Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel opportunities for CFTR-targeting drug development using organoids

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR mutations lead to production of non-functional CFTR, reduced amounts of normal functioning CFTR or misfolded CFTR with defects in trafficking or function. For decades, CF treatment has been focused on the symptoms of CF, but pharmacotherapy using small molecules that target the basic defect of CF, the mutant CFTR protein, is now possible for a limited amount of subjects with CF. This raises the exciting possibility that the majority of people with CF may receive effective treatment targeting the different CFTR mutants in the future. We recently described a functional CFTR assay using rectal biopsies from subjects with CF that were cultured in vitro into self-organizing mini-guts or organoids. We here describe how this model may assist in the discovery of new CFTR-targeting drugs, the subjects that may benefit from these drugs, and the mechanisms underlying variability in CFTR genotype-phenotype relations.
Syntactic Differences Between Speech and Writing

ORE THAN FIFTY YEARS AGO, Woolbert (1922, p. 269) called attention to a linguistic problem: "Speaking and writing are alike-and different. Just how like and how different has never been adequately stated. " Less than a decade ago, Gleason (1965, p. 368) observed that the problem still had not been solved: "We know that written and spoken structures differ to some extent, and that there are differences in the underlying grammatical structure, but we have no accurate idea of their magnitude. "
The severity of obstructive sleep apnoea is associated with insulin resistance

SUMMARY Oral glucose tolerance tests (OGTT) were performed on eighteen patients with suspected obstructive sleep apnoea who also completed a whole‐night polygraphic recording with oximetry. Insulin resistance indices (IRI) were calculated as the product of areas under glucose and insulin curves. In the resulting multiple regression analysis the dependent variable was IRI and the independent variables were age, body mass index (BMI) and the number of nocturnal hypoxic episodes with over 4% desaturation per hour (ODI4).
Fibronectin and β-Catenin Act in a Regulatory Loop in Dermal Fibroblasts to Modulate Cutaneous Healing*

β-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate β-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating β-catenin and found an increase in β-catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3β-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased β-catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of β-catenin signaling. Because fibronectin is a transcriptional target of β-catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.
Enhanced Spoken Term Detection Using Support Vector Machines and Weighted Pseudo Examples

Spoken term detection (STD) is a key technology for retrieval of spoken content, which will be very important to retrieve and browse multimedia content over the Internet. The discriminative capability of machine learning methods has recently been used to facilitate STD. This paper presents a new approach to improve STD using support vector machines (SVM) based on acoustic information. The concept of pseudo-relevance feedback (PRF) well used in the retrieval of text, image and video is used here. The basic idea of using PRF here is to assume some spoken segments in the first-pass retrieved results are relevant (or pseudo-relevant) and some others irrelevant (or pseudo-irrelevant), and take these segments as positive and negative examples to train a query-specific SVM. This SVM is then used for re-ranking the first-pass retrieved results, and only the re-ranked results are shown to the user. In this paper, feature vectors representing the spoken segments based on acoustic information to be used in SVM are considered and analyzed. Furthermore, conventionally in PRF the items with the highest and lowest scores in the first-pass retrieved results are respectively taken as pseudo-relevant and -irrelevant, but in this way some incorrect examples are inevitably included in the training data especially when the recognition accuracy is poor. Here we further propose an enhanced SVM which not only better selects positive/negative examples considering the reliability of the spoken segments, but emphasizes more on more reliable training examples by modifying the SVM formulation. Experiments on two different sets of spoken archives with different speaking styles and different levels of recognition accuracies demonstrated significant improvements offered by the proposed approaches.
Longitudinal Magnetic Resonance Imaging Study of Cortical Development through Early Childhood in Autism

Cross-sectional magnetic resonance imaging (MRI) studies have long hypothesized that the brain in children with autism undergoes an abnormal growth trajectory that includes a period of early overgrowth; however, this has never been confirmed by a longitudinal study. We performed the first longitudinal study of brain growth in toddlers at the time symptoms of autism are becoming clinically apparent using structural MRI scans at multiple time points beginning at 1.5 years up to 5 years of age. We collected 193 scans on 41 toddlers who received a confirmed diagnosis of autistic disorder at ∼48 months of age and 44 typically developing controls. By 2.5 years of age, both cerebral gray and white matter were significantly enlarged in toddlers with autistic disorder, with the most severe enlargement occurring in frontal, temporal, and cingulate cortices. In the longitudinal analyses, which we accounted for age and gender effect, we found that all regions (cerebral gray, cerebral white, frontal gray, temporal gray, cingulate gray, and parietal gray) except occipital gray developed at an abnormal growth rate in toddlers with autistic disorder that was mainly characterized by a quadratic age effect. Females with autistic disorder displayed a more pronounced abnormal growth profile in more brain regions than males with the disorder. Given that overgrowth clearly begins before 2 years of age, future longitudinal studies would benefit from inclusion of even younger populations as well as further characterization of genetic and other biomarkers to determine the underlying neuropathological processes causing the onset of autistic symptoms.
Influence of Culture Media on Growth and Pigment Production by Fusarium moniliforme KUMBF1201 Isolated from Paddy Field Soil

