Miracle-dz/UniFAR-FTUs huggingface dataset:
Protection against Hydrogen Peroxide-Mediated Cytotoxicity in Friedreich's Ataxia Fibroblasts Using Novel Iron Chelators of the 2-Pyridylcarboxaldehyde Isonicotinoyl Hydrazone Class

Iron-loading diseases remain an important problem because of the toxicity of iron-catalyzed redox reactions. Iron loading occurs in the mitochondria of Friedreich's ataxia (FA) patients and may play a role in its pathogenesis. This suggests that iron chelation therapy could be useful. We developed previously the lipophilic iron chelators known as the 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH) ligands and identified 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH) as the most promising analog. Hence, this study assessed the efficacy of PCTH and other PCIH analogs compared with various chelators, including deferiprone and desferrioxamine (DFO). Age- and sex-matched control and FA fibroblasts were preincubated with iron chelators and subsequently challenged with 50 μM H2O2 for up to 24 h. The current study demonstrates an interesting structure-activity relationship among the closely related PCIH series of ligands, with only PCTH being highly effective at preventing H2O2-induced cytotoxicity. PCTH increased FA fibroblast cell viability by up to 70%, whereas DFO rescued viability by 1 to 5% only. Hence, PCTH, which was well tolerated by cells was far more effective than DFO at preventing oxidative stress. It is noteworthy that kinetic studies demonstrated PCTH to rapidly penetrate cells to induce 59Fe efflux, whereas DFO, PCIH, 2-pyridylcarboxaldehyde benzoyl hydrazone, and 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone were far slower, indicating it is the rate of chelator permeation that is crucial for protection against H2O2. In addition, PCTH was found to be as effective as or more effective than conventional radical scavengers or the antioxidant idebenone (which has undergone clinical trials) at protecting cells against H2O2-mediated cytotoxicity. These findings further indicate the potential of PCTH for treatment of iron overload.
Developmental aspects of error and high-conflict-related brain activity in pediatric obsessive-compulsive disorder: a fMRI study with a Flanker task before and after CBT.

BACKGROUND Heightened error and conflict monitoring are considered central mechanisms in obsessive-compulsive disorder (OCD) and are associated with anterior cingulate cortex (ACC) function. Pediatric obsessive-compulsive patients provide an opportunity to investigate the development of this area and its associations with psychopathology. METHODS Repeated measures were carried out using functional magnetic resonance imaging (fMRI) during the performance of an interference task, the arrow version of the Flanker paradigm, before and after cognitive-behavioral treatment of 25 medication-free pediatric obsessive-compulsive patients compared with age- and gender-matched healthy controls. RESULTS During error trials compared to correct trials, pediatric OCD patients and controls showed an interaction effect of Group × Time × Age in the ACC and insula. This effect was mainly driven by an increased activation in older OCD subjects, which was also present after treatment. During high-conflict trials compared with low-conflict trials, a Group × Time × Age interaction effect was found in bilateral insula. This effect was driven by an increase of BOLD (blood oxygen level dependent) signal in older OCD patients before but not after treatment. In addition, a Group × Time interaction effect in dorsomedial prefrontal cortex, premotor region and ACC was found. This effect was driven by an increase of BOLD signal in OCD subjects relative to controls over time. CONCLUSIONS Compared to healthy controls, children and adolescents with OCD show increased activation of the ACC during error responses and in bilateral insular cortex during high-conflict tasks, which is age dependent and which is only partially affected by cognitive-behavioral therapy (CBT). Therefore, we suggest that ACC functioning is a vulnerability marker in pediatric OCD, whereas insular dysfunction may be state dependent.
A Comparison of Behavioral Methods for Indexing the Auditory Processing of Temporal Fine Structure Cues

