Miracle-dz/UniFAR-FTUs huggingface dataset:
Pushing functional MRI spatial and temporal resolution further: High‐density receive arrays combined with shot‐selective 2D CAIPIRINHA for 3D echo‐planar imaging at 7 T

To be able to examine dynamic and detailed brain functions, the spatial and temporal resolution of 7 T MRI needs to improve. In this study, it was investigated whether submillimeter multishot 3D EPI fMRI scans, acquired with high‐density receive arrays, can benefit from a 2D CAIPIRINHA sampling pattern, in terms of noise amplification (g‐factor), temporal SNR and fMRI sensitivity. High‐density receive arrays were combined with a shot‐selective 2D CAIPIRINHA implementation for multishot 3D EPI sequences at 7 T. In this implementation, in contrast to conventional inclusion of extra kz gradient blips, specific EPI shots are left out to create a CAIPIRINHA shift and reduction of scan time. First, the implementation of the CAIPIRINHA sequence was evaluated with a standard receive setup by acquiring submillimeter whole brain T2*‐weighted anatomy images. Second, the CAIPIRINHA sequence was combined with high‐density receive arrays to push the temporal resolution of submillimeter 3D EPI fMRI scans of the visual cortex. Results show that the shot‐selective 2D CAIPIRINHA sequence enables a reduction in scan time for 0.5 mm isotropic 3D EPI T2*‐weighted anatomy scans by a factor of 4 compared with earlier reports. The use of the 2D CAIPIRINHA implementation in combination with high‐density receive arrays, enhances the image quality of submillimeter 3D EPI scans of the visual cortex at high acceleration as compared to conventional SENSE. Both the g‐factor and temporal SNR improved, resulting in a method that is more sensitive to the fMRI signal. Using this method, it is possible to acquire submillimeter single volume 3D EPI scans of the visual cortex in a subsecond timeframe. Overall, high‐density receive arrays in combination with shot‐selective 2D CAIPIRINHA for 3D EPI scans prove to be valuable for reducing the scan time of submillimeter MRI acquisitions.
The Role of Potassium Ion and Water Channels in an Animal Model of Multiple Sclerosis

II DEDICATION. IV ACKNOWLEDGMENTS . V VITA. VI TABLE OF CONTENTS . IX LIST OF TABLES . XII LIST OF FIGURES . XIII CHAPTER 1: INTRODUCTION . 1 NEUROINFLAMMATION AND NEURODEGENERATION. 1 DEMYELINATION . 2 MULTIPLE SCLEROSIS . 3 NEUROPROTECTION . 4 ION CHANNELS IN NEUROTRANSMISSION . 5 ION AND WATER CHANNELS IN THE NEUROVASCULAR UNIT . 7 ASTROCYTE CHANNEL PROTEINS . 10 Water channel AQP4 . 10 Inwardly rectifying potassium channel Kir4.1 . 13 Ca2+ and Voltage-activated BK channels . 17 Two-pore-domain K+ channels . 19 Voltage-gated calcium channels . 21 PERSPECTIVES FOR ASTROCYTIC ION CHANNEL RESEARCH . 24 Recently identified channel proteins expressed in astrocytes . 24 Regulation of astrocytic channel functions by intracellular signaling pathways . 27 SUMMARY . 29 OVERALL GOAL . 30 CHAPTER 2: K+ CHANNEL ALTERATIONS IN EAE . 3
An RNA aptamer with potent affinity for a toxic dimer of amyloid β42 has potential utility for histochemical studies of Alzheimer's disease

