Miracle-dz/UniFAR-FTUs huggingface dataset:
BMPR2 Mutations Influence Phenotype More Obviously in Male Patients With Pulmonary Arterial Hypertension

Background—BMPR2 mutations predispose to idiopathic and heritable pulmonary arterial hypertension (IPAH and HPAH). The influence of BMPR2 mutations on clinical outcome is not concordant in different ethnic groups. Although the BMPR2 mutation spectrum and mutation rate in Chinese PAH patients has been reported previously, the influence of genotype on phenotype and whether this influence is associated with sex have not been investigated. Methods and Results—We analyzed data from 305 PAH patients considered as either idiopathic or heritable who underwent genetic counseling in Shanghai Pulmonary Hospital. The clinical, functional, and hemodynamic characteristics of BMPR2 mutation carriers and noncarriers were compared. The more severe hemodynamic compromise at diagnosis in BMPR2 mutation carriers versus noncarriers is concordant with other ethnic groups. In the Chinese PAH cohort, BMPR2 mutations were associated with a higher risk of mortality after adjustment for age and sex (hazard ratio, 1.971; 95% confidence interval, 1.121–3.466; P=0.018). The overall survival difference between mutation carriers and noncarriers was more obvious in male patients, which was reflected by a higher mortality risk of male mutation carriers than that of male noncarriers after adjustment for age at diagnosis (hazard ratio, 3.702; 95% confidence interval, 1.416–9.679; P=0.008). In females, this trend did not reach statistical significance. Conclusions—BMPR2 mutations influence phenotype more obviously in male PAH patients. The pathogenesis of female PAH patients is more complicated, and the influence of BMPR2 mutations may be modified by other unknown factors, making disparities in the prognosis between female mutation carriers and noncarriers less evident.
Unbiased, High-Throughput Electron Microscopy Analysis of Experience-Dependent Synaptic Changes in the Neocortex

Neocortical circuits can be altered by sensory and motor experience, with experimental evidence supporting both anatomical and electrophysiological changes in synaptic properties. Previous studies have focused on changes in specific neurons or pathways—for example, the thalamocortical circuitry, layer 4–3 (L4–L3) synapses, or in the apical dendrites of L5 neurons— but a broad-scale analysis of experience-induced changes across the cortical column has been lacking. Without this comprehensive approach, a full understanding of how cortical circuits adapt during learning or altered sensory input will be impossible. Here we adapt an electron microscopy technique that selectively labels synapses, in combination with a machine-learning algorithm for semiautomated synapse detection, to perform an unbiased analysis of developmental and experience-dependent changes in synaptic properties across an entire cortical column in mice. Synapse density and length were compared across development and during whisker-evoked plasticity. Between postnatal days 14 and 18, synapse density significantly increases most in superficial layers, and synapse length increases in L3 and L5B. Removal of all but a single whisker row for 24 h led to an apparent increase in synapse density in L2 and a decrease in L6, and a significant increase in length in L3. Targeted electrophysiological analysis of changes in miniature EPSC and IPSC properties in L2 pyramidal neurons showed that mEPSC frequency nearly doubled in the whisker-spared column, a difference that was highly significant. Together, this analysis shows that data-intensive analysis of column-wide changes in synapse properties can generate specific and testable hypotheses about experience-dependent changes in cortical organization. SIGNIFICANCE STATEMENT Development and sensory experience can change synapse properties in the neocortex. Here we use a semiautomated analysis of electron microscopy images for an unbiased, column-wide analysis of synapse changes. This analysis reveals new loci for synaptic change that can be verified by targeted electrophysiological investigation. This method can be used as a platform for generating new hypotheses about synaptic changes across different brain areas and experimental conditions.
Microwell engineering characterization for mammalian cell culture process development

