping-based VF reconstructions to an fMRI method that uses more robust visual stimulation (on-off block design) in combination with individualized anatomy-driven retinotopic atlas-information (atlas-based VF). We investigated participants with sizable peripheral VF-deficits due to advanced glaucoma (n = 4) or retinitis pigmentosa (RP; n = 2) and controls (n = 6) with simulated scotoma. We obtained (1) standard automated perimetry (SAP) data as reference VFs and 3T fMRI data for (2) pRF-mapping [8-direction bar stimulus, fixation color change task] and (3) block-design full-field stimulation [8-direction drifting contrast patterns during (a) passive viewing (PV) and (b) one-back-task (OBT; reporting successions of identical motion directions) to probe the impact of previously reported task-related unspecific visual cortex activations]. Correspondence measures between the SAP and fMRI-based VFs were accuracy, assisted by sensitivity and specificity. We found an accuracy of pRF-based VF from V1 in patients [median: 0.62] that was similar to previous reports and increased by adding V2 and V3 to the analysis [0.74]. In comparison to the pRF-based VF, equivalent accuracies were obtained for the atlas-based VF for both PV [0.67] and, unexpectedly, the OBT [0.59], where, however, unspecific cortical activations were reflected by a reduction in sensitivity [0.71 (PV) and 0.35 (OBT)]. In conclusion, in patients with peripheral VF-defects, we demonstrate that previous fMRI procedures to obtain VF-estimates might be enhanced by: (1) pooling V1-V3 to enhance accuracy; (2) reporting sensitivity and specificity measures to increase transparency of the VF-reconstruction metric; (3) applying atlas-based procedures, if pRF-based VFs are not available or difficult to obtain; and (4) giving, counter-intuitively, preference to PV. These findings are expected to provide guidance to overcome current limitations of translating fMRI-based methods to a clinical work-up.
Demographics, Pattern of Care, and Outcome Analysis of Malignant Melanomas - Experience From a Tertiary Cancer Centre in India
Authors: Bajpai Jyoti , Abraham George , Saklani Avanish P. , Agarwal Anshul , Das Sashanka , Chatterjee Ambarish , Kapoor Akhil , Eaga Prathyusha , Mondal Pradip Kumar , Chandrasekharan Arun , Bhargava Prabhat Ghanshyam , Srinivas Sujay , Turkar Siddharth , Rekhi Bharat , Khanna Nehal , Janu Amit Kumar , Bal Munita , Ostwal Vikas Sureshchand , Ramaswamy Anant , Rohila Jitender , Desouza Ashwin L. , Guha Amrita , Kumar Rajiv , Menon Nandini Sharrel , Rath Sushmita , Patil Vijay Maruti , Noronha Vanita Maria , Joshi Amit Prakashchandra , Laskar Siddhartha , Rangarajan Venkatesh , Prabhash Kumar , Gupta Sudeep , Banavali Shripad
Published: September 2021

Background

Treatment of malignant melanoma has undergone a paradigm shift with the advent of immune checkpoint inhibitors (ICI) and targeted therapies. However, access to ICI is limited in low-middle income countries (LMICs).

Patients and Methods

Histologically confirmed malignant melanoma cases registered from 2013 to 2019 were analysed for pattern of care, safety, and efficacy of systemic therapies (ST).

Results

There were 659 patients with a median age of 53 (range 44–63) years; 58.9% were males; 55.2% were mucosal melanomas. Most common primary sites were extremities (36.6%) and anorectum (31.4%). Nearly 10.8% of the metastatic cohort were BRAF mutated. Among 368 non-metastatic patients (172 prior treated, 185 de novo, and 11 unresectable), with a median follow-up of 26 months (0–83 months), median EFS and OS were 29.5 (95% CI: 22–40) and 33.3 (95% CI: 29.5–41.2) months, respectively. In the metastatic cohort, with a median follow up of 24 (0–85) months, the median EFS for BSC was 3.1 (95% CI 1.9–4.8) months versus 3.98 (95% CI 3.2–4.7) months with any ST (HR: 0.69, 95% CI: 0.52–0.92; P = 0.011). The median OS was 3.9 (95% CI 3.3–6.4) months for BSC alone versus 12.0 (95% CI 10.5–15.1) months in any ST (HR: 0.38, 95% CI: 0.28–0.50; P < 0.001). The disease control rate was 51.55%. Commonest grade 3–4 toxicity was anemia with chemotherapy (9.5%) and ICI (8.8%). In multivariate analysis, any ST received had a better prognostic impact in the metastatic cohort.

