Miracle-dz/UniFAR-FTUs huggingface dataset:
Deficiencies in tRNA synthetase editing activity cause cardioproteinopathy

Significance Misfolded proteins are a hallmark of diverse human cardiac disorders including desmin-related cardiomyopathy and systemic amyloidosis. Defects in translational fidelity can cause neurodegeneration, however the consequences of mistranslation in other tissues, including the heart, are unknown. The fidelity of protein synthesis is largely ensured by aminoacyl-tRNA synthetases, and many tRNA synthetases contain editing domains that hydrolyze mischarged tRNAs, preventing incorporation of incorrect amino acids into proteins. Here, we show that diminished editing efficacy of the alanyl-tRNA synthetase causes misfolded protein aggregation and cell death in the mammalian heart. These results illuminate the importance of translational fidelity in cardiac homeostasis and suggest that genetic factors that disrupt the accuracy of translation may contribute to proteinopathies of the heart and other tissues. Misfolded proteins are an emerging hallmark of cardiac diseases. Although some misfolded proteins, such as desmin, are associated with mutations in the genes encoding these disease-associated proteins, little is known regarding more general mechanisms that contribute to the generation of misfolded proteins in the heart. Reduced translational fidelity, caused by a hypomorphic mutation in the editing domain of alanyl-tRNA synthetase (AlaRS), resulted in accumulation of misfolded proteins in specific mouse neurons. By further genetic modulation of the editing activity of AlaRS, we generated mouse models with broader phenotypes, the severity of which was directly related to the degree of compromised editing. Severe disruption of the editing activity of AlaRS caused embryonic lethality, whereas an intermediate reduction in AlaRS editing efficacy resulted in ubiquitinated protein aggregates and mitochondrial defects in cardiomyocytes that were accompanied by progressive cardiac fibrosis and dysfunction. In addition, autophagic vacuoles accumulated in mutant cardiomyocytes, suggesting that autophagy is insufficient to eliminate misfolded proteins. These findings demonstrate that the pathological consequences of diminished tRNA synthetase editing activity, and thus translational infidelity, are dependent on the cell type and the extent of editing disruption, and provide a previously unidentified mechanism underlying cardiac proteinopathy.
Information needs in parents of children with a rheumatic disease.

BACKGROUND AND OBJECTIVE Incorporating the patient's perspective and expectations into the delivery of health care has become an important indicator of today's quality of medical care. Our aim was consequently to explore the information needs of parents of children with juvenile idiopathic arthritis and other rheumatic diseases. MATERIALS AND METHODS Cross-sectional, anonymous survey using a purpose-designed questionnaire, which separately assessed sources of information and topics. With respect to sources, we also asked about their degree of helpfulness, and regarding topics, we also asked about further interests (information needs). The questionnaire was sent to 146 families continuously attending our paediatric rheumatology outpatient clinic. The response rate was 79.5%. The mean age of the children was 6.9 +/- 4.3 years, 69% were girls and disease duration averaged 2.6 +/- 4.3 years. Mean Child Health Assessment Questionnaire score as a measure of functional disability was 0.259 (+/-0.45; range 0.0-2.13). RESULTS Regarding sources, those with a professional medical background were appreciated, while information from friends and family members, in particular, was not. Overall, parents considered themselves well-informed. Parents had frequently received information on core domains of medical aspects. They described deficits related to psychosocial impact, to (vocational) education and to complementary therapy. However, their interest in further information was high almost irrespective of the amount of prior information. CONCLUSION For further tailored information and support strategies it should be taken into account that even for topics largely covered by usual medical advice, residual interest and information needs of parents remain high.
Pure Protein Bilayers and Vesicles from Native Fungal Hydrophobins

Pure protein bilayers and vesicles are formed using the native, fungal hydrophobin HFBI. Bilayers with hydrophobic (red) and hydrophilic (blue) core are produced and, depending on the type of core, vesicles in water, oily media, and even in air can be created using microfluidic jetting. Vesicles in water are even able to incorporate functional gramicidin A pores.
GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time

Significance How animals track the seasons has long been a mystery. We found a mechanism that explains how day length is encoded within the neuronal network of suprachiasmatic nucleus (SCN). Using an integrated approach combining experiments and modeling, we find evidence for changes in the coupling in the SCN that divides the clock oscillations into two clusters as a function of day length. We show that asymmetric distribution of intracellular chloride across the SCN causes this coupling change. Blocking GABA or chloride import erases the oscillator organization formed by day-length entrainment. These demonstrate that coupling through GABA is a key ingredient of day-length encoding in the SCN. The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock gene Bmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABAA-mediated synaptic input. We show that increasing day-length changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABAA signaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation–inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN.
Information flow between interacting human brains: Identification, validation, and relationship to social expertise

