Miracle-dz/UniFAR-FTUs huggingface dataset:
Crystal Structure of the Biglycan Dimer and Evidence That Dimerization Is Essential for Folding and Stability of Class I Small Leucine-rich Repeat Proteoglycans*

Biglycan and decorin are two closely related proteoglycans whose protein cores contain leucine-rich repeats flanked by disulfides. We have previously shown that decorin is dimeric both in solution and in crystal structures. In this study we determined whether biglycan dimerizes and investigated the role of dimerization in the folding and stability of these proteoglycans. We used light scattering to show that biglycan is dimeric in solution and solved the crystal structure of the glycoprotein core of biglycan at 3.40-Å resolution. This structure reveals that biglycan dimerizes in the same way as decorin, i.e. by apposition of the concave inner surfaces of the leucine-rich repeat domains. We demonstrate that low concentrations of guanidinium chloride denature biglycan and decorin but that the denaturation is completely reversible following removal of the guanidinium chloride, as assessed by circular dichroism spectroscopy. Furthermore, the rate of refolding is dependent on protein concentration, demonstrating that it is not a unimolecular process. Upon heating, decorin shows a single structural transition at a Tm of 45-46 °C but refolds completely upon cooling to 25 °C. This property of decorin enabled us to show both by calorimetry and light scattering that dimer to monomer transition coincided with unfolding and monomer to dimer transition coincided with refolding; thus these processes are inextricably linked. We further conclude that folded monomeric biglycan or decorin cannot exist in solution. This implies novel interrelated functions for the parallel β sheet faces of these leucine-rich repeat proteoglycans, including dimerization and stabilization of protein folding.
Apolipoprotein gene E4 allele promoter polymorphisms as risk factors for Alzheimer's disease

Alzheimer's disease is a complex neurodegenerative disorder, characterized by progressive cognitive decline and distinct neuropathology. The apolipoprotein gene E4 allele (APOE 4) is a major risk factor for the disease. Promoter polymorphisms at −491 and −427 may also contribute to the risk. We examined the two polymorphisms in 178 Alzheimer's patients and 141 controls. The −491AA genotype was overrepresented among the patients (68 versus 54%, P=0.01). However, in patients who were APOE4 carriers, the −491AA genotype more than doubled the risk [odds ratio (OR)=2.5; 95% confidence interval (CI)=1.2–5.4], especially in combination with −427TT [odds ratio (OR)=3.3; 95% confidence interval (CI)=1.5–7.7]. Moreover, the −491A/−427T/APOE4/APOC1A haplotype was threefold higher for patients. These results contribute to the evidence that regulation of APOE4 expression modulates risk for Alzheimer's disease.
Laparoscopic adrenalectomy for large-volume (> or = 5 cm) adrenal masses.

