Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural basis for integration of GluD receptors within synaptic organizer complexes

Transmitting signals across the synapse Glutamate receptors located on neuronal cells play a role in mediating electrical signals at excitatory synapses. These glutamatergic synapses are extremely important for nearly all cognitive functions. Elegheert et al. analyzed a complex that bridges the synapse, comprising β-neurexin 1, a cell adhesion molecule on the surface of presynaptic axons; cerebellin 1, a synaptic organizer; and the postsynaptic glutamate receptor GluD2. The structural and functional analysis provides insight into the mechanism of synaptic signaling. Science, this issue p. 295 A molecular bridge across excitatory synapses provides a structural framework that facilitates signaling in the cerebellum. Ionotropic glutamate receptor (iGluR) family members are integrated into supramolecular complexes that modulate their location and function at excitatory synapses. However, a lack of structural information beyond isolated receptors or fragments thereof currently limits the mechanistic understanding of physiological iGluR signaling. Here, we report structural and functional analyses of the prototypical molecular bridge linking postsynaptic iGluR δ2 (GluD2) and presynaptic β-neurexin 1 (β-NRX1) via Cbln1, a C1q-like synaptic organizer. We show how Cbln1 hexamers “anchor” GluD2 amino-terminal domain dimers to monomeric β-NRX1. This arrangement promotes synaptogenesis and is essential for d-serine–dependent GluD2 signaling in vivo, which underlies long-term depression of cerebellar parallel fiber–Purkinje cell (PF-PC) synapses and motor coordination in developing mice. These results lead to a model where protein and small-molecule ligands synergistically control synaptic iGluR function.
Speciation in the Derrida–Higgs model with finite genomes and spatial populations

The speciation model proposed by Derrida and Higgs demonstrated that a sexually reproducing population can split into different species in the absence of natural selection or any type of geographic isolation, provided that mating is assortative and the number of genes involved in the process is infinite. Here we revisit this model and simulate it for finite genomes, focusing on the question of how many genes it actually takes to trigger neutral sympatric speciation. We find that, for typical parameters used in the original model, it takes the order of 105 genes. We compare the results with a similar spatially explicit model where about 100 genes suffice for speciation. We show that when the number of genes is small the species that emerge are strongly segregated in space. For a larger number of genes, on the other hand, the spatial structure of the population is less important and the species distribution overlap considerably.
Funding for U.S. Biomedical Research

The U.S. biomedical research community finds itself at a particularly consequential moment. Since the end of the Fiscal Year (FY) 1998-2003 NIH budget doubling period, brought to fruition with bipartisan leadership, the Federal investment in biomedical research has been declining. The NIH budget has actually decreased in constant dollars since FY 2004. Across-the-board cuts included in the Budget Control Act of 2011 would result in a loss of $2.4 billion and roughly 2,300 research project grants in FY 2013 alone, unless Congress acts to intervene before January 2013. Many of the beneficiaries of NIH support view advocacy for research funding as “someone else’s job”. The case to reverse this mindset must be made. Members of Congress and their staffers are open to consideration of the case for sustaining Federal investments in science, even during these difficult budget times. However, the advocacy effort must be broad-based and repeatedly presented to effect change. The figures on economic return from spending on biomedical research are compelling, but they do not tell the entire story. The results of biomedical research improve and save lives every single day, a fact that should not be lost on our elected leaders.
The human touch: participatory practice and the role of facilitation in designing with communities

Traditional PD research offers a range of methods for participant engagement. Yet little is shared of the microdynamics of participation at its most intense, when the designer as facilitator is challenged by a range of social contingencies. Engaging people in change can be a messy process, especially when emotions run high. This paper explores two situations where communities were asked to collaborate on disaster mitigation plans and looks at how facilitation took place to engage with these concerns. It considers the relationship between method and its enactment, between the participatory practitioner and participant group, and between intention and outcome. In doing so, it questions the prevalent research culture that anonymises facilitation and its agency. Instead, we offer a more synthesised reading of practice, by focusing on aspects that compound the designers' task, such as the dynamics of the group and emotions manifested by participants. We argue that we need to orientate towards understanding the designers' participatory practice, rather than reporting participatory methods alone. The act of engaging others involves an embodied knowing, with moment-by-moment shifts in position, focus and delivery. Acknowledging this involves a rethink of our frameworks for reflecting and reporting on design.
Expression of Cystathionine β-synthase and Cystathionine γ-lyase in Human Pregnant Myometrium and Their Roles in the Control of Uterine Contractility