Oligomers of β-amyloid 42 (Aβ42), rather than fibrils, drive the pathogenesis of Alzheimer's disease (AD). In particular, toxic oligomeric species called protofibrils (PFs) have attracted significant attention. Herein, we report RNA aptamers with higher affinity toward PFs derived from a toxic Aβ42 dimer than toward fibrils produced from WT Aβ42 or from a toxic, conformationally constrained Aβ42 variant, E22P–Aβ42. We obtained these RNA aptamers by using the preincubated dimer model of E22P–Aβ42, which dimerized via a linker located at Val-40, as the target of in vitro selection. This dimer formed PFs during incubation. Several physicochemical characteristics of an identified aptamer, E22P–AbD43, suggested that preferential affinity of this aptamer toward PFs is due to its higher affinity for the toxic dimer unit (KD = 20 ± 6.0 nm) of Aβ42 than for less-toxic Aβ40 aggregates. Comparison of CD data from the full-length and random regions of E22P–AbD43 suggested that the preferential binding of E22P–AbD43 toward the dimer might be related to the formation of a G-quadruplex structure. E22P–AbD43 significantly inhibited the nucleation phase of the dimer and its associated neurotoxicity in SH-SY5Y human neuroblastoma cells. Of note, E22P–AbD43 also significantly protected against the neurotoxicity of WT Aβ42 and E22P–Aβ42. Furthermore, in an AD mouse model, E22P–AbD43 preferentially recognized diffuse aggregates, which likely originated from PFs or higher-order oligomers with curvilinear structures, compared with senile plaques formed from fibrils. We conclude that the E22P–AbD43 aptamer is a promising research and diagnostic tool for further studies of AD etiology.
Fast responses to stepping‐target displacements when walking

Goal‐directed arm movements can be adjusted at short latency to target shifts. We tested whether similar adjustments are present during walking on a treadmill with shifting stepping targets. Participants responded at short latency with an adequate gain to small shifts of the stepping targets. Movements of the feet during walking are controlled in a similar way to goal‐directed arm movements if balance is not violated.
Bayesian joint modeling of ordinal longitudinal measurements and competing risks survival data for analysing Tehran Lipid and Glucose Study

ABSTRACT In this paper, joint modeling of longitudinal ordinal measurements and time to some events of interest as competing risks is discussed. For this purpose, a latent variable sub-model under linear mixed-effects assumption is considered for modeling ordinal longitudinal measurements. Also, a Weibull cause-specific sub-model is used to model competing risks data. These two sub-models are simultaneously considered in a unique model by a shared parameter model framework. Some simulation studies are performed for illustration of the proposed approaches; also, the proposed approaches are used for analyzing 15 years of lipid and glucose follow-up study in Tehran.
GAA compound heterozygous mutations associated with autophagic impairment cause cerebral infarction in Pompe disease

Clinical manifestations of the late-onset adult Pompe disease (glycogen storage disease type II) are heterogeneous. To identify genetic defects of a special patient population with cerebrovascular involvement as the main symptom, we performed whole-genome sequencing (WGS) analysis on a consanguineous Chinese family of total eight members including two Pompe siblings both had cerebral infarction. Two novel compound heterozygous variants were found in GAA gene: c.2238G>C in exon 16 and c. 1388_1406del19 in exon 9 in the two patients. We verified the function of the two mutations in leading to defects in GAA protein expression and enzyme activity that are associated with autophagic impairment. We further performed a gut microbiome metagenomics analysis, found that the child’s gut microbiome metagenome is very similar to his mother. Our finding enriches the gene mutation spectrum of Pompe disease, and identified the association of the two new mutations with autophagy impairment. Our data also indicates that gut microbiome could be shared within Pompe patient and cohabiting family members, and the abnormal microbiome may affect the blood biochemical index. Our study also highlights the importance of deep DNA sequencing in potential clinical applications.
Helminth infection modulates systemic pro-inflammatory cytokines and chemokines implicated in type 2 diabetes mellitus pathogenesis

Background The prevalence of helminth infections exhibits an inverse association with the prevalence of Type 2 diabetes mellitus (T2DM), and helminths are postulated to mediate a protective effect against T2DM. However, the biological mechanism behind this effect is not known. Aims/Methods We postulated that helminth infections act by modulating the pro-inflammatory cytokine and chemokine milieu that is characteristic of T2DM. To examine the association of cytokines and chemokines in helminth-diabetes co-morbidity, we measured the plasma levels of a panel of pro-inflammatory cytokines and chemokines in individuals with Strongyloides stercoralis infection (Ss+) and T2DM at the time of Ss diagnosis and then 6 months after definitive anthelmintic treatment along with uninfected control individuals with T2DM alone (Ss-). Principal findings Ss+ individuals exhibited significantly diminished levels of the pro-inflammatory cytokines–IL-1α, IL-1β, IL-6, IL-12, IL-18, IL-23, IL-27, G-CSF and GM-CSF and chemokines–CCL1, CCL2, CCL3, CCL11, CXCL1, CXCL2, CXCL8, CXCL9, CXCL10 and CXCL11. In contrast, Ss+ individuals exhibited significantly elevated levels of IL-1Ra. Anthelmintic treatment resulted in increased levels of all of the cytokines and chemokines. Conclusions Thus, helminth infections alleviate and anthelmintic therapy partially restores the plasma cytokine and chemokine levels in helminth-diabetes co-morbidity. Our data therefore offer a plausible biological mechanism for the protective effect of helminth infections against T2DM.
Modulation of muscle synergies for multiple forearm movements under variant force and arm position constraints

