Miracle-dz/UniFAR-FTUs huggingface dataset:
Emerging treatment options for the mucopolysaccharidoses

Roberto Giugliani1–6 Andressa Federhen1,4 Andre Anjos Silva1,5 Camila Matzenbacher Bittar1,5 Carolina Fischinger Moura de Souza1 Cristina Brinckmann Oliveira Netto1 Fabiana Quoos Mayer2,7 Guilherme Baldo1,2,8 Ursula Matte1–5 1Medical Genetics Service, 2Gene Therapy Center, Hospital de Clinicas (HCPA), Porto Alegre, RS, Brazil; 3Department of Genetics, 4Postgraduate Program in Child and Adolescent Health, 5Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; 6National Institute of Population Medical Genetics (INAGEMP), Porto Alegre, RS, Brazil; 7Fundacao Estadual de Pesquisa Agropecuaria (FEPAGRO), Eldorado do Sul, RS, Brazil; 8Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
Fast glutamate uptake via EAAT2 shapes the cone‐mediated light offset response in bipolar cells

Excitatory amino acid transporters (EAATs) are responsible for extracellular glutamate uptake within the retina, and are expressed by retinal neurons and Müller cells. Their role within glutamatergic synapses is not completely understood. In the salamander retina, five distinct EAAT‐encoding genes have been cloned, making the amphibian retina an excellent system to study EAAT function. This study focused on sEAAT2, which is expressed in photoreceptor terminals and Off‐bipolar cells in two isoforms, sEAAT2A and sEAAT2B. Using whole‐cell patch‐clamp recording, florescence imaging and antibody labelling methods, we systematically studied the functions of these two isoforms at the synapse between photoreceptors and bipolar cells, both in dark and with photic stimulation. Both sEAAT2A and sEAAT2B were sensitive to dihydrokainic acid (DHKA), a known EAAT2‐specific inhibitor. Each isoform of sEAAT2 was found to play a role in tonic glutamate uptake at the cone synapse in darkness. Furthermore, presynaptic sEAAT2A strongly suppressed the rapid, transient glutamate signal from cones following light‐offset. This was achieved by quickly binding exocytosed glutamate, which subsequently limited glutamate spillover to adjacent receptors at postsynaptic sites. Since the intensity and duration of photic stimulation determine the magnitude of these cone transient signals, we postulate that presynaptic cone EAATs contribute to the encoding of contrast sensitivity in cone vision.
Quinidine interaction with Shab K+ channels: pore block and irreversible collapse of the K+ conductance

Quinidine is a commonly used antiarrhythmic agent and a tool to study ion channels. Here it is reported that quinidine equilibrates within seconds across the Sf9 plasma membrane, blocking the open pore of Shab channels from the intracellular side of the membrane in a voltage‐dependent manner with 1:1 stoichiometry. On binding to the channels, quinidine interacts with pore K+ ions in a mutually destabilizing manner. As a result, when the channels are blocked by quinidine with the cell bathed in an external medium lacking K+, the Shab conductance GK collapses irreversibly, despite the presence of a physiological [K+] in the intracellular solution. The quinidine‐promoted collapse of Shab GK resembles the collapse of Shaker GK observed with 0 K+ solutions on both sides of the membrane: thus the extent of GK drop depends on the number of activating pulses applied in the presence of quinidine, but is independent of the pulse duration. Taken together the observations indicate that, as in Shaker, the quinidine‐promoted collapse of Shab GK occurs during deactivation of the channels, at the end of each activating pulse, with a probability of 0.1 per pulse at −80 mV. It appears that when Shab channels are open, the pore conformation able to conduct is stable in the absence of K+, but on deactivation this conformation collapses irreversibly.
Complementary spatial firing in place cell–interneuron pairs

