Miracle-dz/UniFAR-FTUs huggingface dataset:
Influence of semisynthetic modification of the scaffold of a contact domain of HbS on polymerization: role of flexible surface topology in polymerization inhibition

A new variant of HbS, HbS-Einstein with a deletion of segment α23–26 in the B-helix, has been assembled by semisynthetic approach. B-helix of the α chain of cis αβ-dimer of HbS plays dominant role in the quinary interactions of deoxy HbS dimer. This B-helix is the primary scaffold that provides the orientation for the side chains of contact residues of this intermolecular contact domain. The design of HbS-Einstein has been undertaken to map the influence of perturbation of molecular surface topology and the flexibility of surface residues in the polymerization. The internal deletion exerts a strong inhibitory influence on Val-6 (β)-dependent polymerization, comparable to single contact site mutations and not for complete neutralization of Val-6(β)-dependent polymerization. The scaffold modification in cis-dimer is inhibitory, and is without any effect when present on the trans dimer. The flexibility changes in the surface topology in the region of scaffold modification apparently counteracts the intrinsic polymerization potential of the molecule. The inhibition is close to that of Le Lamentin mutation [His-20 (α) → Gln] wherein a mutation engineered without much change in flexibility of the contact domain. Interestingly, the chimeric HbS with swine–human chimeric α chain with multiple non-conservative mutations completely inhibits the Val-6(β)-dependent polymerization. The deformabilities of surface topology of chimeric HbS are comparable to HbS in spite of the multiple contact site mutations in the α-chain. We conclude that the design of antisickling Hbs for gene therapy of sickle cell disease should involve multiple mutations of intermolecular contact sites.
Imaging of the inflammatory response in reperfusion injury after transient cerebral ischemia in rats: correlation of superparamagnetic iron oxide-enhanced magnetic resonance imaging with histopathology

Background: Acute inflammatory responses have been thought to play a central role in ischemia-reperfusion injury after acute ischemic stroke. Superparamagnetic iron oxide (SPIO) particles have been known to enable in-vivo monitoring of macrophage infiltration by magnetic resonance imaging (MRI) in the experimental ischemic rat brain. Purpose: To determine whether the accumulation of macrophages could be seen in vivo in a reperfusion animal model after focal cerebral ischemia using SPIO-enhanced MRI. Material and Methods: Thirty-four adult male rats were enrolled in this study. SPIO particles were injected into the rats at different time points after 1-hour transient occlusion of the middle cerebral artery, and three-dimensional (3D) T2*-weighted magnetic resonance (MR) images with a gradient-echo sequence were performed 24 hours later. Histochemical iron staining was compared with T2* signal abnormalities. Results: At days 3 and 4 post-reperfusion, focal areas of signal loss indicating local accumulation of SPIO particles appeared in a part of the damaged brain. Areas of signal loss corresponded to local accumulation of iron-laden macrophages in histologic sections, and SPIO-induced signal loss indicated active macrophage transmigration into the reperfused brain. Conclusion: SPIO-enhanced MRI demonstrated through in-vivo monitoring that macrophages participate in reperfusion injury at early stages of injury development. SPIO-enhanced MRI could be a useful tool to examine the inflammatory mechanisms involved in reperfusion brain injury.
Agricultural Biotechnology's Complementary Intellectual Assets

We formulate and test a hypothesis for the dramatic restructuring that the plant breeding and seed industry has recently undergone: the reorganization can be explained in part by the desire to exploit complementarities between intellectual assets needed to create genetically modified organisms. This hypothesis is tested using data on agricultural biotechnology patents, notices for field tests of genetically modified organisms, and firm characteristics. The presence of complementarities is identified with a positive covariance in the unexplained variation of asset holdings. Results indicate that coordination of complementary assets has increased under the consolidation of the industry.
The use of a hemoglobin-based oxygen-carrying solution (HBOC-201) for extracorporeal membrane oxygenation in a porcine model with acute respiratory distress syndrome