BACKGROUND AND PURPOSE Laparoscopic adrenalectomy has emerged as the standard of care at many centers for small surgical adrenal masses. However, the role of laparoscopic adrenalectomy in the treatment of large adrenal masses has not been specifically addressed. Our aim was to evaluate the outcome of laparoscopic v open adrenalectomy for large-volume (> or =5 cm) adrenal masses and to compare laparoscopic adrenalectomy for large- and small-volume (<5 cm) masses. PATIENTS AND METHODS Data from 14 patients with large adrenal masses undergoing laparoscopic adrenalectomy between February 1998 and March 1999 (Group I) were retrospectively compared with 14 contemporary large-volume open adrenalectomies between December 1992 and May 1998 (Group II) and 45 small-volume laparoscopic adrenalectomies between July 1997 and November 1998 (Group III). RESULTS In Group I and Group II, the mean surgical time (205 min v 216 min) and blood loss (400 mL v 584 mL) were similar. Although the mean adrenal size was also comparable (8 cm v 7.8 cm), the specimen weight of the en bloc adrenal gland and periadrenal fat was greater in Group I (168 g v 106 g). The hospital stay was shorter in Group I (2.4 days v 7.7 days). Minor complications occurred in 21.4% of Group I and 50% of Group II patients. On comparing Group I and Group III (laparoscopic <5 cm), Group I had larger specimen weight (168 g v 51.4 g), longer surgical time (205 min v 158 min), greater blood loss (400 mL v 113 mL), longer hospital stay (2.4 days v 1.5 days), a higher complication rate (21.4% v 8.9%), and a higher incidence of open surgical conversion (14.3% v 2.2%). Over a mean follow-up of 9.9 months, no local or port-site recurrences have been noted in Group I. CONCLUSIONS Laparoscopic adrenalectomy for large-volume adrenal masses is technically feasible and seems to replicate open surgical oncologic principles of achieving a wide-margin, en bloc excision of the adrenal gland and periadrenal fat. Successful laparoscopic resection is not impacted by the large size of the adrenal mass per se but rather by the presence of local invasion and poorly defined tissue planes that may be encountered in adrenal malignancy. As such, laparoscopic adrenalectomy for large masses should be attempted only by experienced laparoscopic surgeons and then with a low threshold for open conversion.
Mold‐sensitivity in children with moderate‐severe asthma is associated with HLA‐DR and HLA‐DQ

To cite this article: Knutsen AP, Vijay HM, Kumar V, Kariuki B, Santiago LA, Graff R, Wofford JD, Shah MR. Mold‐sensitivity in children with moderate‐severe asthma is associated with HLA‐DR and HLA‐DQ. Allergy 2010; 65: 1367–1375.
The colourless canvas: Representation, therapeutic action and the creation of mind

Freud’s initial formulations viewed psychoanalysis as working towards the rediscovery of psychic elements – thoughts, feelings, memories, wishes, etc. – that were once known – represented in the mind, articulatable, thinkable – but then disguised and/or barred from consciousness. His subsequent revisions implicated a second, more extensive category of inchoate forces that either lost or never attained psychic representation and, although motivationally active, were not fixed in meaning, symbolically embodied, attached to associational chains, etc. Following Freud’s theory of representation, the author conceptualizes these latter forces as “unrepresented” or “weakly represented” mental states that make a demand upon the mind for work and require transformation into something that is represented in the psyche, if they are to be thought about or used to think with. This paper describes, discusses and presents illustrations of this transformational process (figurability),that moves intersubjectively from unrepresented or weakly represented mental states to represented mental states, from force to meaning, from the inchoate to mental order.
Systemic administration of lidocaine reduces morphine requirements and postoperative pain of patients undergoing thoracic surgery after propofol–remifentanil-based anaesthesia

Background and objective Remifentanil is being increasingly used as an analgesic in fast-track surgery, but severe postoperative pain may happen occasionally. In this study, we evaluated the effects of systemic administration of lidocaine on postoperative pain and morphine requirements after propofol–remifentanil-based anaesthesia. Methods Forty patients undergoing thoracic surgery were randomly assigned to lidocaine (33.0 μg kg−1 min−1) and physiological saline control groups in propofol–remifentanil-based anaesthesia. The setting of the plasma concentration (Cp) of the target-controlled infusion of propofol was adjusted according to the bispectral index of the electroencephalogram and blood pressure. The Cp and effect-site concentration (Ce) of propofol were calculated by target-controlled infusion pump during the intraoperative period. Pain scoring includes a four-point verbal rating scale, Riker's sedation–agitation scale and a visual analogue scale; the morphine requirement in the postanaesthesia care unit and the morphine consumption via a patient-controlled analgesia device on the ward were recorded during the postoperative period. Results Morphine requirements within 30, 30–60 and 0–120 min in the postanaesthesia care unit of the lidocaine group decreased significantly (P < 0.05, n = 20 per group) compared with that of the control group. The four-point verbal rating scale at 30 min in the postanaesthesia care unit, visual analogue scale at 6 h on coughing and patient-controlled analgesia morphine consumption during 2–6 h postoperative time were also significantly (P < 0.05, n = 20 per group) reduced in the lidocaine group. In addition, the intraoperative propofol Ce in the lidocaine group during the periods of intubation, organ resection, closing of chest cavity and extubation was significantly lower (P < 0.05, n = 20 per group) than that in the control group under the same hypnotic depth. Conclusion Systemic administration of lidocaine could reduce morphine requirements, postoperative pain and intraoperative propofol Ce of patients undergoing thoracic surgery after propofol–remifentanil-based anaesthesia.
The Political Determinants of Foreign Direct Investment: A Firm-Level Analysis