The hippocampal formation plays a pivotal role in representing the physical environment. While CA1 pyramidal cells display sharply tuned location‐specific firing, the activity of many interneurons show weaker but significant spatial modulation. Although hippocampal interneurons were proposed to participate in the representation of space, their interplay with pyramidal cells in formation of spatial maps is not well understood. In this study, we investigated the spatial correlation between CA1 pyramidal cells and putative interneurons recorded concurrently in awake rats. Positively and negatively correlated pairs were found to be simultaneously present in the CA1 region. While pyramidal cell–interneuron pairs with positive spatial correlation showed similar firing maps, negative spatial correlation was often accompanied by complementary place maps, which could occur even in the presence of a monosynaptic excitation between the cells. Thus, location‐specific firing increase of hippocampal interneurons is not necessarily a simple product of excitation by a pyramidal cell with a similarly positioned firing field. Based on our observation of pyramidal cells firing selectively in the low firing regions of interneurons, we speculate that the location‐specific firing of place cells is partly determined by the location‐specific decrease of interneuron activity that can release place cells from inhibition.
TRPC6 channels stimulated by angiotensin II are inhibited by TRPC1/C5 channel activity through a Ca2+‐ and PKC‐dependent mechanism in native vascular myocytes

The present work investigated interactions between TRPC1/C5 and TRPC6 cation channel activities evoked by angiotensin II (Ang II) in native rabbit mesenteric artery vascular smooth muscle cells (VSMCs). In low intracellular Ca2+ buffering conditions (0.1 mm BAPTA), 1 nm and 10 nm Ang II activated both 2 pS TRPC1/C5 channels and 15–45 pS TRPC6 channels in the same outside‐out patches. However, increasing Ang II to 100 nm abolished TRPC6 activity but further increased TRPC1/C5 channel activity. Comparison of individual patches revealed an inverse relationship between TRPC1/C5 and TRPC6 channel activity suggesting that TRPC1/C5 inhibits TRPC6 channel activity. Inclusion of anti‐TRPC1 and anti‐TRPC5 antibodies, raised against intracellular epitopes, in the patch pipette solution blocked TRPC1/C5 channel currents but potentiated by about six‐fold TRPC6 channel activity evoked by 1–100 nm Ang II in outside‐out patches. Bath application of T1E3, an anti‐TRPC1 antibody raised against an extracellular epitope, also increased Ang II‐evoked TRPC6 channel activity. With high intracellular Ca2+ buffering conditions (10 mm BAPTA), 10 nm Ang II‐induced TRPC6 channel activity was increased by about five‐fold compared to channel activity with low Ca2+ buffering. In addition, increasing intracellular Ca2+ levels ([Ca2+]i) at the cytosolic surface inhibited 10 nm Ang II‐evoked TRPC6 channel activity in inside‐out patches. Moreover, in zero external Ca2+ (0 [Ca2+]o) 100 nm Ang II induced TRPC6 channel activity in outside‐out patches. Pre‐treatment with the PKC inhibitor, chelerythrine, markedly increased TRPC6 channel activity evoked by 1–100 nm Ang II and blocked the inhibitory action of [Ca2+]i on TRPC6 channel activity. Co‐immunoprecipitation studies shows that Ang II increased phosphorylation of TRPC6 proteins which was inhibited by chelerythrine, 0 [Ca2+]o and the anti‐TRPC1 antibody T1E3. These results show that TRPC6 channels evoked by Ang II are inhibited by TRPC1/C5‐mediated Ca2+ influx and stimulation of PKC, which phosphorylates TRPC6 subunits. These conclusions represent a novel interaction between two distinct vasoconstrictor‐activated TRPC channels expressed in the same native VSMCs.
Segmental patterns of vestibular‐mediated synaptic inputs to axial and limb motoneurons in the neonatal mouse assessed by optical recording