Background Human uterus undergoes distinct molecular and functional changes during pregnancy and parturition. Hydrogen sulfide (H2S) has recently been shown to play a key role in the control of smooth muscle tension. The role of endogenous H2S produced locally in the control of uterine contractility during labour is unknown. Methodology/Principal Findings Human myometrium biopsies were obtained from pregnant women undergoing cesarean section at term. Immunohistochemistry analysis showed that cystathionine-γ-lyase (CSE) and cystathionine-β-synthetase (CBS), the principle enzymes responsible for H2S generation, were mainly localized to smooth muscle cells of human pregnant myometrium. The mRNA and protein expression of CBS as well as H2S production rate were down-regulated in labouring tissues compared to nonlabouring tissues. Cumulative administration of L-cysteine (10−7–10−2 mol/L), a precursor of H2S, caused a dose-dependent decrease in the amplitude of spontaneous contractions in nonlabouring and labouring myometrium strips. L-cysteine at high concentration (10−3 mol/L) increased the frequency of spontaneous contractions and induced tonic contraction. These effects of L-cysteine were blocked by the inhibitors of CBS and CSE. Pre-treatment of myometrium strips with glibenclamide, an inhibitor of ATP-sensitive potassium (KATP) channels, abolished the inhibitory effect of L-cysteine on spontaneous contraction amplitude. The effects of L-cysteine on the amplitude of spontaneous contractions and baseline muscle tone were less potent in labouring tissues than that in nonlabouring strips. Conclusion/Significance H2S generated by CSE and CBS locally exerts dual effects on the contractility of pregnant myometrium. Expression of H2S synthetic enzymes is down-regulated during labour, suggesting that H2S is one of the factors involved in the transition of pregnant uterus from quiescence to contractile state after onset of parturition.
An efficient model-based multirate method for reconstruction of audio signals across long gaps

This paper presents an efficient model-based interpolator for reconstructing long portions of missing samples in audio signals. A simple modification to an existing interpolation method is proposed, optimizing the balance between computational requirements and qualitative performance. Moreover, a post-processing multirate interpolation scheme is introduced to further enhance the quality of the restored signals. Subjective quality assessments of the reconstructed signals via listening tests substantiate the improved performance of the proposed algorithm
Future of Strained Si/Semiconductors in Nanoscale MOSFETs

The maximum electron and hole mobility enhancement for uniaxial process-induced strained silicon is modeled and experimentally measured using a flexure based 4-point wafer bending jig. The highest known uniaxial stress to date is introduced into the channel of MOSFETs (applied mechanical stress of ~1.0GPa on samples with initial process stress of 1GPa for a total channel stress of ~2Pa). The maximum mobility enhancement from uniaxial stress is found to be greater than ~4.0 and ~1.7 times for holes and electrons, respectively. The physics behind the strain enhanced mobility is explained and future cases of technological importance to the industry are investigated
The Predictive Value of ΣΔST/ΔHR Index for Restenosis after Percutaneous Coronary Intervention