ABSTRACT Many large-N cross-national studies claim to show that political institutions and phenomena determine where foreign direct investment (FDI) flows. In this article, I argue that these studies tend to overemphasize statistical significance and often neglect to assess the explanatory or predictive power of their theories. To illustrate the problem, I estimate variations of a statistical model published in an influential article on “Political Risk, Institutions, and FDI. ” I find that none of the political variables that the authors consider accounts for much of the variation in aggregate FDI inflows. To ensure that this underwhelming result is not driven by misspecification or measurement error, I leverage a large firm-level data set on the investment location decisions of thousands of multinational firms. Using nonparametric machine-learning techniques and out-of-sample tests, I show that gravity variables can help us develop very accurate expectations about firm behavior but that none of the 31 “political determinants” of FDI that I consider can do much to improve our expectations. These findings have important implications because they suggest that governments retain some room to move in the face of economic globalization.
Two Seizure-Onset Types Reveal Specific Patterns of High-Frequency Oscillations in a Model of Temporal Lobe Epilepsy

High-frequency oscillations (HFOs; 80–500 Hz) are thought to mirror the pathophysiological changes occurring in epileptic brains. However, the distribution of HFOs during seizures remains undefined. Here, we recorded from the hippocampal CA3 subfield, subiculum, entorhinal cortex, and dentate gyrus to quantify the occurrence of ripples (80–200 Hz) and fast ripples (250–500 Hz) during low-voltage fast-onset (LVF) and hypersynchronous-onset (HYP) seizures in the rat pilocarpine model of temporal lobe epilepsy. We discovered in LVF seizures that (1) progression from preictal to ictal activity was characterized in seizure-onset zones by an increase of ripple rates that were higher when compared with fast ripple rates and (2) ripple rates during the ictal period were higher compared with fast ripple rates in seizure-onset zones and later in regions of secondary spread. In contrast, we found in HYP seizures that (1) fast ripple rates increased during the preictal period and were higher compared with ripple rates in both seizure-onset zones and in regions of secondary spread and (2) they were still higher compared with ripple rates in both seizure-onset zones and regions of secondary spread during the ictal period. Our findings demonstrate that ripples and fast ripples show distinct time- and region-specific patterns during LVF and HYP seizures, thus suggesting that they play specific roles in ictogenesis.
Evidence for impaired axonal regeneration in PMP22 duplication: studies in nerve xenografts

Abstract Whether axonal regeneration in Charcot‐Marie‐Tooth (CMT) neuropathies is impaired has not been addressed in detail. Our studies in nude mice harboring xenografts from patients with different primary Schwann cell (SC) genetic defects suggested an intimate association between the onset of myelination and impairment in the growth capacity of nude mice axons engulfed by the mutant SCs. To assess the effects of peripheral myelin protein 22 (PMP22) gene duplication on the regeneration process, we conducted morphometric studies to generate temporal growth profiles of myelinated axons within the xenografts obtained from CMT1A patients and from healthy controls. Axon size distribution histograms in controls at different time intervals revealed that size differentiation of myelinated fibers within the grafts is established as early as 2 weeks, and that the temporal pattern of myelination of different sized axons has striking similarities to myelination during development. In PMP22 duplication grafts, the onset of myelination is delayed and the regeneration capacity of all fiber sizes is impaired. This defect, however, is most pronounced for the large diameter axons. In addition, significant large fiber loss occurred after 12 weeks with a concomitant new cycle of regeneration of small size axons. These studies show that the PMP22 duplication in SCs have profound effects on the regeneration process, which might be a contributing factor to preferential distal axonal loss.
Identifying novel glioma associated pathways based on integrated ‘omics’ data