Proper control of movement and posture occurs partly via descending projections from the vestibular nuclei to spinal motor circuits. Days before birth in rodents, vestibulospinal neurons develop axonal projections that extend to the spinal cord. How functional these projections are just after birth is unknown. Our goal was to assess the overall functional organization of vestibulospinal inputs to spinal motoneurons in a brainstem–spinal cord preparation of the neonatal mouse (postnatal day (P) 0–5). Using calcium imaging, we recorded responses evoked by electrical stimulation of the VIIIth nerve, in many motoneurons simultaneously throughout the spinal cord (C2, C6, T7, L2 and L5 segments), in the medial and lateral motor columns. Selective lesions in the brainstem and/or spinal cord distinguished which tracts contributed to the responses: those in the cervical cord originated primarily from the medial vestibulospinal tracts but with a substantial contribution from the lateral vestibulospinal tract; those in the thoracolumbar cord originated exclusively from the lateral vestibulospinal tract. In the thoracolumbar but not the cervical cord, excitatory commissural connections mediated vestibular responses in contralateral motoneurons. Pharmacological blockade of GABAA receptors showed that responses involved a convergence of excitatory and inhibitory inputs which in combination produced temporal response patterns specific for different segmental levels. Our results show that by birth vestibulospinal projections in rodents have already established functional synapses and are organized to differentially regulate activity in neck and limb motoneurons in a tract‐ and segment‐specific pattern similar to that in adult mammals. Thus, this particular set of descending projections develops several key features of connectivity appropriately at prenatal stages. We also present novel information about vestibulospinal inputs to axial motoneurons in mammals, providing a more comprehensive platform for future studies into the overall organization of vestibulospinal inputs and their role in regulating postural stability.
Reduction in social activities mediates the relationship between diarrhea and distress in rectal/anal cancer survivors

Over 45 000 new cases of rectal and anal cancer (RACa) are diagnosed yearly in the United States. Treatment typically requires a combination of surgery, chemotherapy, and radiation and may result in persistent bowel dysfunction. Bowel symptoms include increased frequency and urgency, incontinence, leakage/soilage, abnormal sensation or painful bowel movements, evacuation difficulties, and diarrhea. Deterioration of bowel functioning has been described with concurrent disruptions in daily routines, sexual difficulties as well as lowered emotional well‐being and quality of life (QOL). Symptoms are frequent and can be severe, especially in the first year after treatment but may persist beyond that as well. Five years postsurgery, 5% to 63% of patients persistent bowel problems. In colorectal cancer, greater severityofbowel symptomswas related to increaseddepressionandanxiety. Understanding themechanism bywhich bowel dysfunction affects psychological variables is an important step to improvingRACasurvivorship. The objective of this study was to examine the relationship among bowel dysfunction and the psychosocial variables of social functioning, depression, and anxiety in a sample of RACa survivors. It was hypothesized that greater severity of bowel symptoms would lead to increased depression and anxiety and that disruptions in social functioning would mediate the relationship between bowel dysfunction and increased depression and anxiety. Given the chronic nature of these side effects and associated impairments in daily functioning and QOL, findings may have important implications for posttreatment survivorship care.
Cognitive reactions of nurses exposed to cancer patients' traumatic experiences: A qualitative study to identify triggers of the onset of compassion fatigue

Nurses in cancer care are considered to be at risk for compassion fatigue because they are frequently exposed to patients' traumatic experiences. However, only a few effective empirical studies have been conducted in this field, and cognitive factors in particular have not been sufficiently studied. This study aims to describe the components of nurses' cognitive reactions from their exposure to cancer patients' traumatic experience to the onset of compassion fatigue.
Future orientation in adolescent and young adult cancer survivors and unaffected peers

Diagnosis and treatment of childhood cancer is a significant, stressful life event that shifts adolescent and young adult cancer survivors' (AYACS) perspectives and delays normative transitions to adulthood (eg, completing education and partnering). Shifts in AYACS future‐ oriented perspectives may explain delays in adult role transitions. Future orientation is the cognitive, motivational, affective, and temporal aspects of individuals' beliefs about their futures and is important for identifying goals and behaviors needed to accomplish goals to support goal achievement. Experiencing cancer may alter how AYACS conceptualize their futures; however, this has not been empirically investigated due to the absence of a validated measure of future orientation for AYACS. Understanding future orientation in AYACS and whether it differs from peers without cancer is important because future orientation is modifiable andmay be useful in supporting the well‐being of AYACS. As a first step toward investigating the utility of future orientation in AYACS, this study examined the reliability of a measure of future orientation in a sample of AYACSs compared with unaffected peers.
Simultaneous Analysis of Two Phytohormones in Chili and Wheat Using HPLC Using Novel Calixarene as SPE Sorbent.