Experimentation in shaken microplate formats offers a potential platform technology for the rapid evaluation and optimization of cell culture conditions. Provided that cell growth and antibody production kinetics are comparable to those found in currently used shake flask systems then the microwell approach offers the possibility to obtain early process design data more cost effectively and with reduced material requirements. This work describes a detailed engineering characterization of liquid mixing and gas–liquid mass transfer in microwell systems and their impact on suspension cell cultures. For growth of murine hybridoma cells producing IgG1, 24‐well plates have been characterized in terms of energy dissipation (P/V) (via Computational Fluid Dynamics, CFD), fluid flow, mixing and oxygen transfer rate as a function of shaking frequency and liquid fill volume. Predicted kLa values varied between 1.3 and 29 h−1; liquid‐phase mixing time, quantified using iodine decolorization experiments, varied from 1.7 s to 3.5 h; while the predicted P/V ranged from 5 to 35 W m−3. CFD simulations of the shear rate predicted hydrodynamic forces will not be detrimental to cells. For hybridoma cultures however, high shaking speeds (>250 rpm) were shown to have a negative impact on cell growth, while a combination of low shaking speed and high well fill volume (120 rpm, 2,000 µL) resulted in oxygen limited conditions. Based on these findings a first engineering comparison of cell culture kinetics in microwell and shake flask formats was made at matched average energy dissipation rates. Cell growth kinetics and antibody titer were found to be similar in 24‐well microtiter plates and 250 mL shake flasks. Overall this work has demonstrated that cell culture performed in shaken microwell plates can provide data that is both reproducible and comparable to currently used shake flask systems while offering at least a 30‐fold decrease in scale of operation and material requirements. Linked with automation this provides a route towards the high throughput evaluation of robust cell lines under realistic suspension culture conditions. Biotechnol. Bioeng. 2010; 105: 260–275. © 2009 Wiley Periodicals, Inc.
Increased Response to β2-Adrenoreceptor Stimulation Augments Inhibition of IKr in Heart Failure Ventricular Myocytes

Background Increasing evidence indicates that the rapid component of delayed rectifier potassium current (IKr) is modulated by α- and β-adrenergic stimulation. However, the role and mechanism regulating IKr through β2-adrenoreceptor (β-AR) stimulation in heart failure (HF) are unclear. Methodology/Principal Findings In the present study, we investigated the effects of fenoterol, a highly selective β2-AR agonist, on IKr in left ventricular myocytes obtained from control and guinea pigs with HF induced by descending aortic banding. IKr was measured by using whole cell patch clamp technique. In control myocytes, superfusion of fenoterol (10 µM) caused a 17% decrease in IKr. In HF myocytes, the same concentration of fenoterol produced a significantly greater decrease (33%) in IKr. These effects were not modified by the incubation of myocytes with CGP-20712A, a β1-AR antagonist, but were abolished by pretreatment of myocytes with ICI-118551, a β2-AR antagonist. An inhibitory cAMP analog, Rp-cAMPS and PKA inhibitor significantly attenuated fenoterol-induced inhibition of IKr in HF myocytes. Moreover, fenoterol markedly prolonged action potential durations at 90% (APD90) repolarization in HF ventricular myocytes. Conclusions The results indicate that inhibition of IKr induced by β2-AR stimulation is increased in HF. The inhibitory effect is likely to be mediated through a cAMP/PKA pathway in HF ventricular myocytes.
Children with specific language impairment: The effect of argument-structure complexity on auditory sentence comprehension

Children with specific language impairment (SLI) demonstrate consistent comprehension problems. The present study investigated whether these problems are driven primarily by structural complexity or length. A picture-sentence matching task was presented to 30 children: (1) 10 children with SLI, (2) 10 comprehension-matched children with typical language development (TLD) and (3) 10 children with TLD matched for chronological age. Argument-structure complexity was manipulated independently of length, which was also independently varied. Results showed that argument-structure complexity had a greater influence on comprehension in children with SLI than in the comparison groups, with transitive sentences eliciting more errors than intransitive ones. This effect was not dependent on sentence length, which did not appear to affect the comprehension level. The results support the view that comprehension problems in children with SLI are principally related to the structural complexity of the sentence rather than the amount of material to be processed.
Evolution of doctoral education in Pakistan: Challenges and successes of doctoral students of education in a public sector university of Pakistan