Microarray represents a high throughput technology for analyzing expression profiles, and thus it has been widely applied in the study of pathogenesis of glioma. However, most of the analyses focused on detecting the differentially expressed genes in glioma. Although it is well accepted that the pathway-derived signatures is more reproducible than that at gene level, few meta-analyses of multiple microarray datasets at system level have been previously performed. In this article, we performed meta-analysis on different published glioma expression profiles and compared the overlapping of signature at gene and pathway level. Pathway enrichment analysis result of GeneGO database and Gene Set Enrichment Analysis (GSEA) showed that 100% and 64% of the similarity was higher than that of genes respectively. Moreover, we integrated other omics data on glioma, such as MicroRNA expression profiles and Chip-Seq data, for further verification. The results showed that the significant signatures of different data sets are more similar at pathway level than at gene level. 12 pathways found by GeneGO database were shared by four stages among several datasets. 5 of these pathways, such as Regulation of epithelial-to-mesenchymal transition (EMT), TGF-beta-dependent induction of EMT via SMADs, were putative novel pathways on glioma and need further experimental verification.
Regions of Interest as nodes of dynamic functional brain networks

Abstract The properties of functional brain networks strongly depend on how their nodes are chosen. Commonly, nodes are defined by Regions of Interest (ROIs), predetermined groupings of fMRI measurement voxels. Earlier, we demonstrated that the functional homogeneity of ROIs, captured by their spatial consistency, varies widely across ROIs in commonly used brain atlases. Here, we ask how ROIs behave as nodes of dynamic brain networks. To this end, we use two measures: spatiotemporal consistency measures changes in spatial consistency across time and network turnover quantifies the changes in the local network structure around an ROI. We find that spatial consistency varies non-uniformly in space and time, which is reflected in the variation of spatiotemporal consistency across ROIs. Furthermore, we see time-dependent changes in the network neighborhoods of the ROIs, reflected in high network turnover. Network turnover is nonuniformly distributed across ROIs: ROIs with high spatiotemporal consistency have low network turnover. Finally, we reveal that there is rich voxel-level correlation structure inside ROIs. Because the internal structure and the connectivity of ROIs vary in time, the common approach of using static node definitions may be surprisingly inaccurate. Therefore, network neuroscience would greatly benefit from node definition strategies tailored for dynamical networks.
Wet and wild: results from a pilot study assessing injuries among recreational water users in Western Australia

To identify, describe and compare injuries among three water sport activities: kite surfing (KS), personal watercraft (PWC) and towed water sports (TWS). The study was a cross sectional, online survey. The setting was on Perth, Western Australia's popular beaches and riverbanks. Main outcome measures were number of injuries and level of severity; level of exposure and protection measures. Overall, 43% reported at least one injury in the past 12 months, a rate of 22.3 injuries per 100 h. Kite surfers were more likely to report an injury than PWC or TWS. One-half of injuries occurred while on the water. Most injuries were caused by landing awkwardly (56%) and/or trying new tricks (41%). Despite 90% of respondents having used at least one personal protective equipment (PPE) item, half (49%) reported always using a personal floatation device. This study provided information on KS, PWC and TWS injuries as well as a range of safety behaviours. It is recommended that these results form the basis of further research to reduce injury rates and encourage the use of PPE items.
In vitro transcription catalyzed by heat-treated human rotavirus