Purpose Growing evidence supports the inclusion of perceptual tests that quantify the processing of temporal fine structure (TFS) in clinical hearing assessment. Many tasks have been used to evaluate TFS in the laboratory that vary greatly in the stimuli used and whether the judgments require monaural or binaural comparisons of TFS. The purpose of this study was to compare laboratory measures of TFS for inclusion in a battery of suprathreshold auditory tests. A subset of available TFS tasks were selected on the basis of potential clinical utility and were evaluated using metrics that focus on characteristics important for clinical use. Method TFS measures were implemented in replication of studies that demonstrated clinical utility. Monaural, diotic, and dichotic measures were evaluated in 11 young listeners with normal hearing. Measures included frequency modulation (FM) tasks, harmonic frequency shift detection, interaural phase difference (TFS–low frequency), interaural time difference (ITD), monaural gap duration discrimination, and tone detection in noise with and without a difference in interaural phase (N0S0, N0Sπ). Data were compared with published results and evaluated with metrics of consistency and efficiency. Results Thresholds obtained were consistent with published data. There was no evidence of predictive relationships among the measures consistent with a homogenous group. The most stable tasks across repeated testing were TFS–low frequency, diotic and dichotic FM, and N0Sπ. Monaural and diotic FM had the lowest normalized variance and were the most efficient accounting for differences in total test duration, followed by ITD. Conclusions Despite a long stimulus duration, FM tasks dominated comparisons of consistency and efficiency. Small differences separated the dichotic tasks FM, ITD, and N0Sπ. Future comparisons following procedural optimization of the tasks will evaluate clinical efficiency in populations with impairment.
ACTN3 R577X Genotype and Exercise Phenotypes in Recreational Marathon Runners

Background: Homozygosity for the X-allele in the ACTN3 R577X (rs1815739) polymorphism results in the complete absence of α-actinin-3 in sarcomeres of fast-type muscle fibers. In elite athletes, the ACTN3 XX genotype has been related to inferior performance in speed and power-oriented sports; however, its influence on exercise phenotypes in recreational athletes has received less attention. We sought to determine the influence of ACTN3 genotypes on common exercise phenotypes in recreational marathon runners. Methods: A total of 136 marathoners (116 men and 20 women) were subjected to laboratory testing that included measurements of body composition, isometric muscle force, muscle flexibility, ankle dorsiflexion, and the energy cost of running. ACTN3 genotyping was performed using TaqMan probes. Results: 37 runners (27.2%) had the RR genotype, 67 (49.3%) were RX and 32 (23.5%) were XX. There was a difference in body fat percentage between RR and XX genotype groups (15.7 ± 5.8 vs. 18.8 ± 5.5%; effect size, ES, = 0.5 ± 0.4, p = 0.024), whereas the distance obtained in the sit-and-reach-test was likely lower in the RX than in the XX group (15.3 ± 7.8 vs. 18.4 ± 9.9 cm; ES = 0.4 ± 0.4, p = 0.046). Maximal dorsiflexion during the weight-bearing lunge test was different in the RR and XX groups (54.8 ± 5.8 vs. 57.7 ± 5.1 degree; ES = 0.5 ± 0.5, p = 0.044). Maximal isometric force was higher in the RR than in the XX group (16.7 ± 4.7 vs. 14.7 ± 4.0 N/kg; ES = −0.5 ± 0.3, p = 0.038). There was no difference in the energy cost of running between genotypes (~4.8 J/kg/min for all three groups, ES ~0.2 ± 0.4). Conclusions: The ACTN3 genotype might influence several exercise phenotypes in recreational marathoners. Deficiency in α-actinin-3 might be accompanied by higher body fatness, lower muscle strength and higher muscle flexibility and range of motion. Although there is not yet a scientific rationale for the use of commercial genetic tests to predict sports performance, recreational marathon runners who have performed such types of testing and have the ACTN3 XX genotype might perhaps benefit from personalized strength training to improve their performance more than their counterparts with other ACTN3 genotypes.
Stress-Induced Suppression of Milk Protein is Involved in a Noradrenergic Mechanism in the Mammary Gland.