This paper presents a part of the findings from a larger study undertaken to explore the experience of graduate students in education in Pakistan. Analysis of a smaller slice of data collected from students who were enrolled in the PhD and MPhil programmes of the Department of Education in a large public sector university in Northern Pakistan was undertaken. The purpose was to develop understanding of their experience of the programme, with a specific focus on induction and coursework. The findings illustrate that students perceive and experience the PhD as a professional degree rather than a research degree. It also appears that the doctoral programme and policies are both in evolution and will require time and effort to mature. Sustained and continuous effort is required to develop among the students the identity of a doctoral student as someone who "creates" new knowledge.
Characterization of N-(Adamantan-1-ylmethyl)-5-[(3R-aminopyrrolidin-1-yl)methyl]-2-chloro-benzamide, a P2X7 Antagonist in Animal Models of Pain and Inflammation

Recent evidence suggests that the P2X7 receptor may play a role in the pathophysiology of preclinical models of pain and inflammation. Therefore, pharmacological agents that target this receptor may potentially have clinical utility as anti-inflammatory and analgesic therapy. We investigated and characterized the previously reported P2X7 antagonist N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, hydrochloride salt (AACBA; GSK314181A). In vitro, AACBA was a relatively potent inhibitor of both human P2X7-mediated calcium flux and quinolinium,4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]-1-[3-(triemethylammonio)propyl]-diiodide (YO-PRO-1) uptake assays, with IC50 values of approximately 18 and 85 nM, respectively. Compared with the human receptor, AACBA was less potent at the rat P2X7 receptor, with IC50 values of 29 and 980 nM in the calcium flux and YO-PRO-1 assays, respectively. In acute in vivo models of pain and inflammation, AACBA dose-dependently reduced lipopolysaccharide-induced plasma interleukin-6 release and prevented or reversed carrageenan-induced paw edema and mechanical hypersensitivity. In chronic in vivo models of pain and inflammation, AACBA produced a prophylactic, but not therapeutic-like, prevention of the clinical signs and histopathological damage of collagen-induced arthritis. Finally, AACBA could not reverse L5 spinal nerve ligation-induced tactile allodynia when given therapeutically. Consistent with previous literature, these results suggest that P2X7 receptors do play a role in animal models of pain and inflammation. Further study of P2X7 antagonists both in preclinical and clinical studies will help elucidate the role of the P2X7 receptor in pain and inflammatory mechanisms and may help identify potential clinical benefits of such molecules.
An independent H-TCP implementation under FreeBSD 7.0: description and observed behaviour

A key requirement for IETF recognition of new TCP algorithms is having an independent, interoperable implementation. This paper describes our BSD-licensed implementation of H-TCP within FreeBSD 7.0, publicly available as a dynamically loadable kernel module. Based on our implementation experience we provide a summary description of the H-TCP algorithm to assist other groups build further interoperable implementations. Using data from our live testbed we demonstrate that our version exhibits expected H-TCP behavior, and describe a number of implementation-specific issues that influence H-TCP's dynamic behavior. Finally, we illustrate the actual collateral impact on path latency of using H-TCP instead of NewReno. In particular we illustrate how, compared to NewReno, H-TCP's cwnd growth strategy can cause faster fluctuations in queue sizes at, yet lower median latency through, congestion points. We believe these insights will prove valuable predictors of H-TCP's potential impact if deployed in consumer end-hosts in addition to specialist, high-performance network environments.
Fatty Acids Composition of Vegetable Oils and Its Contribution to Dietary Energy Intake and Dependence of Cardiovascular Mortality on Dietary Intake of Fatty Acids