A new strain of Fusarium moniliforme KUMBF1201 was isolated from paddy field soil for the production of natural pigment. From an industrial point of view the necessity to obtain a suitable medium for enhanced pigment production by Fusarium moniliforme KUMBF1201 was the aim of this work. Out of eight different solid and six liquid media studied, Fusarium moniliforme KUMBF1201 grew well on Potato Dextrose Agar (PDA) and Potato Dextrose Broth (PDB) media. It required optimum temperature (28±1°C), pH (5.5) for the growth, pigment production and sporulation. From the results, the glucose (2 %) as the carbon source and yeast extract (2 %) as nitrogen source has played a major role in enhanced cell growth and pigment production.
The spectral slope coefficient of chromophoric dissolved organic matter (S275–295) as a tracer of terrigenous dissolved organic carbon in river‐influenced ocean margins

The present study demonstrates that the spectral slope coefficient of chromophoric dissolved organic matter (CDOM) between 275 nm and 295 nm (S275–295) can be used as a tracer of the percent terrigenous dissolved organic carbon (%tDOC) in river‐influenced ocean margins, where rivers exert an important control on carbon dynamics and CO2 fluxes. Absorption coefficients of CDOM and concentrations of dissolved organic carbon (DOC) and dissolved lignin were measured on a seasonal basis in the Mississippi and Atchafalaya rivers and in surface waters of the northern Gulf of Mexico (NGoM). A strong, linear relationship between lignin concentrations and CDOM absorption coefficients indicated lignin is an important chromophore in this environment. The dual nature of lignin as an important chromophore in CDOM and as a terrigenous component of DOC facilitated development of the tracer. The applicability of the tracer relies on the existence of a strong, nonlinear relationship between S275–295 and the DOC‐normalized lignin yield in rivers and along the freshwater–marine continuum in the NGoM. Physical mixing and the effects of photodegradation on S275–295 and dissolved lignin were largely responsible for maintaining this relationship, suggesting the tracer is applicable to surface waters of most river‐influenced ocean margins. The spectral slope coefficient (S275–295) provides new capabilities to trace tDOC on synoptic scales of relevance to ocean margins and represents an important tool for improving ocean carbon budgets.
Five year results of a prospective very low calorie diet or conventional weight loss programme in type 2 diabetes.

AIMS To complete 5-year follow-up of an intensive weight loss programme in established type 2 diabetic subjects. METHODS Forty-five obese type 2 diabetic subjects, Body mass index (BMI) > 30, expressed interest in an intensive weight loss programme. Group 1 comprised 15 who selected very low calorie diet (VLCD), Group 2, 15 selected intensive conventional diet and exercise (ICD), 15 failed to follow either programme. Group sessions of eight to 15 subjects continued weekly for 6 months, then monthly for 12 months with prospective recording at 3, 6 and 12 months and then annually of quality of life, BMI, waist/hip ratio, blood pressure, fasting blood glucose, serum fructosamine and serum lipids. RESULTS Weight loss was slower in the intensive conventional diet group than in the VLCD group, but better maintained at 5 years: group 1, 4.8 +/- 6 kg; group 2, 8.9 +/- 4 kg. In the intensive conventional diet group, 5 year high-density lipoprotein cholesterol was increased 1.78 +/- 0.26 mmol L-1 vs. 1.10 +/- 0.32 mmol L-1 at baseline, and diastolic blood pressure reduced 74.5 +/- 13.3 vs. 85.5 +/- 13.3 at baseline, both P < 0.05. CONCLUSIONS Out-patient VLCD treatment proved safe and effective in overweight diabetic subjects but those who chose conventional diet and exercise had a slower but more sustained weight loss. Diabetic patients willing to attempt VLCD may safely lose sufficient weight to allow major surgery, but weight regain is inevitable. Patients willing to undertake a long-term group programme of conventional diet can sustain significant weight loss for 5 years, but still require antidiabetic medication.
Generation and Characterization of Novel Human IRAS Monoclonal Antibodies