Objective. To promote clinical applications of muscle-synergy-based neurorehabilitation techniques, this study aims to clarify any potential modulations of both the muscular compositions and temporal activations of forearm muscle synergies for multiple movements under variant force levels and arm positions. Approach. Two groups of healthy subjects participated in this study. Electromyography (EMG) signals were collected when they performed four hand and wrist movements under variant constraints—three different force levels for one group and five arm positions for the other. Muscle synergies were extracted from the EMGs, and their robustness across variant force levels and arm positions was separately assessed by evaluating their across-condition structure similarity, cross-validation, and cluster analysis. The synergies’ activation coefficients across the variant constraints were also compared, and the coefficients were used to discriminate the different force levels and the arm positions, respectively. Main results. Overall, the muscle synergies were relatively fixed across variant constraints, but they were more robust to variant forces than to changing arm positions. The activations of muscle synergies depended largely on the level of contraction force and could discriminate the force levels very well, but the coefficients corresponding to different arm positions discriminated the positions with lower accuracy. Similar results were found for all types of forearm movement analyzed. Significance. With our experiment and subject-specific analysis, only slight modulation of the muscular compositions of forearm muscle synergies was found under variant force and arm position constraints. Our results may shed valuable insights to future design of both muscle-synergy-based assistive robots and motor-function assessments.
Comparing Fatigue, Physical Activity, and Posture among Nurses in Two Staffing Models

The high variability and complexity of patient care needs have led to the development of various nurse staffing models. While “pod nursing” has been observed to result in favorable outcomes such as improved patient access, professional communication, and job satisfaction among nurses, the effects of pod nursing on important metrics related to nurse health have not been previously reported. This study compared self-reported estimates of fatigue and directly measured estimates of physical activity and exposure to non-neutral working postures of the trunk and upper arms obtained from registered nurses working in a pod nursing model to estimates obtained from registered nurses working in a total patient care (TPC) model. Results suggested that nurses working in the pod model had similar exposures to nurses working in the TPC model. Consistent with previous work, nurses were observed to spend a small percentage of work time performing moderate or greater intensity physical activity.
Long range correlations of the ion current in SV channels. Met3PbCl influence study

The long-range correlations within the current signal time series of the Beta vulgaris vacuolar membrane under the influence of organolead compound (Met3PbCl) are investigated. The current time series is transformed into a dwell time series. Then the rescaled range and detrended fluctuations analyses are used. It is shown that the presence of Met3PbCl in the solution decreases the mean value of the Hurst exponent and therefore influences the long-range correlations in ionic channel current. This observation is statistically significant. An ion channel model is built and the experimental results reconstructed and analysed.
Employers' Preference for Foreign Trained Graduates - Myth or Reality?

The purpose of this research paper is to examine: (i) whether employers’ prefer foreign trained graduates (FG) vis-a-vis local graduates (LG) and graduates from local twinning programmes (TG), and (ii) whether there is a significant difference in the overall performance perception (OPP) of these 3 groups of graduates over three different time frames. Data was collected from Human Resource Managers, Administrative Managers, Chief Executive Officers, Managing Directors and Managers of public listed companies as well as from Small and Medium Enterprises (SMEs) in the northern region of Malaysia (Penang, Kedah, Perlis and northern Perak) using an online survey. Results supported both hypotheses, with employers’ perceiving foreign graduates to be superior in terms of: communication skills (verbal and written); confidence/self-image; computer/IT skills; creative/innovative skills; analytical research skills and flexibility/adaptability compared to their local counterparts (LG) and graduates from local twinning programmes (TG). In terms of overall performance perception (OPP), foreign graduates too were deemed superior. The generalizability of the survey findings should be interpreted with caution owing to the low response rate. Nevertheless, local universities as well as local graduates should take cognizance of these findings and seek ways to narrow this perceived gap.
The quality of life of children with epilepsy in Poland – the opinion of children and their parents