The in vitro characteristics of human rotavirus transcription have been examined. The virus has an associated RNA polymerase activity which was activated after a heat shock treatment. The enzyme required the presence of the four ribonucleoside triphosphates and a divalent cation (Mg2+), and it required an optimum pH of 8.5. The polymerase was activated by monovalent salts and inhibited by Na PPi. The addition of actinomycin D, alpha-amanitin, or rifampin did not inhibit the polymerase activity. After thermal shock of the virus, at least eight different RNA species were synthesized which may correspond to independent transcripts. Transcription also requires a hydrolyzable form of ATP. Analogs such as beta,gamma-imido ATP or beta,gamma-methylene ATP were inhibitory, whereas others, such as the beta-gamma-imido or methylene analogs of CTP, UTP, or GTP, were not inhibitory. This suggests that ATP is related to reactions other than polymerization, probably to initiation or elongation of RNA molecules, as has been described for vesicular stomatitis virus or vaccinia virus.
Outcome of Alzheimer's disease: potential impact of cholinesterase inhibitors.

BACKGROUND Alzheimer's disease is fast becoming a major public health concern with serious economic consequences. The cholinesterase inhibitors (CEIs) offer some benefit in the symptomatic treatment of the disease. This study aims to investigate the effect of CEIs on three clinically relevant domains (rapid cognitive decline, institutionalization, and weight loss) in patients with Alzheimer's disease. METHODS A prospective observational study was performed in which a population of 455 Alzheimer's disease patients were recruited and followed up for at least 1 year between 1994 and 2002. Patients were reevaluated at 6 monthly intervals using standardized neurocognitive and geriatric evaluations in addition to complete clinical examination, standard paraclinical investigations, and recording of treatment received. RESULTS The risk of rapid cognitive deterioration was significantly decreased in patients taking CEIs for at least 1 year compared to untreated patients (odds ratio [OR]=0.56, 95% confidence interval [CI], 0.34-0.93; p=.025). The potential benefit of CEI use was also found on institutionalization (OR=0.2, 95% CI, 0.08-0.48; p<.001) and weight loss (OR=0.56, 95% CI, 0.32-0.97; p=.039) after 1 year of follow-up. CONCLUSION The special interest of this study is that all patients were recruited and followed in the same center with the same management care plan and the same medical team. This follow-up offers us a unique opportunity to compare the 1-year evolution of the disease in clinical practice before and after the marketing of CEIs and allows us to demonstrate a clinically significant improvement in patient outcome over time.
Double‐masked randomised placebo‐controlled trial of the effect of prismatic corrections on rate of reading and the relationship with symptoms

Practitioners’ decisions on when to intervene in decompensated heterophoria are often based on symptoms, which are in some cases an unreliable indicator of whether an intervention will be helpful. The aim of our study was to determine when prismatic corrections improve performance at a measure of dynamic visual function: the Wilkins Rate of Reading Test (WRRT). All participants manifested an aligning prism (associated heterophoria) on the near Mallett Unit of 0. 5Δ or greater. There were 80 participants, of whom 58 had exophoria, 15 esophoria, and seven hyperphoria. The effect of the aligning prism on the WRRT was compared with a control lens using a double‐masked randomised design. For exophoria, an aligning prism of 2Δ and above has a sensitivity of 67% and a specificity of 79% for improving performance at the WRRT by 5% or more. It is not possible from our data to achieve a good compromise between sensitivity and specificity for the other types of heterophoria. Patients in the horizontal (but not vertical) heterophoria groups had significantly more symptoms than a control group. The patients whose visual performance is improved by prismatic correction are not necessarily those who report the most symptoms. Our data suggest that exophoric patients of any age are likely to have improved visual performance with an intervention if they have an aligning prism of 2Δ or more, even in the absence of symptoms. We stress that although the Mallett Unit Fixation Disparity test provides useful information, its results need to be considered in the overall context of the patient's symptoms, lifestyle, and the results of other optometric tests. Although this study evaluated prismatic corrections, we note that interventions for decompensated heterophoria include not only prismatic corrections, but also eye exercises and refractive modification.