Imidazoline receptors were first proposed by Bousquet et al., when they studied antihypertensive effect of clonidine. A strong candidate for I1R, known as imidazoline receptor antisera-selected protein (IRAS), has been cloned from human hippocampus. We reported that IRAS mediated agmatine-induced inhibition of opioid dependence in morphine-dependent cells. To elucidate the functional and structure properties of I1R, we developed the newly monoclonal antibody against the N-terminal hIRAS region including the PX domain (10–120aa) through immunization of BALB/c mice with the NusA-IRAS fusion protein containing an IRAS N-terminal (10–120aa). Stable hybridoma cell lines were established and monoclonal antibodies specifically recognized full-length IRAS proteins in their native state by immunoblotting and immunoprecipitation. Monoclonal antibodies stained in a predominantly punctate cytoplasmic pattern when applied to IRAS-transfected HEK293 cells by indirect immunofluorescence assays and demonstrated excellent reactivity in flow immunocytometry. These monoclonal antibodies will provide powerful reagents for the further investigation of hIRAS protein functions.
Obesity, insulin resistance, and type 1 diabetes mellitus

Purpose of reviewTo summarize recent studies about obesity, insulin resistance, and type 1 diabetes mellitus (T1DM). Recent findingsOverweight and obesity continue to be prevalent among individuals with T1DM. Obesity rates appear to have reached a plateau among children with T1DM in some parts of the world. The risk for development of T1DM is increased by obesity and may occur at an earlier age among obese individuals with a predisposition. Obesity increases the risk for comorbidities among individuals with T1DM, especially metabolic syndrome, and microvascular and macrovascular diseases. Metformin, glucagon-like peptide-1 agonist therapy, sodium glucose cotransporter-2 inhibitor therapy, and bariatric surgery may be beneficial therapies for glucose control, comorbidity management, and obesity among adults with T1DM. Insulin resistance may be improved among obese individuals with T1DM by biguanides (metformin) and glucagon-like peptide-1 agonists (exenatide). SummaryWe review the last 18 months of literature on obesity, insulin resistance, and T1DM to highlight new epidemiologic results and treatments.
Chronopharmacokinetics and cardiovascular effects of nifedipine.

Circadian phase dependency in pharmacokinetics and hemodynamic effects on blood pressure and heart rate of different galenic formulations of nifedipine (immediate-release, sustained-release, and i.v. solution) were studied in healthy subjects or in hypertensive patients. Pharmacokinetics of immediate-release but not sustained-release and i.v. nifedipine were dependent on time of day: immediate-release nifedipine had higher Cmax (peak concentration) and shorter tmax (time-to-peak concentration) after morning than evening application, and bioavailability in the evening was reduced by about 40%. Circadian rhythm in estimated hepatic blood flow as determined by indocyanine green kinetics may contribute to these chronokinetics. A circadian time dependency was also found in nifedipine-induced effects on blood pressure and heart rate as monitored by 24-h ambulatory blood pressure measurements. In conclusion, the dose response relationship of oral nifedipine is influenced by the circadian organization of the cardiovascular system as well as by the galenic drug formulation.
The effect of instructional and motivational self-talk on volleyball serving performance.

In today’s world, physical activities are of great importance because of having educational and therapeutic effects and human’s need for motion and activity. At the same time, physical activities are controlled by preeminent parts of mind. Therefore, the present study seeks to examine the effectiveness of instructional and motivational self-talk on volleyball serving, so that we would examine the effect of one of these preeminent functions of mind. This is a quasi-experimental research, featuring a pretest and post-test with control group. The statistical population of this study includes undergraduate female students of non-physical education majors in central Isfahan Payam-e Noor University in the academic year 2013-2014. The statistical sample of this study includes 114 subjects who have been selected using multi-stage random sampling method. AAHPERD's standard test of volleyball serving and selftalk questionnaire were used for data collection. ANOVA was used to determine the effect of self-talk on participants’ motor performance, and Tukey’s post hoc test was run to determine the differences between the groups. The level of significance was considered to be 0.05. Results of this study showed that instructional self-talk did not exert a significant effect on volleyball serving performance, but motivational self-talk had a significant impact on this performance. Moreover, the effect of instructional and motivational self-talk on this performance was not different among the groups. The present study shows that different types of self-talk have different effects on volleyball serving performance.
Correlates of African-American Undergraduate Student Achievement: Implications for the Prize Initiative

Male and female African-American college students (n = 131) at a large urban predominately White publicly funded institution participated in a survey measuring the effect of a multitude of psychosocial constructs and factors on grade point average (GPA). Part One of the study's analysis focused on three of the six total constructs examined within this study: Barriers to Achievement, Ethnic Identity, and Intrapersonal Attributes. Cronbach's alpha tests and item analyses found that each subscale was determined sufficiently reliable with the exception of Ethnic Identity. Pearson correlations indicated that the Interpersonal Attributes subscale and its individual factors were most significant in predicting academic success. The Barriers to Achievement subscale did not significantly affect student GPA, though family problems and maintaining employment were found detrimental to GPA. While the Ethnic Identity construct was not reliable, the factor “ethnic fit” was significant.
Which Cue to “Want?” Central Amygdala Opioid Activation Enhances and Focuses Incentive Salience on a Prepotent Reward Cue