Characterizations of fatty acids composition in % of total methylester of fatty acids (FAMEs) of fourteen vegetable oils—safflower, grape, silybum marianum, hemp, sunflower, wheat germ, pumpkin seed, sesame, rice bran, almond, rapeseed, peanut, olive, and coconut oil—were obtained by using gas chromatography (GC). Saturated (SFA), monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA), palmitic acid (C16:0; 4.6%–20.0%), oleic acid (C18:1; 6.2%–71.1%) and linoleic acid (C18:2; 1.6%–79%), respectively, were found predominant. The nutritional aspect of analyzed oils was evaluated by determination of the energy contribution of SFAs (19.4%–695.7% ERDI), PUFAs (10.6%–786.8% ERDI), n-3 FAs (4.4%–117.1% ERDI) and n-6 FAs (1.8%–959.2% ERDI), expressed in % ERDI of 1 g oil to energy recommended dietary intakes (ERDI) for total fat (ERDI—37.7 kJ/g). The significant relationship between the reported data of total fat, SFAs, MUFAs and PUFAs intakes (% ERDI) for adults and mortality caused by coronary heart diseases (CHD) and cardiovascular diseases (CVD) in twelve countries has not been confirmed by Spearman’s correlations.
Organ transplantation and osteoporosis.

Organ transplantation offers new life to patients who suffer from incurable disease. The problem of rejection of the transplanted organ has been overcome with the use of potent immunosuppressive drugs. These drugs, although they allow graft tolerance and graft survival, also are associated with complications such as osteoporosis. Although factors such as nutrition, gonadal status, and ambulatory status are important, the use of immunosuppressive drugs appears to be the main factor in the development of osteoporosis. The drugs that are responsible for this bone loss are glucocorticoids and the calcineurin phosphatase inhibitors, cyclosporine and tacrolimus. The incidence of bone disease depends, in part, on which organ is transplanted. Kidney transplant recipients appear to be less susceptible to the development of overt osteoporosis than do heart or liver transplant recipients. The most critical period of bone loss in organ recipients appears to be within the first 6 months, with the most dramatic reduction occurring within the first 3 months following transplantation. Trabecular (cancellous) bone of the spine appears to be most at risk, with vertebral fractures occurring most commonly. Transplant recipients should be evaluated by bone mineral densitometry and measurement of vitamin D metabolites, blood urea nitrogen, creatinine, calcium, and phosphate. Markers of bone turnover may help in assessing the rate of remodeling. Gonadal function should be ascertained by measurement of serum testosterone (males) or estradiol (females) levels. Therapy should be directed toward prevention of bone loss as well as helping to restore what already may have been lost. Administration of calcium and vitamin D and sex hormone replacement, if indicated, should be considered. (ABSTRACT TRUNCATED AT 250 WORDS)
Involvement of Tn 4430 in Transfer of Bacillus anthracis Plasmids Mediated by Bacillus thuringiensis Plasmid pXO 12

The self-transmissible plasmid pXO12 (112.5 kilobases [kbj), originally isolated from strain 4042A of BaciUus thuringiensis subsp. thuringiensis, codes for production of the insecticidal crystal protein (Cry'). The mechanism of pXO12-mediated plasmid transfer was investigated by monitoring the cotransfer of the tetracycline resistance plasmid pBC16 (4.2 kb) and the Bacillus anthracis toxin and capsule plasmids, pXOl (168 kb) and pXO2 (85.6 kb), respectively. In matings of B. anthracis donors with B. anthracis and Bacillus cereus recipients, the number of Tcr transcipients ranged from 4.8 x 104 to 3.9 x 106/ml (frequencies ranged from 1.6 x 10-4 to 7.1 x 10-2), and 0.3 to 0.4% of them simultaneously inherited pXO1 or pXO2. Physical analysis of the transferred plasmids suggested that pBC16 was transferred by the process of donation and that the large B. anthracis plasmids were transferred by the process of conduction. The transfer of pXO1 and pXO2 involved the transposition of Tn4430 from pXO12 onto these plasmids. DNA-DNA hybridization experiments demonstrated that Tn4430 was located on a 16.0-kb AvaI fragment of pXO12. Examination of Traand Cryderivatives of pXO12 showed that this fragment also harbored information involved in crystal formation and
The Harvard Cooperative Stroke Registry