Stress decreases milk components such as milk protein as well as milk yield. The objective of this study was to investigate whether noradrenaline (NA) in milk constituted a factor associated with stress-induced changes in milk proteins such as β-casein. Breast milk obtained from eight healthy nursing women contained NA at concentrations ranging from 12.7 to 115.5 nM. The expression of tyrosine hydroxylase (TH), a rate-limiting enzyme of NA synthesis, was observed in primary human mammary epithelial cells (HMECs), and in MCF-12A and MCF-10A cell lines. The mean NA concentration in culture medium used by MCF-12A transfected with TH siRNA was significantly lower than that of cells transfected with control siRNA. NA concentration in milk in restraint-stressed nursing mice was significantly higher than that of non-stressed nursing mice, owing to elevated TH expression in the mammary epithelium. The mean of β-casein concentration in milk in restraint-stressed mice was significantly lower than that of non-stressed mice. NA treatment resulted in a concentration-dependent decrease in β-casein expression in HMECs. The expression of β2 receptor (ADBR2) was observed in HMEC, MCF-12A, and MCF-10A, and immunohistochemical analysis of ADBR2 using mammary epithelium sections obtained from mice at day 10 of lactation showed that ADBR2 was expressed at the apical membrane of mammary epithelium. Treatment with salbutamol, an ADBR2 stimulant, decreased β-casein expression in a concentration-dependent manner in MCF-12A. Our results showed that endogenous NA derived from mammary epithelial cells likely comprises one of the factors involved in stress-induced changes in milk proteins such as β-casein.
Seeking culturally safe care: a qualitative systematic review of the healthcare experiences of women and girls who have undergone female genital mutilation/cutting

Objective To explore the experiences of accessing and receiving healthcare related to female genital mutilation/cutting (FGM/C) across the life course from the perspective of women and girls who have undergone FGM/C. Design A systematic review of qualitative research studies using a thematic synthesis approach. Methods Inclusion criteria were qualitative studies (including grey literature) of any design, from Organisation for Economic Co-operation and Development (OECD) countries, of any date and any language. Sixteen electronic databases were searched from inception to December 2017, supplemented by reference list searching. Papers were screened, selected and quality-appraised by two reviewers using established tools from the Joanna Briggs Institute. NVivo software was used to extract study characteristics and code study findings. An inductive thematic synthesis approach was undertaken to identify descriptive themes and interpret these into higher order analytical constructs. Confidence in the review findings was assessed using Grading of Recommendations, Assessment, Development and Evaluations-Confidence in Evidence from Reviews of Qualitative Research (GRADE-CERQual). Results Fifty-seven papers (from 55 distinct studies) from 14 different OECD countries were included (50% published within the last 8 years). One-third of studies focused exclusively on maternity care experiences, whereas others covered a range of foci. No studies reported explicitly on girls’ experiences or on experiences of health service-led safeguarding interventions. Only three studies addressed psychological care. The synthesis developed 17 descriptive themes, organised into 5 analytical constructs. These related to communication, access to care, experiences of cultural dissonance/integrity, disempowering care experiences and positive care encounters. The themes illuminate significant challenges to obtaining timely and holistic care (especially for deinfibulation), and highlight different ways in which women may experience care as disrespectful, unsafe and disempowering. Key elements of ‘culturally safe care’ are identified. Conclusions This review has highlighted key knowledge gaps, especially around (1) girls’/unmarried women’s experiences and (2) the impact of recent safeguarding interventions. There is an ongoing need for community engagement, service development and staff training. PROSPERO registration number CRD420150300012015.
Opportunities for behavioral rescue under rapid environmental change

Laboratory measurements of physiological and demographic tolerances are important in understanding the impact of climate change on species diversity; however, it has been recognized that forecasts based solely on these laboratory estimates overestimate risk by omitting the capacity for species to utilize microclimatic variation via behavioral adjustments in activity patterns or habitat choice. The complex, and often context‐dependent nature, of microclimate utilization has been an impediment to the advancement of general predictive models. Here, we overcome this impediment and estimate the potential impact of warming on the fitness of ectotherms using a benefit/cost trade‐off derived from the simple and broadly documented thermal performance curve and a generalized cost function. Our framework reveals that, for certain environments, the cost of behavioral thermoregulation can be reduced as warming occurs, enabling behavioral buffering (e.g., the capacity for behavior to ameliorate detrimental impacts) and “behavioral rescue” from extinction in extreme cases. By applying our framework to operative temperature and physiological data collected at an extremely fine spatial scale in an African lizard, we show that new behavioral opportunities may emerge. Finally, we explore large‐scale geographic differences in the impact of behavior on climate‐impact projections using a global dataset of 38 insect species. These multiple lines of inference indicate that understanding the existing relationship between thermal characteristics (e.g., spatial configuration, spatial heterogeneity, and modal temperature) is essential for improving estimates of extinction risk.
An analysis of the sequence of the BAD gene among patients with maturity-onset diabetes of the young (MODY)