Conclusions

Large real-world data reflects the treatment patterns adopted in LMIC for melanomas and poor access to expensive, standard of care therapies. Other systemic therapies provide meaningful clinical benefit and are worth exploring especially when the standard therapies are challenging to administer.
Danlou Tablets Inhibit Atherosclerosis in Apolipoprotein E-Deficient Mice by Inducing Macrophage Autophagy: The Role of the PI3K-Akt-mTOR Pathway
Authors: Liu Chunping , Chen Guiling , Chen Yanfen , Dang Yue , Nie Guangning , Wu Dinghong , Li Jinhua , Chen Zide , Yang Hailong , He Dongyue , Li Xiong , Sun Jingbo , Lu Jiahong , Wang Lei
Published: September 2021

Atherosclerosis (AS) is a type of chronic vascular disease, and its etiology is not yet fully understood. AS is characterized by lipid deposition, atherosclerotic plaque formation, vascular stenosis or even complete blockage of the blood vessel wall. Clinical studies have shown that Danlou tablets (DLTs) can improve the heart function, quality of life, and prognosis of patients with coronary heart disease and myocardial infarction. However, its mechanism of action remains unknown. Our study revealed that DLTs ameliorated ApoE−/−AS mouse aortic atherosclerotic plaques [hematoxylin-eosin (HE) staining and small animal ultrasound] and reduced CD68+ macrophage infiltration, the expression of the inflammatory factor interferon-gamma (IFN-γ), vascular smooth muscle α-actin, and serum lipid levels. In vitro, in the macrophage foaming model, DLTs partially restored the activity of RAW264.7 cells, reduced the uptake of lipid droplets, and inhibited lipid droplet accumulation and apoptosis within BMDMs. We also found that Torin1, an autophagy agonist, reduced intracellular lipid deposition in BMDMs, as did DLTs. Moreover, DLTs upregulated the expression of the autophagy-related protein LC3II and decreased p62 accumulation in RAW264.7 cells. DLTs also inhibited the phosphorylation of p-PI3K, p-Akt, and p-mTOR, leading to upregulated autophagy in RAW264.7 cells. In summary, our results suggested that DLTs can promote autophagy in macrophages by inhibiting the PI3K/Akt/mTOR signaling pathway, thereby reducing foam cell formation and improving atherosclerosis.
Nicorandil Inhibits Osteoclast Formation Base on NF-κB and p-38 MAPK Signaling Pathways and Relieves Ovariectomy-Induced Bone Loss
Authors: Xu Shenggui , Cao Xiankun , Yu Zhenxing , He Wenxin , Pang Yichuan , Lin Wang , Chen Zhiqian , Guo Weizhong , Lu Xiongwei , Lin Chengshou
Published: September 2021

