Miracle-dz/UniFAR-FTUs huggingface dataset:
Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short‐rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis–van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.
Vestibular Stimulation Interferes with the Dynamics of An Internal Representation of Gravity

The remembered vanishing location of a moving target has been found to be displaced downward in the direction of gravity (representational gravity) and more so with increasing retention intervals, suggesting that the visual spatial updating recruits an internal model of gravity. Despite being consistently linked with gravity, few inquiries have been made about the role of vestibular information in these trends. Previous experiments with static tilting of observers’ bodies suggest that under conflicting cues between the idiotropic vector and vestibular signals, the dynamic drift in memory is reduced to a constant displacement along the body's main axis. The present experiment aims to replicate and extend these outcomes while keeping the observers’ bodies unchanged in relation to physical gravity by varying the gravito-inertial acceleration using a short-radius centrifuge. Observers were shown, while accelerated to varying degrees, targets moving along several directions and were required to indicate the perceived vanishing location after a variable interval. Increases of the gravito-inertial force (up to 1.4G), orthogonal to the idiotropic vector, did not affect the direction of representational gravity, but significantly disrupted its time course. The role and functioning of an internal model of gravity for spatial perception and orientation are discussed in light of the results.
Genetic contribution of retinoid‐related genes to neural tube defects

Rare variants are considered underlying causes of complex diseases. The complex and severe group of disorders called neural tube defects (NTDs) results from failure of the neural tube to close during early embryogenesis. Neural tube closure requires the coordination of numerous signaling pathways, including the precise regulation of retinoic acid (RA) concentration, which is controlled by enzymes involved in RA synthesis and degradation. Here, we used a case–control mutation screen study to reveal rare variants in retinoid‐related genes in a Han Chinese NTD population by sequencing six genes in 355 NTD cases and 225 controls. More specific rare variants were found in exonic and upstream regions in NTD cases. The RA‐responsive genes CYP26A1, CRABP1, and ALDH1A2 harbored NTD‐specific rare variants in their upstream regions. Unexpectedly, the majority of missense variants in NTD cases were found in CYP26B1, which encodes a RA degradation enzyme, whereas no missense variants in this gene were found in controls. Functional analysis indicated that the CYP26B1 NTD variants were inefficient in the degradation of RA using assays of RA‐induced transcription and RA‐initiated neuronal differentiation. Our study supports the contribution of rare variants in RA‐related genes to the etiology of human NTDs.
MeCP2 AT‐Hook1 mutations in patients with intellectual disability and/or schizophrenia disrupt DNA binding and chromatin compaction in vitro

Mutations in the methyl‐CpG‐binding protein‐2 gene (MECP2) are commonly associated with Rett syndrome. However, it has long been appreciated that there exists a spectrum of neuropsychiatric phenotypes associated with MECP2 variants. The most frequent Rett missense mutations are located in either the methyl‐CpG‐binding domain (MBD) or transcription repression domain (TRD). Clinical roles for mutations in other domains such as the intervening domain (ID) or AT‐Hook domains have yet to be determined. Here, we report functional analysis of MECP2 missense mutations, located in AT‐Hook1 within the ID, in a large Pakistani family with childhood onset cognitive decline and schizophrenia (SCZ), de novo in a girl with atypical Rett syndrome, and de novo in a woman with SCZ. We show that both p.Arg190His and p.Arg190Cys affect the ability of MeCP2 to bind to AT‐rich DNA, also the brain‐derived neurotrophic factor (BDNF) promoter, with the more drastic effects seen for p.Arg190Cys. Both mutations also affect nuclear chromatin clustering in vitro. These data support a possible molecular link between MECP2 AT‐Hook1 mutations and psychosis. Given the ongoing large‐scale whole exome and whole genome sequencing projects for psychiatric disorders, our findings suggest that rare missense variants in MECP2 be carefully evaluated for molecular consequences.
The early processing of metaphors and similes: Evidence from eye movements

This eye movement study examined how people read nominal metaphors and similes in order to investigate how the surface form, or wording, of these expressions affected early processing. Participants silently read metaphors (knowledge is a river) and similes (knowledge is like a river). The identical words were used in the topic–vehicle pair (knowledge–river) in both conditions. Experiments 1 and 2 demonstrated longer reading times and a higher proportion of regressions in metaphors than in similes. Familiarity modulated later metaphor effects in Experiment 1, but not in Experiment 2. Reading ability did not modulate the metaphor effects in Experiment 2. Results indicate that readers revised their initial interpretation of metaphors before moving on to read new text. This suggests that readers did not initially hold figurative interpretations of apt nominal metaphors that are somewhat familiar. Metaphor interpretation may be fast, but it is not easy.
Visual cortex activation predicts visual preference: Evidence from Britain and Egypt