In this paper, a high-performance liquid chromatography with ultraviolet (HPLC-UV) detection method, using tetraazacalix[2]arene[2]triazine-modified silica gel (NCS) as solid-phase extraction (SPE) sorbent, was developed for extracting and purifying the two phytohormones (indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA)) in chili and wheat samples from different organs of chili and wheat. The limits of detection were about 0.02 and 0.04 μg/mL, and the limits of quantification were 0.04 and 0.20 μg/mL for IAA and IBA, respectively. The intraday and interday RSDs (n = 6) of peak areas and retention times were in the range of 0.76-1.20%. In addition, overall recoveries through the extraction and NCS-SPE purification ranged from 78.4% to 86.8% for IAA and IBA were obtained. Compared with the commercial SPE sorbents, NCS featured excellent selectivity to retain IAA and IBA in the sample matrices. In addition, the results more clearly indicated that high IAA and IBA content existed in roots and leaves of wheat and chili; in other organs of the plants, the concentration of the two phytohormones is lower. The results from theoretical computation were consistent with the retention behaviors of IAA and IBA on NCS. The proposed NCS-SPE-HPLC method is highly effective for trace analysis of the two phytohormones in plant samples.
Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms

Non‐technical summary Wasting and severely impaired function of skeletal muscle is frequently observed in critically ill intensive care unit (ICU) patients, with negative consequences for recovery and quality of life. An experimental rat ICU model has been used to study the mechanisms underlying this unique wasting condition in neuromuscularly blocked and mechanically ventilated animals at durations varying between 6 h and 2 weeks. The complete ‘mechanical silencing’ of skeletal muscle (removal of both weight bearing and activation) resulted in a specific myopathy frequently observed in ICU patients and characterized by a preferential loss of the motor protein myosin. A highly complex and coordinated protein synthesis and degradation system was observed in the time‐resolved analyses. It is suggested the ‘mechanical silencing’ of skeletal muscle is a dominating factor triggering the specific myopathy associated with the ICU intervention, and strongly supporting the importance of interventions counteracting the complete unloading in ICU patients.
l‐Dopa activates histaminergic neurons

Non‐technical summary L‐Dopa is an effective medication for Parkinson's disease (PD), but loses efficiency with time. This can be delayed by treatment with histamine antagonists. We show histaminergic neurons in the hypothalamus controlling wakefulness are excited by L‐Dopa, which they can take up and transform to dopamine. They innervate the whole brain, in particular the striatum which is deficient of dopamine in PD. We revealed mechanisms of excitation of histaminergic neurons by L‐Dopa and dopamine opening new avenues for the treatment of PD and sleep disorders.
Management of cystic fibrosis related diabetes: A survey of UK cystic fibrosis centers

Cystic fibrosis related diabetes (CFRD), a poor prognostic factor in cystic fibrosis (CF), is an increasing problem and guidelines regarding its management have recently been published. However, the evidence base for CFRD screening and diagnosis is not comprehensive and its current management in the UK is unknown. We therefore conducted a questionnaire survey of all recognized UK CF centers to assess clinical practice and determine adherence to these recent recommendations.
Congruent Validity and Reliability of Two Metabolic Systems to Measure Resting Metabolic Rate

Abstract Determine the congruent validity and intra- and inter-day reliability of RMR measures assessed by the ParvoMedics Trueone 2 400 hood dilution method (Parvo) and Cosmed K4b2 (Cosmed) breath-by-breath metabolic systems. Participants underwent 6 RMR assessments over 2 consecutive mornings, 3 with the Parvo (Day 1: Parvo 1; Day 2: Parvo 2, 3), 3 with the Cosmed (Day 1: Cosmed 1; Day 2: Cosmed 2, 3). Measured VE, FEO2, FECO2, VO2, VCO2, kcal/day, and HR values were averaged over a minimum of 10 min. Intra- and inter-day reliability within each system was determined with RMANOVA, and congruent validity was assessed via paired sample t-tests. 31 participants (13 females, 18 males; 27.3±7 years, 24.8±3.1 kg.m2) completed the study. There were no significant differences in any within or between day Parvo values or Cosmed values. When systems were compared, there was a significant difference between VE (Parvo2: 25.03 L/min, Cosmed2: 8.98 L/min) and FEO2 (Parvo2: 19.68%, Cosmed2: 16.63%), however, there were no significant difference in device-calculated RMR (kcals/day). The Parvo and Cosmed are reliable metabolic system with no intra- or inter-day differences in RMR. Due to differences in measurement technology, FEO2, VE were significantly different between systems, but the resultant RMR values were not significantly different.
Replicate Measurements of Haemoglobin Mass during a Single Day are Feasible and Precise