Osteolytic bone disorders are characterized by an overall reduction in bone mineral density which enhances bone ductility and vulnerability to fractures. This disorder is primarily associated with superabundant osteoclast formation and bone resorption activity. Nicorandil (NIC) is a vasodilatory anti-anginal drug with ATP-dependent potassium (KATP) channel openings. However, NIC is adopted to manage adverse cardiovascular and coronary events. Recent research has demonstrated that NIC also possesses anti-inflammatory peculiarity through the regulation of p38 MAPK and NF-κB signaling pathways. Both MAPK and NF-κB signaling pathways play pivotal roles in RANKL-induced osteoclast formation and bone resorption function. Herein, we hypothesized that NIC may exert potential biological effects against osteoclasts, and revealed that NIC dose-dependently suppressed bone marrow macrophage (BMM) precursors to differentiate into TRAP + multinucleated osteoclasts in vitro. Furthermore, osteoclast resorption assays demonstrated anti-resorptive effects exhibited by NIC. NIC had no impact on osteoblast differentiation or mineralization function. Based on Biochemical analyses, NIC relieved RANKL-induced ERK, NF-κB and p38 MAPK signaling without noticeable effects on JNK MAPK activation. However, the attenuation of NF-κB and p38 MAPK activation was sufficient to hamper the downstream induction of c-Fos and NFATc1 expression. Meanwhile, NIC administration markedly protected mice from ovariectomy (OVX)-induced bone loss through in vivo inhibition of osteoclast formation and bone resorption activity. Collectively, this work demonstrated the potential of NIC in the management of osteolytic bone disorders mediated by osteoclasts.
The Effect of Foliar Application of Melatonin on Changes in Secondary Metabolite Contents in Two Citrus Species Under Drought Stress Conditions
Authors: Jafari Marziyeh , Shahsavar Alireza
Published: September 2021

Plant secondary metabolites are compounds that play an important role in plant interactions and defense. Persian lime and Mexican lime as the two most important sour lime varieties with high levels of secondary metabolites, are widely cultivated in tropical and subtropical areas. Melatonin is a pleiotropic molecule that plays a key role in protecting plants against drought stress through regulating the secondary metabolite biosynthesis pathway. This study was performed as a factorial experiment consisting of three factors in a completely randomized design (CRD), including four concentrations of melatonin (0, 50, 100, and 150 μM), three levels of drought stress [100% (control), 75% (moderate stress), and 40% (severe stress) field capacity (FC)], and two Citrus cultivars. The experiment was conducted for 60 days in a greenhouse condition. Based on the results of this study under severe drought stress, melatonin-treated crops had higher total flavonoid and total phenolic contents than the untreated crops. The highest level of essential oils components was observed on 100 μM foliar application of melatonin under severe drought stress in both varieties. The main component of the essential oil was limonene in both Citrus species. Moreover, based on the analysis of the results, hesperidin was the main polyphenol in both varieties. Since the use of melatonin often increases the production of secondary metabolites, this study can be considered as a very effective method for controlling the adverse effects of drought stress in citrus for both industrial and horticultural aims.
Voltage-Dependent Anion-Selective Channels and Other Mitochondrial Membrane Proteins Form Diverse Complexes in Beetroots Subjected to Flood-Induced Programmed Cell Death
Authors: Rojas-Méndez Karla J. , Sánchez Segura Lino , Chagolla Alicia , Lino Bárbara , González de la Vara Luis E.
Published: September 2021

In plants, programmed cell death (PCD) is involved in both the development and the response to biotic and abiotic aggressions. In early stages of PCD, mitochondrial membranes are made permeable by the formation of permeability transition pores, whose protein composition is debated. Cytochrome c (cyt c) is then released from mitochondria, inducing the degradation of chromatin characteristic of PCD. Since flooding stress can produce PCD in several plant species, the first goal of this study was to know if flooding stress could be used to induce PCD in Beta vulgaris roots. To do this, 2-month-old beet plants were flood-stressed from 1 to 5 days, and the alterations indicating PCD in stressed beetroot cells were observed with a confocal fluorescence microscope. As expected, nuclei were deformed, and chromatin was condensed and fragmented in flooded beetroots. In addition, cyt c was released from mitochondria. After assessing that flood stress induced PCD in beetroots, the composition of mitochondrial protein complexes was observed in control and flood-stressed beetroots. Protein complexes from isolated mitochondria were separated by native gel electrophoresis, and their proteins were identified by mass spectrometry. The spectra count of three isoforms of voltage-dependent anion-selective channels (VDACs) increased after 1 day of flooding. In addition, the size of the complexes formed by VDAC was higher in flood-stressed beetroots for 1 day (∼200 kDa) compared with non-stressed ones (∼100 kDa). Other proteins, such as chaperonin CPN60-2, also formed complexes with different masses in control and flood-stressed beetroots. Finally, possible interactions of VDAC with other proteins were found performing a cluster analysis. These results indicate that mitochondrial protein complexes formed by VDAC could be involved in the process of PCD in flood-stressed beetroots. Data are available via ProteomeXchange with identifier PXD027781.
Identification of Quantitative Trait Loci Controlling the Development of Prickles in Eggplant by Genome Re-sequencing Analysis
Authors: Qian Zongwei , Zhang Bin , Chen Haili , Lu Lei , Duan Mengqi , Zhou Jun , Cui Yanling , Li Dayong
Published: September 2021