Objective To find out the predictive value of the ΣΔST/ΔHR index for restenosis after percutaneous coronary intervention (PCI). Method Subjects of this research were patients who participated in a cardiac rehabilitation (CR) program as six to eight weeks of a hospital-based program after receiving PCI to treat acute coronary syndrome (ACS). The patients received coronary angiography (CAG) at the onset of the ACS and nine months after that, and also received an exercise tolerance test (ETT) at the start of the CR program and several days before receiving a follow-up CAG. In ETT, we used the sum of the ST depression (ΣΔST index) of leads II, III, aVF, V4-6 as well as the sum of the ΔST/ΔHR (heart rate) (ΣΔST/ΔHR index) in the same leads and the sum of the ΔST/ΔRPP (rate pressure product) (ΣΔST/ΔRPP index) in the same leads. We compared the predictive power of each index of ETT for restenosis after PCI. Results The sensitivity, specificity, positive predictive value, and negative predictive value of ΣΔST index were 69%, 47%, 31%, and 82%. The ΣΔST/ΔHR index was 13.7±5.2 in the restenosis group and 9.3±5.6 in the patent group (p=0.017). The sensitivity, specificity, positive predictive value, and negative predictive value of this index were 85%, 63%, 44%, and 92%. The ΣΔST/ΔRPP index were 0.10±0.08 in the restenosis group and 0.06±0.04 in the patent group (p=0.016). The sensitivity, specificity, positive predictive value, and negative predictive value of this index were 54%, 76%, 44%, and 83%. Conclusion The ΣΔST/ΔHR index showed a much higher sensitivity and negative predictive value for restenosis after PCI compared to the ΣΔST index.
Survivorship in a population based cohort of patients with Sjögren's syndrome, 1976-1992.

OBJECTIVE Sjögren's syndrome (SS) has been associated with development of lymphoid malignancies and other significant medical complications, but the effect of SS on survival in a population based sample has not been reported. We analyzed survival in an incidence cohort of patients diagnosed with SS in residents of Olmsted County, Minnesota, USA, between 1976 and 1992. METHODS All records of physician diagnosed SS were reviewed, as well as all records from patients diagnosed with xerostomia and keratoconjunctivitis sicca, and records of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus. The case definition for SS required 2 of 3 criteria: keratoconjunctivitis sicca, xerostomia, or serologic abnormality. Confounding illnesses were excluded. All patients were white. RESULTS Of the 74 cases of SS identified, 50 (67%) had primary SS and 24 (33%) secondary SS. An average of 7.2 years of followup was available for patients with primary SS and 9.9 years for patients with secondary SS. Compared with the general population, patients with SS had increased mortality (p = 0.04). When patients with primary and secondary SS were studied separately, increased mortality was found in patients with secondary SS (p < 0.005) but not primary SS (p = 0.86). CONCLUSION In this population based cohort, patients with primary SS did not have increased mortality. However, mortality may have been increased in patients with secondary SS, the majority of whom had RA.
Immunologic differentiation of two high‐affinity neurotensin receptor isoforms in the developing rat brain

Earlier studies have demonstrated overexpression of NT1 neurotensin receptors in rat brain during the first 2 weeks of life. To gain insight into this phenomenon, we investigated the identity and distribution of NT1 receptor proteins in the brain of 10‐day‐old rats by using two different NT1 antibodies: one (Abi3) directed against the third intracellular loop and the other (Abi4) against the C‐terminus of the receptor. Immunoblot experiments that used Abi3 revealed the presence of two differentially glycosylated forms of the NT1 receptor in developing rat brain: one migrating at 54 and the other at 52 kDa. Whereas the 54‐kDa form was expressed from birth to adulthood, the 52‐kDa form was detected only at 10 and 15 days postnatal. Only the 52‐kDa isoform was recognized by Abi4. By immunohistochemistry, both forms of the receptor were found to be predominantly expressed in cerebral cortex and dorsal hippocampus, in keeping with earlier radioligand binding and in situ hybridization data. However, whereas Abi4 immunoreactivity was mainly concentrated within nerve cell bodies and extensively colocalized with the Golgi marker α‐mannosidase II, Abi3 immunoreactivity was predominantly located along neuronal processes. These results suggest that the transitorily expressed 52‐kDa protein corresponds to an immature, incompletely glycosylated and largely intracellular form of the NT1 receptor and that the 54‐kDa protein corresponds to a mature, fully glycosylated, and largely membrane‐associated form. They also indicate that antibodies directed against different sequences of G‐protein‐coupled receptors may yield isoform‐specific immunohistochemical labeling patterns in mammalian brain. Finally, the selective expression of the short form of the NT1 receptor early in development suggests that it may play a specific role in the establishment of neuronal circuitry. J. Comp. Neurol. 425:45–57, 2000. © 2000 Wiley‐Liss, Inc.
Titanium:sapphire laser trabeculoplasty versus argon laser trabeculoplasty in patients with open-angle glaucoma.