Objective: To evaluate whether hemoglobin-based oxygen-carrying solution (HBOC)-201 (Biopure) is an effective alternative to donor blood for extracorporeal membrane oxygenation support in a porcine model of acute respiratory distress syndrome (ARDS). Design: Randomized animal clinical trial. Setting: Animal surgical research laboratory. Subjects: Immature Yorkshire swine were assigned to one of three groups: 1, noninjured animals, donor porcine blood primed circuit; 2, ARDS-injured, HBOC-201 primed circuit; or 3, ARDS-injured, donor blood primed. Interventions: ARDS injury was induced in groups 2 and 3 with oleic acid infusion before bypass. All animals were placed on full venoarterial extracorporeal membrane oxygenation support for 8 hrs. Measurements and Main Results: Physiologic variables and laboratory samples were measured at baseline and hourly for 8 hrs. Data analysis consisted of repeated-measures analysis of variance with post hoc analysis. We found that 100% of animals survived on extracorporeal membrane oxygenation for the duration of the study period. HBOC-supported animals had comparable oxygen delivery to both donor blood groups. Mean pulmonary artery pressure, heart rate, and lactate concentrations were higher in the injury groups. Blood pressure was mildly increased in HBOC animals (p < .05 vs. control animals). Methemoglobin concentrations in the HBOC group were elevated and increased over time on extracorporeal membrane oxygenation (p < .001). Conclusions: HBOC-201 appears to be an effective alternative circuit-priming agent for use during extracorporeal membrane oxygenation. HBOC offers the advantages of rapid availability and diminished donor blood cell exposure. The efficacy of HBOC in longer duration bypass, and its associated methemoglobinemia, need to be further investigated.
Late infections after allogeneic bone marrow transplantations: comparison of incidence in related and unrelated donor transplant recipients.

Infectious complications are a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). We have evaluated the incidence of late infections (beyond day +50) in recipients of related (RD) and unrelated donor (URD) allogeneic BMT, factors associated with increased risks of infection, and the impact of the late infections on survival. Between 1989 and 1991, 249 patients received an RD (n = 151) or URD (n = 98) allogeneic BMT at the University of Minnesota and all late infections were investigated. Three hundred sixty-seven late infectious events developed in 162 patients between 50 days and 2 years after BMT. The incidence of any late infection was greater in URD versus RD recipients (84.7% v 68.2%, respectively; P = .009). In multivariate analysis, advanced graft-versus-host disease (GVHD) was significantly associated with late infections. The effect of GVHD was apparent only in RD recipients (relative risk [RR], 2.29; P = .003), whereas URD recipients, with or without GVHD, had more late infections compared with RD recipients without GVHD. Multivariate analysis showed that late posttransplantation infections were the dominant independent factor associated with increased nonrelapse mortality (RR, 5.5; P = .0001), resulting in improved 3-year survival for RD versus URD recipients (49.9% +/- 8% v 34.4% +/- 10%; P = .004). In this study, we observed that late infections are more frequent in URD recipients, resulting in substantially higher nonrelapse mortality. This prolonged period of increased infectious risk in URD recipients suggests the need for aggressive surveillance and therapy of late infections and perhaps prolonged antibiotic prophylaxis for all URD BMT recipients.
First Newborn Baby to Receive Experimental Therapies Survives Ebola Virus Disease

Abstract A neonate born to an Ebola virus–positive woman was diagnosed with Ebola virus infection on her first day of life. The patient was treated with monoclonal antibodies (ZMapp), a buffy coat transfusion from an Ebola survivor, and the broad-spectrum antiviral GS-5734. On day 20, a venous blood specimen tested negative for Ebola virus by quantitative reverse-transcription polymerase chain reaction. The patient was discharged in good health on day 33 of life. Further follow-up consultations showed age-appropriate weight gain and neurodevelopment at the age of 12 months. This patient is the first neonate documented to have survived congenital infection with Ebola virus.
Electron microscopy of intestinal epithelial cells of piglets infected with a transmissible gastroenteritis virus.

An electron microscopic study of intestinal epithelial cells of neonatal piglets infected with transmissible gastroenteritis (TGE) virus revealed a unique parasite-host cell interaction. Entry of the TGE virus into intestinal epithelial cells of newborn piglets is mediated through a network of cytoplasmic tubules of plasmalemma origin. the tubules, called microcanaliculi, are morphologically distinct from endoplasmic reticulum and Golgi. In uninfected animals similar tubules appear to be responsible for the indiscriminate uptake of large quantities of macromolecules from colostrum during the first few days of life.Thin-section profiles of plasmalemma invaginations resembled tubules or canals and frequently contained viral particles. TGE viral particles developed and accumulated within cytoplasmic vacuoles. Initially the vacuoles were continuous with the microcanaliculi formed by deep plasmalemma invagination. Mature viral particles were 60 to 85 mu in diameter with an electron dense doughnut-shaped nucleoid surrounded by a trilaminar membrane which resembled the vacuolar wall. Abundant evidence of viral effects was observed in absorbtive epithelial cells of the jejunum and ileum but not of the duodenum. The ability of absorbtive intestinal epithelial cells to form deep cytoplasmic tubular invaginations is temporally related to the pathogenesis of TGE and may explain in part why pigs usually are fatally affected by TGE only during the neonatal period.
Postnatal development of the collagen matrix in rabbit tibial plateau articular cartilage