Summary Background Every chronic illness, including epilepsy, has a negative effect on both the quality of life of the sufferer as well as on their relationship with their surroundings. Aims To investigate the quality of life of children suffering from epilepsy and analyse how they assessed and scored their experiences compared to their parents. Materials and methods The study included 209 children with epilepsy and their parents. The research tool was a questionnaire for gathering demographic and clinical data as well as the Pediatric Quality of Life Inventory™ 4.0 Generic Core Scales (PedsQL™ 4.0) questionnaire in two versions, one for 8–12 year olds and one for 13–18 year olds and their parents. Results Cronbach’s alpha coefficient for the entire PedsQL™ 4.0 questionnaire was 0.91 and 0.93 for children with epilepsy and their parents respectively. Children rated their Total Scale Score higher (67.5 points) than their parents (62.5 points). Whilst analyzing children’s functioning in different areas it was observed that girls’ assessments were higher than boys’, except for Emotional Functioning. Both parents and children scored School Functioning the lowest. The greatest agreement of responses was observed in the domain of Physical Functioning, the smallest in the domain of Emotional Functioning. Conclusions Quality of life was rated higher by both age groups of children suffering from epilepsy than by their parents. A statistically significant difference was found when comparing the assessment scores of children and parents in light of the following variables; child age, gender, illness duration, seizure frequency and treatment effectiveness.
Perioperative Continuous Femoral Nerve Block Reduces Postoperative Cognitive Dysfunction of High-Risk Patients with Femoral Neck Fracture: Evidence from a Retrospective Propensity-Matched Study

Background Elderly patients often suffer from postoperative cognitive impairment which increases mortality, morbidity, and the economic burden. However, how continuous femoral nerve block (cFNB) influence the incidence of postoperative cognitive dysfunction (POCD) has never been reported. This study tried to explore how cFNB affects the incidence of POCD among low-risk and high-risk patients with femoral neck fractures. Material/Methods We conducted a retrospective propensity score-matched study and allocated matched patients (n=172) with femoral neck fractures into the cFNB group (n=86) and the control group (n=86). Demographical and clinical data were collected and compared, including the visual analog scale (VAS) score, the morphine consumption, and the POCD incidence. Subgroup analysis of high-risk patients (Mini-Cog score ≤2) and low-risk patients (Mini-Cog score ≥3) was also carried out. Results After matching, baseline characteristics of 2 groups were comparable between the 2 groups (all P>0.05). Compared with the control group, the cFNB group had significantly lower visual analog scale (VAS) score and morphine consumption in the postoperative 3 days (P<0.05). For high-risk patients, the Kaplan-Meier survival curve suggested that the incidence of POCD the cFNB group was significantly lower than the control group (P=0.005), without statistical difference for total or low-risk patients (P>0.05). Multivariate Cox hazard regression analysis showed that the adoption of cFNB conferred a protective effect on POCD (HR=0.556, 95% CI 0.316–0.981, P=0.043). Conclusions For patients undergoing femoral neck fracture surgery, perioperative cFNB administration is useful in decreasing the incidence of POCD, especially for high-risk patients with a Mini-Cog score equal to or less than 2 points.
Glaucoma Surgery and Aqueous Dynamics

Reduction in intraocular pressure is the only proven method to treat glaucoma. When medical treatment does not achieve adequate intraocular pressure reduction with acceptable adverse effects, laser or incisional surgeries are introduced. In this chapter, we discuss the physiological basis for the established surgical procedures as well as the newer surgical procedures. Most new surgical innovations have been designed according to natural physiology by routing aqueous as nature intended, through the Schlemm’s canal. This has been possible because of better understanding of the outflow system and the availability of micro-technology to manipulate it.
Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling

These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell–like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3+/−), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients. Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.
CDK9 Blockade Exploits Context-dependent Transcriptional Changes to Improve Activity and Limit Toxicity of Mithramycin for Ewing Sarcoma

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor–targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1–targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic “class” effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC50 and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1–targeted combination therapy for Ewing sarcoma.