The term “Perceptual goodness” refers to the strength, obviousness, or salience of a visual configuration. Recent work has found strong agreement between theoretical, neural, and behavioural measures of perceptual goodness across a wide range of different symmetrical visual patterns. We used these pattern types again to explore the relationship between perceptual goodness and aesthetic preference. A group of 50 U.K. participants rated the patterns on a 0 to 100 scale. Preference ratings positively correlated with four overlapping measures of perceptual goodness. We then replicated this finding in Egypt, suggesting that our results reflect universal aspects of human preference. The third experiment provided consistent results with a different stimulus set. We conclude that symmetry is an aesthetic primitive that is attractive because of the way it is processed by the visual system.
Social cognition in premotor and parietal cortex

Abstract Socially correct behavior requires constant observation of the social environment. Behavior that was appropriate a few seconds ago is not guaranteed to be appropriate now. The brain keeps the eyes focused on the current social space and constantly updates its internal representation of the environment and social context. Monitoring the behavior of others is essential for this updating. The neural systems involved in perceiving the actions of others have been explored extensively, but the detailed, quantitative character of the system at the single-cell level remains poorly understood. To address this question, we used the new technique of multidimensional recording to record neuronal activity in monkeys simultaneously from ventral premotor cortex (PM) and parietal cortex in the left hemisphere while they performed a food grab task. Motion-related (MR) response was shown by 35% (52/148) of PM neurons and 54% (94/174) of parietal neurons, meaning their activity increased in response to various combinations of arm motions made by self and/or other. Both areas showed robust lateralized preference to Self–Right action. When it came to recognizing the actions of the other monkey, PM-MR neurons showed the same kind of right-arm preference as self-action while parietal-MR neurons, in contrast, did not show arm preference. And while both areas discriminated self-action from other, a significantly larger proportion of PM-MR neurons did so. These results suggest that PM neurons provide information about an action's agent and effector as primitives of action cognition within the mirror neuron network, while parietal neurons represent social space and participate in the recognition of another agent's actions in relation to one's own actions within the parieto-prefrontal network.
Cannabis‐related deficits in real‐world memory

Research shows that cannabis users exhibit deficits in prospective memory (PM) and executive function, which persist beyond acute intoxication. However, many studies rely on self‐reports of memory failures or use laboratory‐based measures that may not mimic functional deficits in the real world. The present study aimed to assess real‐world memory functioning.
The neural processing of voluntary completed, real and virtual violent and nonviolent computer game scenarios displaying predefined actions in gamers and nongamers

Abstract Studies investigating the effects of violent computer and video game playing have resulted in heterogeneous outcomes. It has been assumed that there is a decreased ability to differentiate between virtuality and reality in people that play these games intensively. FMRI data of a group of young males with (gamers) and without (controls) a history of long-term violent computer game playing experience were obtained during the presentation of computer game and realistic video sequences. In gamers the processing of real violence in contrast to nonviolence produced activation clusters in right inferior frontal, left lingual and superior temporal brain regions. Virtual violence activated a network comprising bilateral inferior frontal, occipital, postcentral, right middle temporal, and left fusiform regions. Control participants showed extended left frontal, insula and superior frontal activations during the processing of real, and posterior activations during the processing of virtual violent scenarios. The data suggest that the ability to differentiate automatically between real and virtual violence has not been diminished by a long-term history of violent video game play, nor have gamers' neural responses to real violence in particular been subject to desensitization processes. However, analyses of individual data indicated that group-related analyses reflect only a small part of actual individual different neural network involvement, suggesting that the consideration of individual learning history is sufficient for the present discussion.
Phase II trial of dasatinib in triple-negative breast cancer: results of study CA180059.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #3118 Background : Dasatinib (SprycelR; BMS-354825) is a potent orally-available inhibitor of Src-family kinases and other kinases with anti-proliferative, anti-osteoclastic and anti-metastatic activity demonstrated pre-clinically. Expression profiling suggested that basal-like cancers may be preferentially sensitive to dasatinib. Methods : A Phase II single-agent trial of dasatinib, using a continuous schedule, was performed in patients with advanced triple-negative (as proxy for basal-like) breast cancers. Subjects were required to have measurable locally-advanced or metastatic triple-negative (ER/PR-negative, Her2-normal) disease and prior anthracycline and/or taxane therapy. A 2-stage Gehan design was adopted, with RECIST-defined response as primary endpoint; subjects discontinued for toxicity were considered non-responders. The original dasatinib dose of 100 mg BID (n=21) was reduced to 70 mg BID (n=23) to improve tolerability. Biomarkers were analyzed in tumor and plasma samples obtained for PK analysis. Results : From 12/06 through 12/07, 44 subjects were treated at 14 institutions: median age 55 yrs, median time from diagnosis 30 mo, prior therapy for advanced disease in 29 (66%). Of 43 response-evaluable subjects, 7 discontinued for toxicity prior to on-study assessment. Of 36 subjects with radiographic assessment, there were 2 confirmed PR [1 continues >1 year + 1 discontinued for intolerance at week 16] plus 2 SD lasting >16 weeks. Four additional subjects had transient clinical benefit reflected by improvement in bone pain (anecdotal) or short-term tumor shrinkage (reductions of 11 - 29%). Tolerability was improved at a dose of 70 mg compared with 100 mg BID. In preliminary analysis, fewer subjects experienced any serious adverse event (13% at 70 mg BID vs 48% at 100 mg BID), fewer reported Grade 3 toxicity, including gastrointestinal (10% vs 26%), pleural effusion (4% vs 9%), generalized edema (0% vs 9%) or pericardial effusion (0% vs 9%), and fewer had dasatinib dose reduction (24% vs 61%). Fatigue, myalgia/arthralgia and headache were comparable at the two doses. No Grade 4 drug-related events occurred. Grade 3-4 abnormal laboratory values were uncommon. Biomarker and PK data will be presented. Conclusions : Modest but encouraging single-agent activity was observed with dasatinib in patients with advanced triple-negative breast cancers, with clinical benefit rate of 9.3% (4/43). Future studies are warranted to address optimal dose and schedule of dasatinib in combination with chemotherapy for this challenging tumor type. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3118.
Through the eyes of the own-race bias: Eye-tracking and pupillometry during face recognition