Eggplant (Solanum melongena L.) is the third most important crop in the family of Solanaceae. Prickles are considered as the undesirable traits during the plantation of eggplant and the transportation of fruits. In this study, we constructed a high-quality genetic linkage Bin map derived from the re-sequencing analysis on a cross of a prickly wild landrace, 17C01, and a cultivated variety, 17C02. The major quantitative trait locus (QTL) controlling the development of prickles on the calyx (explained 30.42% of the phenotypic variation), named as qPC.12, was identified on a ~7 kb region on chromosome 12. A gene within qPC.12, which encodes a WUSCHEL-related homeobox-like protein, with higher expression levels in 17C01 calyx and 22-bp deletion in 17C02 was probably the functional gene for prickle formation. Results from this study would ultimately facilitate uncovering the molecular regulatory mechanisms underlying the development of a prickle in eggplant.
Styling the Self: Clothing Practices, Personality Traits, and Body Image Among Israeli Women
Authors: Stolovy Tali
Published: September 2021

Research has shown that women tend to use clothes to present or disguise their bodies and that clothing practices can be predicted by body image. This study explored the relationships between clothing practices, personality traits, and body image among Israeli women, using the Big Five personality traits model (NEO-FFI) and a body image measure (MBSRQ) to explore clothing styles and practices among Israeli women (N = 792, Mean age = 42.19). It found that women with more openness to experience (OR = 1.8; IC 95%: 1.05–3.0), who seek fashion (OR = 2.05; IC 95%: 1.37–3.05) and individuality (OR = 3.96; IC 95%: 2.46–6.3) are more likely to exhibit an urban, sophisticated style of dress. These women are less motivated by comfort (OR = 0.49; IC 95%: 0.31–0.77) and camouflage (OR = 2.05; IC 95%: 1.37–3.05), that are associated with casual, minimalist style of dress. This study indicates that openness to experience may foster body-positive clothing practices. In this way, their choice of clothing can help women overcome objectification and cultural body-ideal pressures, promoting self-validation and mastery.
The Influence of Autonomy-Supportive Teaching on EFL Students’ Classroom Autonomy: An Experimental Intervention
Authors: Alrabai Fakieh
Published: September 2021

Based on the framework of self-determination theory (SDT), this two-wave longitudinal empirical investigation examined the actual practicality of certain strategies that have been theoretically acknowledged as having potential positive effect on English as a foreign language (EFL) learner’s autonomy. Strategies targeting learners’ self-determined learning in the classroom in terms of satisfying learner basic psychological needs (BPNs) of autonomy, competence, and relatedness as well as SDT key concepts, such as learner sense of choice, intrinsic motivation, control over learning, goals and needs, and metacognitive skills, were implemented in a treatment group for 12weeks. A classroom observation was used to evaluate teachers’ autonomy-supportive teaching and a student self-report measure, and an observation were used to assess learners’ autonomy. The findings derived out from analyses of variance, covariance and a hierarchical regression revealed that the experimental intervention led to statistically significant increased EFL autonomy for learners in the experimental group. Learner perceived choice, autonomy support, competence, and intrinsic motivation mediated the relationship between teacher autonomy-supportive teaching and learner autonomy; with perceived choice being the strongest predictor of learner autonomy. These findings acknowledge the vital role of teacher autonomy-supportive teaching in promoting EFL learner autonomy and recommend that, beside satisfying their BPNs, students should always be granted a larger space of freedom of choice, more control over learning, and more involvement in decision-making process.