Abstract Background: Monogenic diabetes is a rare disease caused by single gene mutations. Maturity onset diabetes of the young (MODY) is one of the major forms of monogenic diabetes recognised in the paediatric population. To date, 13 genes have been related to MODY development. The aim of the study was to analyse the sequence of the BCL2-associated agonist of cell death (BAD) gene in patients with clinical suspicion of GCK-MODY, but who were negative for glucokinase (GCK) gene mutations. Methods: A group of 122 diabetic patients were recruited from the “Polish Registry for Paediatric and Adolescent Diabetes – nationwide genetic screening for monogenic diabetes” project. The molecular testing was performed by Sanger sequencing. Results: A total of 10 sequence variants of the BAD gene were identified in 122 analysed diabetic patients. Conclusions: Among the analysed patients suspected of MODY, one possible pathogenic variant was identified in one patient; however, further confirmation is required for a certain identification.
Sucrose-induced Receptor Kinase 1 is Modulated by an Interacting Kinase with Short Extracellular Domain*

The activation of aquaporins by a receptor kinase complex of SIRK1 and QSK1 was studied in detail. Based on phosphoproteomics, pulldown studies and physiological experiments we conclude that SIRK1 may function as a main receptor which forms a complex with coreceptor QSK1. SIRK1 can autophosphorylate and then trans-phosphorylate QSK1. Phosphorylated QSK1 enhanced and stabilized the interaction with aquaporins as substrates of the receptor kinase complex. Graphical Abstract Highlights Functional role of a yet uncharacterized receptor kinase QSK1. Activation model for SIRK1 receptor kinase in a heteromer with QSK1. Role of QSK1 in substrate recruitment and stabilization of the complex. Sucrose as a product of photosynthesis is the major carbohydrate translocated from photosynthetic leaves to growing nonphotosynthetic organs such as roots and seeds. These growing tissues, besides carbohydrate supply, require uptake of water through aquaporins to enhance cell expansion during growth. Previous work revealed Sucrose Induced Receptor Kinase, SIRK1, to control aquaporin activity via phosphorylation in response to external sucrose stimulation. Here, we present the regulatory role of AT3G02880 (QSK1), a receptor kinase with a short external domain, in modulation of SIRK1 activity. Our results suggest that SIRK1 autophosphorylates at Ser-744 after sucrose treatment. Autophosphorylated SIRK1 then interacts with and transphosphorylates QSK1 and QSK2. Upon interaction with QSK1, SIRK1 phosphorylates aquaporins at their regulatory C-terminal phosphorylation sites. Consequently, in root protoplast swelling assays, the qsk1qsk2 mutant showed reduced water influx rates under iso-osmotic sucrose stimulation, confirming an involvement in the same signaling pathway as the receptor kinase SIRK1. Large-scale phosphoproteomics comparing single mutant sirk1, qsk1, and double mutant sirk1 qsk1 revealed that aquaporins were regulated by phosphorylation depending on an activated receptor kinase complex of SIRK1, as well as QSK1. QSK1 thereby acts as a coreceptor stabilizing and enhancing SIRK1 activity and recruiting substrate proteins, such as aquaporins.
A modular Golden Gate toolkit for Yarrowia lipolytica synthetic biology