People are generally better at remembering faces of their own race than faces of a different race, and this effect is known as the own-race bias (ORB) effect. We used eye-tracking and pupillometry to investigate whether Caucasian and Asian face stimuli elicited different-looking patterns in Caucasian participants in a face-memory task. Consistent with the ORB effect, we found better recognition performance for own-race faces than other-race faces, and shorter response times. In addition, at encoding, eye movements and pupillary responses to Asian faces (i.e., the other race) were different from those to Caucasian faces (i.e., the own race). Processing of own-race faces was characterized by more active scanning, with a larger number of shorter fixations, and more frequent saccades. Moreover, pupillary diameters were larger when viewing other-race than own-race faces, suggesting a greater cognitive effort when encoding other-race faces.
Diagnostic and Prognostic Value of Serum Cystatin C in Critically Ill Children With Acute Kidney Injury

Objectives: We aimed to evaluate the value of serum cystatin C for detection of acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease categories in critically ill children and to investigate whether serum cystatin C was associated with outcome. Design: Prospective cohort study. Setting: PICU of a tertiary-care university hospital. Patients: A heterogeneous population of critically ill children. Interventions: None. Measurements and Main Results: Blood and 24-hour urine samples were collected daily over the first 2 days after PICU admission for measurement of serum cystatin C, serum creatinine, and creatinine clearance. Acute kidney injury was classified by pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease criteria. One hundred twenty-two children were prospectively enrolled; 40 (32.8%) developed acute kidney injury. Serum cystatin C was higher in patients with acute kidney injury compared with those who did not develop acute kidney injury at PICU admission (median, 0.90 mg/L vs 0.51 mg/L) and on the first (1.12 mg/L vs 0.57 mg/L) and second PICU days (1.15 mg/L vs 0.58 mg/L). Serum creatinine was higher in acute kidney injury group only on the first (0.50 mg/dL vs 0.40 mg/dL) and second PICU days (0.60 mg/dL vs 0.40 mg/dL). Serum cystatin C was increasingly higher according to acute kidney injury severity (Failure > Injury > Risk). Area under the receiver operating characteristic curve of cystatin C for acute kidney injury detection was 0.89. Serum cystatin C greater than 0.70 mg/L was associated with longer length of PICU stay (adjusted hazard ratio, 1.64) and prolonged duration of mechanical ventilation (adjusted hazard ratio, 1.82). Conclusions: Cystatin C is an early and accurate biomarker for acute kidney injury and pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease categories, and it is associated with adverse clinical outcomes in a heterogeneous population of critically ill children.
The cognitive demands on cooperation in social dilemmas: An fMRI study