Significance Social interaction is the likely driver of human brain evolution, critical for health, and underlies phenomena as varied as childhood development, stock market behavior, and much of what is studied in the humanities. However, appropriate experimental methods to study the underlying brain processes are still developing and technically challenging. Here, we extend previous pioneering approaches in neuroimaging [functional MRI (fMRI) hyperscanning] to provide a method for studying information flow between interacting humans in a two-person approach. A scan environment enabling synchronized data acquisition and interaction-based fMRI tasks is described. We provide a generally applicable analysis method to identify interacting brain systems. Specific social brain systems are identified as drivers of interaction in humans, and we find a link to a measure of social expertise. Social interactions are fundamental for human behavior, but the quantification of their neural underpinnings remains challenging. Here, we used hyperscanning functional MRI (fMRI) to study information flow between brains of human dyads during real-time social interaction in a joint attention paradigm. In a hardware setup enabling immersive audiovisual interaction of subjects in linked fMRI scanners, we characterize cross-brain connectivity components that are unique to interacting individuals, identifying information flow between the sender’s and receiver’s temporoparietal junction. We replicate these findings in an independent sample and validate our methods by demonstrating that cross-brain connectivity relates to a key real-world measure of social behavior. Together, our findings support a central role of human-specific cortical areas in the brain dynamics of dyadic interactions and provide an approach for the noninvasive examination of the neural basis of healthy and disturbed human social behavior with minimal a priori assumptions.
Nanoscale Polymer Metal–Organic Framework Hybrids for Effective Photothermal Therapy of Colon Cancers

A UiO-66 core with various sizes acts as heterogeneous nucleation center and enables aniline polymerization under ambient conditions. The as-synthesized UiO-66@PAN possesses uniform size and excellent dispersibility in aqueous solution. UiO-66@PAN can be internalized by cancer cells via endocytosis, and indicates significant photothermal therapeutic effect in vitro, and can effectively inhibit the growth of colon cancers in vivo.
Temperature‐Mediated Selective Growth of MoS2/WS2 and WS2/MoS2 Vertical Stacks on Au Foils for Direct Photocatalytic Applications

A growth-temperature-mediated two-step chemical vapor deposition strategy is designed to synthesize MoS2 /WS2 and WS2 /MoS2 stacks on Au foils. Predominantly A-A stacked MoS2 /WS2 and A-B stacked WS2 /MoS2 are selectively achieved and confirmed. Relative enhancements or reductions in photocatalytic activities of MoS2 /WS2 or WS2 /MoS2 are observed under illumination, because the type-II band alignment enables directional electron flow from electrode to active site.
How do children perceive health to be affected by domestic water carrying? Qualitative findings from a mixed methods study in rural South Africa.

BACKGROUND Nearly 50% of South African children lack access to clean safe water and many regularly carry water loads. The health effects of carrying water have not been well researched or considered when estimating the burden of disease due to suboptimal water supply. Improved access to safe water has potential to create important health and economic benefits, by reducing childhood exposure to risk factors for injury or disease. The aim of this study was to identify which domains of health children perceive as affected by water carrying. METHODS Qualitative research was used within a broader mixed methods design to investigate children's perceptions about health and water carrying in Limpopo Province, South Africa. Qualitative data from eight semi-structured interviews and three 'natural group meetings', involving a sample of 30 children, were analysed using the framework approach of Ritchie and Spencer. The results were mapped to the International Classification of Functioning Disability and Health (ICF). RESULTS Children broadly conceptualize and describe health to include the functions they perform and activities in which they participate. They perceived water carrying as impacting upon health in various ways, for example to make life better by facilitating water usage, or to make life worse through accidents and pain. Children's accounts demonstrate that they can identify and explain complex interactions between activities, participation and health. CONCLUSIONS The ICF framework facilitates the communication of children's perceptions of health and of relationships between health and water carrying. The model thus derived from their views incorporates not only commonly accepted conceptualizations of health condition, body structure and physiological function, but also of functioning through activities and social participation. Children's accounts suggest a possible association between water carrying and symptoms typical of musculoskeletal disorders. However, further research into the strength of association between water carrying and musculoskeletal disorders is needed.
Asphyxia-activated corticocardiac signaling accelerates onset of cardiac arrest