Abstract Duplicate haemoglobin mass (Hbmass) measurements are recommended before and after altitude training sojourns to identify individual adaptations in athletes with a high level of certainty. Duplicate measurements reduce typical error (TE) and disclose measurement outliers, but are usually made on separate days, which is not a practical protocol for routine services in elite sport settings. The aim of this study was therefore to investigate whether it is safe (carboxyhaemoglobin<10%) to measure Hbmass twice on the same day and to compare TE with measurements made on separate days. 18 healthy men completed 3 different procedures to measure Hbmass twice a day with the carbon monoxide rebreathing method: A (Hbmass measured twice within 6 h), B (dito A, combined with 1 h of hyperoxic training between the tests), C (dito B, within 2 h). First Hbmass measurements of the 3 test days served as procedure D. Carboxyhaemoglobin did not exceed 10% in any procedure. TE and confidence limits for procedures A, B, C and D were 1.4% (1.0–2.1%), 1.1% (0.8–1.7%), 1.3% (1.0–2.0%) and 1.5% (1.2–2.1%), respectively. Duplicate measurements of Hbmass on the same day are feasible and show TE similar to triplicate measurements on separate days.
Emphasizing technology: socio-technical implications

Purpose – This article aims to focus attention on users of information technology (IT), especially mobile telephony. It focuses on what people actually say about mobile technology but also aims to pay attention to what they do not talk about, what is found in the silence, especially with new technology when much can be taken for granted. This latter is, according to Foucault, even more important to understand.Design/methodology/approach – The research draws on empirical research through 11 semi‐structured interviews and interviews with five focus groups, comprising between four and eight care assistants in each group. The interviews were with three women and three men between 25‐70 years old, five female public sector middle managers and care assistants from five focus groups at social services departments in the north of Sweden. A Foucauldian approach is adopted to interpret the findings and explore how their locations within the circuits of socio‐technical networks engender uncertainty with mobile techn.
Excluded again: implications of integrated e-government systems for those at the margins

Purpose – This paper seeks to highlight a poorly‐understood dimension of digital exclusion that is not related to access to information and communication technologies (ICTs), but rather to the reduction in flexibility for providing and administering public services following the implementation of an integrated e‐government system.Design/methodology/approach – A case study of a project focused on reducing barriers to the delivery of driver licensing services to a remote indigenous community in Australia was undertaken and the data were analysed using Kling et al.'s socio‐technical interaction network (STIN) modelling approach.Findings – The paper makes four recommendations to improve the licensing situation for the community that are induced from the findings. In particular the paper draws attention to the need to carefully analyse possible negative impacts of any e‐government initiative for those at the margins of society.Research limitations/implications – The paper aims to analyse the current situation .
Introduction

Orin S. Levine, Niranjan Bhat, Jane Crawley, Maria Deloria-Knoll, Andrea N. DeLuca, Amanda J. Driscoll, Daniel R. Feikin, Ruth A. Karron, David R. Murdoch, Katherine L. O'Brien, and J. Anthony G. Scott 1International Vaccine Access Center, and 2Center for Immunization Research, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; 3Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom; 4Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia; 5Department of Pathology, University of Otago Christchurch, and 6Canterbury Health Laboratories, Christchurch, New Zealand; and 7KEMRI-Welcome Trust Research Programme, Kilifi, Kenya
Adenylate cyclase 1 promotes strengthening and experience‐dependent plasticity of whisker relay synapses in the thalamus

Non‐technical summary Cyclic AMP‐mediated signalling plays an important role in the development and plasticity of synaptic circuits, and adenylate cyclase 1 is a major enzyme for cyclic AMP production in the brain of newborns. We show that in mice deficient in adenylate cyclase 1, developmental strengthening and experience‐dependent plasticity of excitatory synapses are impaired, but developmental pruning of the synapses is not affected. These results increase our understanding of the processes by which neuronal circuits are formed and modified during development.