Data from 694 patients hospitalized with stroke were entered in a prospective, computer-based registry. Three hundred and sixty-four patients (53 percent) were diagnosed as having thrombosis, 215 (31 percent) as having cerebral embolism, 70 (10 percent) as having intracerebral hematoma, and 45 (6 percent) as having subarachnoid hemorrhage from aneurysm or arteriovenous malformations. The 364 patients diagnosed as having thrombosis were divided into 233 (34 percent of all 694 patients) whose thrombosis was thought to involve a large artery and 131 (19 percent) with lacunar infarction. Many of the findings in this study were comparable to those in previous registries based on postmortem data. New observations include the high incidence of lacunes and cerebral emboli, the absence of an identifiable cardiac origin in 37 percent of all emboli, a nonsudden onset in 21 percent of emboli, and the occurrence of vomiting at onset in 51 percent and the absence of headache at onset in 67 percent of hematomas.
Perception of onset asynchronies: Acoustic piano versus synthesized complex versus pure tones

In studies on piano performance, simultaneous notes in the score are almost never played simultaneously by pianists. Melody leads are typically of the order of 30 ms (Palmer, 1989, 1996; Repp, 1996; Goebl, 2001). Here, we investigate the perception of such asynchronies. Previous psychoacoustic studies have found that asynchronies as small as 2 ms can be detected between steady-state synthesized pure and complex tones (Zera & Green, 1993). The temporal order of two sound events can be perceived for asynchronies greater than about 20 ms (Hirsh, 1959; Rosen & Howell, 1987). The complex onset behaviors of real musical sounds such as piano tones suggest that thresholds for detection of asynchrony between such tones will be higher than for steady-state sounds. Our experiments investigated this hypothesis by comparing real and synthesized sounds within the same randomly ordered sequence of trials. We are also interested in the question of why asynchronies are introduced by performers. Rasch (1978) and Palmer (1996) have suggested that the aim of this strategy is to increase the salience of the tone. Since melody leads are more common than lags, this raises the question of which strategy is more audible. Does anticipation of an event make it more or less prominent (salient)? Moreover, does this depend on the type of tone? Each experiment consisted of 88 trials: 4 tone types x 2 interval sizes x 11 asynchronies. Tone types were pure, harmonic complex with 16 partials (-6 dB per octave), MIDI-synthesized piano, and recorded from a computer-monitored grand piano. The pair of tones in each trial spanned an interval of an octave or a major seventh. Asynchronies varied from -50 ms to 50 ms, in 10 ms steps. The tone duration ranged from 300 to 400 ms so that the overlap of the two tones were constant at 350 ms. Musically trained and untrained listeners were asked to judge these stimuli on two separate occasions, each with a two-alternative forced choice paradigm. In the Experiment 1, they indicated which tone was more prominent. In Experiment 2, they indicated which sounded earlier. Preliminary analysis of Experiment 1 firstly confirmed the finding and theory of Bregman and Pinker (1978) that asynchrony encourages harmonic segregation. There was no effect of order, regardless of the tone type: a delayed attack was considered to have the same prominence as an early attack. This casts doubt on the frequently encountered tacit assumption in the music (and especially piano) performance literature that the first onset is perceived as more salient. In Experiment 2, listeners only consistently reported the correct order of the two onsets for asynchronies of greater than about 30 ms–again, regardless of whether the higher or the lower tone began first. Identification of order improved as the sounds became the more artificial: the threshold was around 20 ms at pure tones, and 30 ms for real piano tones. These preliminary experiments suggest that the detection of asynchrony is more difficult in real instrument sounds than in steady-state or artificial stimuli.
Non-coding RNAs in pluripotency and neural differentiation of human pluripotent stem cells

Several studies have demonstrated the important role of non-coding RNAs as regulators of posttranscriptional processes, including stem cells self-renewal and neural differentiation. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (ihPSCs) show enormous potential in regenerative medicine due to their capacity to differentiate to virtually any type of cells of human body. Deciphering the role of non-coding RNAs in pluripotency, self-renewal and neural differentiation will reveal new molecular mechanisms involved in induction and maintenances of pluripotent state as well as triggering these cells toward clinically relevant cells for transplantation. In this brief review we will summarize recently published studies which reveal the role of non-coding RNAs in pluripotency and neural differentiation of hESCs and ihPSC.