Significance How does the heart of a healthy individual cease to function within just a few minutes in the absence of oxygen? We addressed this issue by simultaneously examining the heart and the brain in animal models during asphyxiation and found that asphyxia markedly stimulates neurophysiological and neurochemical activities of the brain. Furthermore, previously unidentified corticocardiac coupling showed increased intensity as the heart deteriorated. Blocking efferent input to the heart markedly increased survival time of both the heart and the brain. The results show that targeting the brain’s outflow may be an effective strategy to delay the death of the heart and the brain from asphyxia. The mechanism by which the healthy heart and brain die rapidly in the absence of oxygen is not well understood. We performed continuous electrocardiography and electroencephalography in rats undergoing experimental asphyxia and analyzed cortical release of core neurotransmitters, changes in brain and heart electrical activity, and brain–heart connectivity. Asphyxia stimulates a robust and sustained increase of functional and effective cortical connectivity, an immediate increase in cortical release of a large set of neurotransmitters, and a delayed activation of corticocardiac functional and effective connectivity that persists until the onset of ventricular fibrillation. Blocking the brain’s autonomic outflow significantly delayed terminal ventricular fibrillation and lengthened the duration of detectable cortical activities despite the continued absence of oxygen. These results demonstrate that asphyxia activates a brainstorm, which accelerates premature death of the heart and the brain.
Flexible brain network reconfiguration supporting inhibitory control

Significance The ability to inhibit distracting stimuli from interfering with goal-directed behavior is crucial for success in most spheres of life and is disrupted across a variety of disorders. Here we show via network analysis that global brain connectivity patterns change when inhibitory demands increase, including greater communication efficiency and robustness against disruption. In addition, the connectivity pattern of regions previously identified as crucial for inhibitory control (right inferior frontal gyrus and anterior insula) become more central network hubs, whereas dorsal anterior cingulate becomes more interconnected within its local network. Findings provide a framework to elucidate and differentiate difficulties in inhibitory control in clinical groups by examining connectivity of specific global network metrics and/or critical hubs known to influence inhibitory control. The ability to inhibit distracting stimuli from interfering with goal-directed behavior is crucial for success in most spheres of life. Despite an abundance of studies examining regional brain activation, knowledge of the brain networks involved in inhibitory control remains quite limited. To address this critical gap, we applied graph theory tools to functional magnetic resonance imaging data collected while a large sample of adults (n = 101) performed a color-word Stroop task. Higher demand for inhibitory control was associated with restructuring of the global network into a configuration that was more optimized for specialized processing (functional segregation), more efficient at communicating the output of such processing across the network (functional integration), and more resilient to potential interruption (resilience). In addition, there were regional changes with right inferior frontal sulcus and right anterior insula occupying more central positions as network hubs, and dorsal anterior cingulate cortex becoming more tightly coupled with its regional subnetwork. Given the crucial role of inhibitory control in goal-directed behavior, present findings identifying functional network organization supporting inhibitory control have the potential to provide additional insights into how inhibitory control may break down in a wide variety of individuals with neurological or psychiatric difficulties.
Inositol phosphate pathway controls transcription of telomeric expression sites in trypanosomes

Significance African trypanosomes cause human and animal diseases and evade the host immune systems by periodically switching which variant surface glycoprotein (VSG) they express. The mechanisms that result in expression of one of the numerous VSG genes at a time and the switching of expression between different VSG genes are poorly understood. We show that specific steps in the inositol phosphate (IP) pathway control both monoallelic VSG gene transcription and the switching of VSG gene expression. The data indicate that the cellular amounts, locations, and molecular interactions of specific IP pathway enzymes and their metabolites control both processes. The results offer new drug targets and insights into the epigenetic control of gene expression by this biologically ubiquitous pathway. African trypanosomes evade clearance by host antibodies by periodically changing their variant surface glycoprotein (VSG) coat. They transcribe only one VSG gene at a time from 1 of about 20 telomeric expression sites (ESs). They undergo antigenic variation by switching transcription between telomeric ESs or by recombination of the VSG gene expressed. We show that the inositol phosphate (IP) pathway controls transcription of telomeric ESs and VSG antigenic switching in Trypanosoma brucei. Conditional knockdown of phosphatidylinositol 5-kinase (TbPIP5K) or phosphatidylinositol 5-phosphatase (TbPIP5Pase) or overexpression of phospholipase C (TbPLC) derepresses numerous silent ESs in T. brucei bloodstream forms. The derepression is specific to telomeric ESs, and it coincides with an increase in the number of colocalizing telomeric and RNA polymerase I foci in the nucleus. Monoallelic VSG transcription resumes after reexpression of TbPIP5K; however, most of the resultant cells switched the VSG gene expressed. TbPIP5K, TbPLC, their substrates, and products localize to the plasma membrane, whereas TbPIP5Pase localizes to the nucleus proximal to telomeres. TbPIP5Pase associates with repressor/activator protein 1 (TbRAP1), and their telomeric silencing function is altered by TbPIP5K knockdown. These results show that specific steps in the IP pathway control ES transcription and antigenic switching in T. brucei by epigenetic regulation of telomere silencing.
Families affected by childhood cancer: an analysis of the provision of social support within online support groups.