BACKGROUND AND OBJECTIVE To compare the medium-term outcome of titanium:sapphire laser trabeculoplasty (TLT) (SOLX, Inc., Waltham, MA) to argon laser trabeculoplasty (ALT) in patients with uncontrolled open-angle glaucoma. PATIENTS AND METHODS Thirty-seven patients with open-angle glaucoma who had uncontrolled intraocular pressure and no previous filtration surgery participated. Eighteen patients were treated with TLT and 19 patients were treated with ALT. All patients underwent comprehensive eye and visual field examinations. RESULTS The 18 patients in the TLT group had an average (+/- standard deviation) reduction of 8.3 (+/- 2.7) mm Hg, or 32%, from preoperative intraocular pressure (P < .001). The 19 patients in the ALT group had an average reduction of 6.5 (+/- 4.3) mm Hg, or 25%, from preoperative intraocular pressure (P < .001). Patients in both groups achieved a similar decrease in intraocular pressure (P > .05). Two patients (1 in each group) underwent trabeculectomy and were considered failures. Mean follow-up time was 15 months. CONCLUSION TLT provides similar efficacy to ALT in intraocular pressure reduction in patients with open-angle glaucoma. If confirmed in additional studies, TLT may be used as an alternative to ALT in patients with open-angle glaucoma.
Involving the End-Users in the Development of Language Learning Material

Printed and digital learning materials are usually developed separately. Therefore, little notice has been given to the possibilities of combining the two. This study introduces a new concept that combines printed and digital materials. A user-centric approach was chosen to develop a "hybrid book", a combination of a traditional schoolbook and a mobile phone. Learning materials were combined into one entity by enabling access to the digital material through images in the book. The user groups of interest were 11-and 12-year-old pupils, their teachers, and parents. The concept was tested with materials for English as a foreign language EFL. After a human-centred design process, the final application was given to one class for actual use and evaluation for a period of three weeks. Many potential benefits of using mobile phones for learning purposes were recognized, as they facilitated utilization of the digital content both inside and outside the classroom.
Covariation of alternative measures of responding in rabbit (Oryctolagus cuniculus) eyeblink conditioning during acquisition training and tone generalization.

The likelihood, size, and speed of eyelid movements are thought to covary during the acquisition and expression of conditioning in rabbits (Oryctolagus cuniculus) and are generally accepted as interchangeable measures of the associative strength activated by the conditioned stimulus (CS). To test this assumption, the authors examined the patterns of covariation in these eyelid movement measures in acquisition and stimulus generalization in the upper eyelid and nictitating membrane. Rather than the expected covariation among these measures, eyelid movement magnitudes during the CS were distributed in approximately a bimodal manner. That is, eyelid activity consisted largely of a mixture of very small (< 0.125 mm) baseline measurements and larger (> 1 mm) movements. The results are discussed with respect to their implications for real-time models of eyelid conditioning.
Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease

Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that impaired one-carbon metabolism resulting from folic acid deficiency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid β-peptide (Aβ) toxicity. Incubation of hippocampal cultures in folic acid-deficient medium or in the presence of methotrexate (an inhibitor of folic acid metabolism) or homocysteine induced cell death and rendered neurons vulnerable to death induced by Aβ. Methyl donor deficiency caused uracil misincorporation and DNA damage and greatly potentiated Aβ toxicity as the result of reduced repair of Aβ-induced oxidative modification of DNA bases. When maintained on a folic acid-deficient diet, amyloid precursor protein (APP) mutant transgenic mice, but not wild-type mice, exhibited increased cellular DNA damage and hippocampal neurodegeneration. Levels of Aβ were unchanged in the brains of folate-deficient APP mutant mice. Our data suggest that folic acid deficiency and homocysteine impair DNA repair in neurons, which sensitizes them to oxidative damage induced by Aβ.
Interleukin‐10 expression and function in experimental murine liver inflammation and fibrosis