The central nucleus of the amygdala (CeA) helps translate learning into motivation, and here, we show that opioid stimulation of CeA magnifies and focuses learned incentive salience onto a specific reward cue (pavlovian conditioned stimulus, or CS). This motivation enhancement makes that cue more attractive, noticeable, and liable to elicit appetitive and consummatory behaviors. To reveal the focusing of incentive salience, we exploited individual differences in an autoshaping paradigm in which a rat prefers to approach, nibble, and sniff one of two reward-associated stimuli (its prepotent stimulus). The individually prepotent cue is either a predictive CS+ that signals reward (8 s metal lever insertion) or instead the metal cup that delivers sucrose pellets (the reward source). Results indicated that CeA opioid activation by microinjection of the μ agonist DAMGO (0.1 μg) selectively and reversibly enhanced the attractiveness of whichever reward CS was that rat's prepotent cue. CeA DAMGO microinjections made rats more vigorously approach their particular prepotent CS and to energetically sniff and nibble it in a nearly frenzied consummatory manner. Only the prepotent cue was enhanced as an incentive target, and alternative cues were not enhanced. Conversely, inactivation of CeA by muscimol microinjection (0.25 μg) suppressed approach, nibbles, and sniffs of the prepotent CS. Confirming modulation of incentive salience, unconditioned food intake was similarly increased by DAMGO microinjection and decreased by muscimol in CeA. We conclude that opioid neurotransmission in CeA helps determine which environmental stimuli become most “wanted,” and how “wanted” they become. This may powerfully guide reward-seeking behavior.
Echocardiographic and morphological correlations in tetralogy of Fallot.

AIMS Our aim was to clarify the location and structure of the outlet septum relative to the free-standing subpulmonary infundibulum in the setting of tetralogy of Fallot and to examine its relationship to the other components of the subpulmonary outflow tract, determining their potential influence on clinical outcome. METHODS AND RESULTS We studied prospectively 41 patients with tetralogy of Fallot (mean age 14 +/- 10.9 months) prior to surgical repair, and compared them with 15 patients undergoing closure of a ventricular septal defect associated with malalignment of the outlet septum but no subpulmonary infundibular stenosis (Eisenmenger ventricular septal defect), and 20 healthy controls. We also examined available autopsied hearts from cases with uncorrected tetralogy of Fallot (8) and Eisenmenger ventricular septal defect (13). Data were indexed for body surface area, and diameter of the tricuspid valve, respectively. The overall length of the subpulmonary infundibulum, including the extent of the muscular outlet septum, was significantly greater for patients with tetralogy of Fallot compared to normals (2.34 +/- 0.6 vs 1.46 +/- 0.34 cm/BSA0.5, P<0.001), whereas the difference between those with tetralogy of Fallot and an Eisenmenger ventricular septal defect was confined to the degree of narrowing of the subpulmonary outlet (0.43 +/- 0.22 vs 2.17 +/- 0.64 cm/BSA0.5, P<0.001). Within the tetralogy of Fallot group, there were linear relationships between deviation of the outlet septum (r= -0.61, P<0.005) and the diameter of the pulmonary valvar orifice (r=0.75, P<0.001), suggesting that growth of the pulmonary arteries may be related to this feature. When patients requiring a transannular patch as part of their surgical repair were compared with those not needing this procedure, differences were found in the diameter of the pulmonary valvar orifice and the pulmonary trunk, but not in the dimensions of the outlet septum. CONCLUSION The position of the outlet septum in relationship to the remainder of the muscular subpulmonary infundibulum represents a hallmark of tetralogy of Fallot, permitting its differentiation from Eisenmenger ventricular septal defects and normal hearts.
Variability modeling in the real: a perspective from the operating systems domain

Variability models represent the common and variable features of products in a product line. Several variability modeling languages have been proposed in academia and industry; however, little is known about the practical use of such languages. We study and compare the constructs, semantics, usage and tools of two variability modeling languages, Kconfig and CDL. We provide empirical evidence for the real-world use of the concepts known from variability modeling research. Since variability models provide basis for automated tools (feature dependency checkers and product configurators), we believe that our findings will be of interest to variability modeling language and tool designers.
Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis

The chemokine monocyte chemoattractant protein (MCP)‐1/CCL2 and its receptor CCR2 have been strongly implicated in disease pathogenesis in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS), whereas data on the CCL2–CCR2 axis are scarce in MS. We studied the expression of CCR2 on leukocytes in blood and cerebrospinal fluid (CSF) from patients with monosymptomatic optic neuritis and MS, and the concentration of CCL2 in the CSF from these patients. Results were compared with the results in non‐inflammatory neurological controls and were correlated with other parameters (magnetic resonance imaging and CSF data). Our findings suggest a limited role for CCL2/CCR2 in early active MS.