BACKGROUND With increasing access to the Internet, there are new opportunities available to families to seek information, advice and support about childhood cancer online. METHODS A total of 487 messages were retrieved from three childhood cancer online support groups and were analysed using deductive thematic analysis for the presence of support-intended communication using Cutrona and Suhr's social support typology. In addition, the messages were examined for negative experiences or disadvantages. RESULTS The results revealed the presence of five types of social support: emotional, informational, esteem support and tangible assistance. In addition, some potential limitations of online support were identified, including a lack of responses and difficulties in maintaining relationships outside the online group context. CONCLUSION This study suggests that online support groups may offer the potential to support family members of children with cancer. In particular, it may be a useful resource for those seeking emotional and information support. However, there may be limitations associated with the use of online support groups.
Spatial proximity of homologous alleles and long noncoding RNAs regulate a switch in allelic gene expression

Significance In diploid organisms, trans-allelic interactions control gene expression, providing a tight spatial and temporal level of transcription regulation. Although homologous trans-allelic interactions are quite abundant in various organisms such as Drosophila, plants, and fungi, they have not been widely reported in mammals. This article demonstrates that such a trans-allelic association is evident in mammals and involves the homologous spatial proximity of Tnfα alleles as a prerequisite for the biallelic expression of the Tnfα gene. We believe the phenomenon we describe here provides mechanistic insights for the regulation of gene allelic expression and mRNA dosage control necessary for fine-tuning physiological processes in mammals. Physiological processes rely on the regulation of total mRNA levels in a cell. In diploid organisms, the transcriptional activation of one or both alleles of a gene may involve trans-allelic interactions that provide a tight spatial and temporal level of gene expression regulation. The mechanisms underlying such interactions still remain poorly understood. Here, we demonstrate that lipopolysaccharide stimulation of murine macrophages rapidly resulted in the actin-mediated and transient homologous spatial proximity of Tnfα alleles, which was necessary for the mono- to biallelic switch in gene expression. We identified two new complementary long noncoding RNAs transcribed from the TNFα locus and showed that their knockdown had opposite effects in Tnfα spatial proximity and allelic expression. Moreover, the observed spatial proximity of Tnfα alleles depended on pyruvate kinase muscle isoform 2 (PKM2) and T-helper-inducing POZ-Krüppel-like factor (ThPOK). This study suggests a role for lncRNAs in the regulation of somatic homologous spatial proximity and allelic expression control necessary for fine-tuning mammalian immune responses.
Parent-adolescent dyads: association of parental autonomy support and parent-adolescent shared diabetes care responsibility.

PURPOSE Parent-adolescent shared responsibility for diabetes care is advocated by experts to achieve beneficial diabetes and psychosocial outcomes for adolescents with type 1 diabetes. Parental autonomy support may be a way to facilitate this sharing. In this dyadic study, we examined parental diabetes-specific autonomy support experienced by adolescents with type 1 diabetes and their parents (n = 89 dyads), and its association with their experience of shared diabetes care responsibility. METHODS Path analysis was used to test an Actor-Partner Interdependence Model for parental autonomy support effects on shared responsibility. This was a secondary analysis of data from 89 parent-early/mid-adolescent dyads. RESULTS Actor effects were identified. Parents' and adolescents' perceptions of parental autonomy support were associated with their respective reports of shared diabetes care responsibility. One partner effect was identified. Adolescents' reports of parental autonomy support were associated with parents' reports of shared responsibility. Parents and adolescents held similar views of autonomy support but discrepant views of shared responsibility. Older adolescents perceived less parental autonomy support. CONCLUSION Increasing parental autonomy support may facilitate parent-adolescent sharing of diabetes care responsibility. Adolescent and parent perceptions influence each other and need to be considered when working with them to strengthen parental autonomy support.