Kupffer cells (KC) play a central role in the initiation and perpetuation of hepatic inflammation, which, if uncontrolled, can result in tissue damage, fibrosis, and cirrhosis. Interleukin‐10 (IL‐10) can inhibit a range of macrophage functions. We hypothesized that the transcription, synthesis, and release of IL‐10 may influence the development of liver injury. Rat KC were activated in vitro with lipopolysaccharide (LPS), and expression of IL‐10 mRNA compared with IL‐13 and IL‐1β by reverse‐transcription polymerase chain reaction (RT‐PCR). The effects of pretreatment with recombinant IL‐10 (rIL‐10) on KC phagocytosis, production of superoxide (SO), and tumor necrosis factor α (TNF‐α) were examined by fluorescent activated cell sorter (FACS), reduction of ferricytochrome C, and bioassay, respectively. Rats were administered intraperitoneal carbon tetrachloride (CCl4), and expression of IL‐10 mRNA and protein in vivo compared with IL‐13 and IL‐1β by RT‐PCR and immunoblotting. Results were correlated with histological inflammatory changes. Finally, IL‐10 gene‐deleted (IL‐10−/−) mice and wild‐type (WT) controls were administered intraperitoneal CCl4 biweekly for up to 70 days, and the development of inflammation and fibrosis compared by scoring histological changes. IL‐10 mRNA was up‐regulated early, both in KC in vitro and in whole liver in vivo, concurrent with that of IL‐1β. IL‐10 was able to inhibit KC production of both SO and TNF‐α in vitro, and this was achieved more effectively than IL‐4 or IL‐13; no such effects were seen on KC phagocytosis. After 70 days of treatment with CCl4, IL‐10−/− mice showed significantly more severe fibrosis and exhibited higher hepatic TNF‐α levels than WT controls. These results suggest that IL‐10 synthesized during the course of liver inflammation and fibrosis may modulate KC actions, and influence subsequent progression of fibrosis.
Complement-dependent Proinflammatory Properties of the Alzheimer's Disease β-Peptide

Large numbers of neuritic plaques (NP), largely composed of a fibrillar insoluble form of the β-amyloid peptide (Aβ), are found in the hippocampus and neocortex of Alzheimer's disease (AD) patients in association with damaged neuronal processes, increased numbers of activated astrocytes and microglia, and several proteins including the components of the proinflammatory complement system. These studies address the hypothesis that the activated complement system mediates the cellular changes that surround fibrillar Aβ deposits in NP. We report that Aβ peptides directly and independently activate the alternative complement pathway as well as the classical complement pathway; trigger the formation of covalent, ester-linked complexes of Aβ with activation products of the third complement component (C3); generate the cytokine-like C5a complement-activation fragment; and mediate formation of the proinflammatory C5b-9 membrane attack complex, in functionally active form able to insert into and permeabilize the membrane of neuronal precursor cells. These findings provide inflammation-based mechanisms to account for the presence of complement components in NP in association with damaged neurons and increased numbers of activated glial cells, and they have potential implications for the therapy of AD.
Tumour Necrosis Factor Alpha-308 Gene Locus Promoter Polymorphism: An Analysis of Association with Health and Disease

-308 whether polymorphisms of several cytokine genes are associated with the responsiveness to TNF with etanercept. 123 patients with active RA were with etanercept and response rates were determined after Rheumatology (ACR)20 activity score (DAS)28 response criteria. Genotyping was done for TNF (-308 TNFA), interleukin (IL)10 (-1087 IL10), transforming growth factor (TGF)beta1 (codon 25 TGFB1), and IL1 receptor antagonist (intron 2 IL1RN). The results indicated that 24 patients (20%) were defined as non-responders owing to their failure to fulfil any of the ACR20 or DAS28 response criteria. None of the recorded alleles was alone significantly associated with responsiveness to treatment. However, a certain combination of alleles (-308 TNF1/TNF1 and -1087 G/G) was associated with good responsiveness to etanercept (p<0.05). In addition, a combination of alleles influencing interleukin 1 receptor antagonist (IL1Ra) and TGFbeta1 production (A2 allele for IL1RN and rare C allele in codon 25 of TGFB1 gene) was associated with non-responsiveness (p<0.05). The study concluded that genetic polymorphisms, and anti-inflammatory cytokines the