The oleaginous yeast Yarrowia lipolytica is an established host for the bio‐based production of valuable compounds and an organism for which many genetic tools have been developed. However, to properly engineer Y. lipolytica and take full advantage of its potential, we need efficient, versatile, standardized and modular cloning tools. Here, we present a new modular Golden Gate toolkit for the one‐step assembly of three transcription units that includes a selective marker and sequences for genome integration. Perfectly suited to a combinatorial approach, it contains nine different validated promoters, including inducible promoters, which allows expression to be fine‐tuned. Moreover, this toolbox incorporates six different markers (three auxotrophic markers, two antibiotic‐resistance markers and one metabolic marker), which allows the fast sequential construction and transformation of multiple elements. In total, the toolbox contains 64 bricks, and it has been validated and characterized using three different fluorescent reporter proteins. Additionally, it was successfully used to assemble and integrate a three‐gene pathway allowing xylose utilization by Y. lipolytica. This toolbox provides a powerful new tool for rapidly engineering Y. lipolytica strains and is available to the community through Addgene.
Recovery of the Cognitive Function by the Non-Invasive Multichannel Neuro-Electrostimulation for Patients with Amnesic Syndrome

The efficiency of non-invasive multichannel neuro-electrostimulation device for recovery of cognitive functions is presented in article. The article contain description of the structural schematic and algorithm of the microcontroller execution program of “SYMPATHOCOR-01” device. The possibility of the “SYMPATHOCOR-01” application for the cognitive disorders treatment is justified. As the example, results are presented that involved five middle-aged men with signs of pronounced organic amnesic syndrome, previously held specialized treatment in hospital. As a result, the stimulation rate during the three weeks of recovery could achieve stable fixing of memory and other cognitive functions in all the patients according to clinical observation and methods of neuropsychological assessments FAB, MoCA and MMSE. A significant positive trend noted by the results of the data analysis of EEG and heart rate variability. A hypothesis mechanism for clinical effect is formulated.
Emerging Transistor Technologies Capable of Terahertz Amplification: A Way to Re-Engineer Terahertz Radar Sensors

This paper reviews the state of emerging transistor technologies capable of terahertz amplification, as well as the state of transistor modeling as required in terahertz electronic circuit research. Commercial terahertz radar sensors of today are being built using bulky and expensive technologies such as Schottky diode detectors and lasers, as well as using some emerging detection methods. Meanwhile, a considerable amount of research effort has recently been invested in process development and modeling of transistor technologies capable of amplifying in the terahertz band. Indium phosphide (InP) transistors have been able to reach maximum oscillation frequency (fmax) values of over 1 THz for around a decade already, while silicon-germanium bipolar complementary metal-oxide semiconductor (BiCMOS) compatible heterojunction bipolar transistors have only recently crossed the fmax = 0.7 THz mark. While it seems that the InP technology could be the ultimate terahertz technology, according to the fmax and related metrics, the BiCMOS technology has the added advantage of lower cost and supporting a wider set of integrated component types. BiCMOS can thus be seen as an enabling factor for re-engineering of complete terahertz radar systems, for the first time fabricated as miniaturized monolithic integrated circuits. Rapid commercial deployment of monolithic terahertz radar chips, furthermore, depends on the accuracy of transistor modeling at these frequencies. Considerations such as fabrication and modeling of passives and antennas, as well as packaging of complete systems, are closely related to the two main contributions of this paper and are also reviewed here. Finally, this paper probes active terahertz circuits that have already been reported and that have the potential to be deployed in a re-engineered terahertz radar sensor system and attempts to predict future directions in re-engineering of monolithic radar sensors.
On MC-CDMA transmission system performance at nonlinear high power amplifier of transmitter over frequency selective fading channel

The study in this paper underlines the importance of correct joint selection of the spreading codes at the transmitter side and detector at the receiver side in the uplink multi-carrier code division multiple access transmission system model (MC-CDMA) in the presence of frequency selective fading environment and nonlinear distortion due to high power amplifier (HPA). For the precise overall performance, different spreading sequences (Walsh code, Gold code, orthogonal Gold code, Golay code and Zadoff-Chu code) and different kinds of receivers (minimum mean-square error receiver (MMSE-MUD) and microstatistic multi-user receiver (MSF-MUD)) are considered in this paper. In order to show the benefits of applying MSF-MUD over MMSE-MUD in presented environment, different computer simulations have been arranged. The results of our analysis will show, that the application of MSF-MUD in combination with Golay codes can outperform significantly the other tested spreading codes and receivers in AWGN as well as in frequency selective fading environment.