This study uses fMRI to investigate the cognitive demands of decision-making in two types of cooperation games: a prisoner's dilemma (PD) eliciting a temptation to free-ride, leading to a dominant, self-interested response, and a stag hunt (SH) that has no dominant response but offers pay-off incentives that make mutual cooperation collectively beneficial but risky. Consequently, the PD poses greater conflict between self- and collective interest, greater demands for computational reasoning to derive the optimal solution, and greater demands for mentalizing to infer the intentions of others. Consistent with these differences between the two games, the results indicate that the PD is associated with increased activity in the anterior cingulate gyrus, prefrontal cortex, parietal lobe, and temporoparietal junction. With less conflict, the demands for computation and mentalizing are reduced in the SH, and cooperation levels increase dramatically. The differences in brain activation elicited by the different incentive structures of the PD and the SH appear to be independent of individual differences in revealed social preferences.
Emotional intelligence correlates with functional responses to dynamic changes in facial trustworthiness

Emotional intelligence (EI) refers to a constellation of traits, competencies, or abilities that allow individuals to understand emotional information and successfully navigate and solve social/emotional problems. While little is known about the neurobiological substrates that underlie EI, some evidence suggests that these capacities may involve a core neurocircuitry involved in emotional decision-making that includes the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), insula, and amygdala. In a sample of 39 healthy volunteers (22 men; 17 women), scores on the Bar-On EQ-i (a trait/mixed model of EI) and Mayer–Salovey–Caruso Emotional Intelligence Test (MSCEIT; an ability model of EI) were correlated with functional magnetic resonance imaging responses during brief presentations of moving facial expressions that changed in the level of perceived trustworthiness. Core emotion neurocircuitry was responsive to dynamic changes in facial features, regardless of whether they reflected increases or decreases in apparent trustworthiness. In response to facial movements indicating decreasing trustworthiness, MSCEIT correlated positively with functional responses of the vmPFC and rostral ACC, whereas the EQ-i was unrelated to regional activation. Systematic differences in EI ability appear to be significantly related to the responsiveness of the vmPFC and rostral ACC to facial movements suggesting potential trustworthiness.
Eye contact during live social interaction modulates infants’ oscillatory brain activity

We examined infants’ oscillatory brain activity during a live interaction with an adult who showed them novel objects. Activation in the alpha frequency range was assessed. Nine-month-old infants responded with desynchronization of alpha-band activity when looking at an object together with an adult during a social interaction involving eye contact. When infant and experimenter only looked at the object without engaging in eye contact, no such effect was observed. Results are interpreted in terms of activation of a generic semantic knowledge system induced by eye contact during a social interaction.
Compassion, guilt and innocence: An fMRI study of responses to victims who are responsible for their fate

Compassion is a human feeling towards an individual who is suffering. However, the responses toward a victim are not always compassionate and may, for example, be moderated by the perceived responsibility of the victim. In the present study, we investigated the neural correlates of compassion and specifically differentiated the responses to other individuals’ misfortunes depending on whether the victim was responsible for the event that occurred. In particular, we identified increased activation of the left insula, medial prefrontal cortex (mPFC), and adjacent anterior cingulate cortex when the participants read sentences with innocent compared with responsible victims. The reverse contrast revealed increased activation of the bilateral temporoparietal junction, right precuneus, and right dorsolateral prefrontal cortex (dlPFC). Using a psycho-physiological interaction (PPI) analysis, we demonstrated that in the responsible condition, right dlPFC activation was accompanied by decreased activation in the left insula, anterior cingulate cortex (ACC), and mPFC. This inverse effective connectivity illustrates the antagonism of the dlPFC and mPFC in compassion-related appraisal of external events. More specifically, our results imply that regulatory mechanisms of compassion are related to the perception of responsibility.
Update on Evidence: Family Caregivers in the Home

Home Health Care Management & Practice / April 2007 / Volume 19, Number 3, 206-208 DOI: 10.1177/1084822306297897 ©2007 Sage Publications Family caregivers are vital in the home care of patients with chronic conditions. To update the evidence related to family caregivers, a literature search was done in the Cumulative Index of Nursing and Allied Health Literature bibliographic database for the years 2005 and 2006.
Association study between glutathione S‐transferase GST‐M1, GST‐T1, and GST‐P1 polymorphisms and tardive dyskinesia

Data from several studies suggest that oxidative stress may play a role in the pathophysiology of tardive dyskinesia (TD). Glutathione S‐transferase (GST) enzymes play important roles in protecting cells against oxidative stress. In the present study, we investigated the hypothesis that polymorphisms in genes for these detoxifying enzymes can influence susceptibility to TD in patients with schizophrenia.