Changes in the 3‐dimensional arrangement of the articular cartilage matrix during growth of the rabbit tibial plateau were studied. Knees from newborn, and 1, 2 and 6 wk‐old rabbits were compared with those of adults by light and electron microscopy. The specimens were fixed, embedded en bloc in epoxy resin and sectioned vertically/coronally through the point where the articular cartilage was thickest in the adult medial tibial plateau. At birth, the proximal tibial epiphysis was cartilaginous, but nascent articular cartilage was recognisable as a densely cellular layer covering the tibial condyle. Within 30 μm of the articular surface, the chondrocytes were flattened and collagen fibres ran among these cells in a direction parallel to the surface. Deeper in the articular cartilage, rounded cells were evenly distributed within a random collagen fibril network. At the centre of the plateau, the tangential layer changed little during growth, whereas the subjacent cellular layer grew in thickness and steadily achieved a more vertical character in the organisation of its constituent collagen and cellular elements. At 1 wk, cells were separated into clusters by acellular regions filled with collagen fibrils. At 2 wk, cells within the forming radial zone were aligned in columns bracketed by vertical collagen fibres. Continuity of these vertical fibres with those in the tangential surface layer was evident at this age. The chondrocytes were surrounded by fibrous capsules typical of chondrons. By 6 wk, the bases of the radial collagen fibres in the very centre of the condyle had calcified, as had the adjacent hypertrophic hyaline cartilage. A solid subchondral plate and tidemark did not appear until skeletal maturity. From birth to age 6 wk, maximum thickness of the layer identified as primordial articular cartilage increased from 0.13 mm to 0.70 mm, and was 1.5 mm in the adult. Throughout growth, however, the thickness of the tangential layer in the centre of the plateau never exceeded 0.05 μm. In the patella, femoral head and peripheral tibial plateau, cartilage development followed the same general sequence. In contrast to the central tibial plateau, the tangential layer also grew in thickness, but at a slower rate than that of the radial zone. At all ages, the developing articular cartilage was structurally distinct from the deeper hyaline cartilage which contributed to growth of the ossification centre through enchondral ossification. The collagen matrix of articular cartilage acquires a characteristic, orderly 3‐dimensional structure soon after birth. Growth in cartilage thickness occurs primarily through enlargement of the radial zone.
The Use of Contrasted Transvaginal Sonography in the Diagnosis of Gynecologic Diseases

The purpose of this study was to evaluate the efficacy of a new contrast‐dedicated ultrasound technology, contrast‐tuned imaging (CnTI), implemented on an endovaginal probe and using the second‐generation contrast agent SonoVue (Bracco International BV, Amsterdam, the Netherlands), compared with the standard ultrasound examination in different gynecologic diseases.
Stop codon recognition in ciliates: Euplotes release factor does not respond to reassigned UGA codon

In eukaryotes, the polypeptide release factor 1 (eRF1) is involved in translation termination at all three stop codons. However, the mechanism for decoding stop codons remains unknown. A direct interaction of eRF1 with the stop codons has been postulated. Recent studies focus on eRF1 from ciliates in which some stop codons are reassigned to sense codons. Using an in vitro assay based on mammalian ribosomes, we show that eRF1 from the ciliate Euplotes aediculatus responds to UAA and UAG as stop codons and lacks the capacity to decipher the UGA codon, which encodes cysteine in this organism. This result strongly suggests that in ciliates with variant genetic codes eRF1 does not recognize the reassigned codons. Recent hypotheses describing stop codon discrimination by eRF1 are not fully consistent with the set of eRF1 sequences available so far and require direct experimental testing.
Intracellular Carbonic Anhydrase of Chlamydomonas reinhardtii

An intracellular carbonic anhydrase (CA; EC 4.2.1.1) was purified to homogeneity from a mutant strain of Chlamydomonas reinhardtii (CW 92) lacking a cell wall. Intact cells were washed to remove periplasmic CA and were lysed and fractionated into soluble and membrane fractions by sedimentation. All of the CA activity sedimented with the membrane fraction and was dissociated by treatment with a buffer containing 200 mM KCl. Solubilized proteins were fractionated by ammonium sulfate precipitation, anionic exchange chromatography, and hydrophobic interaction chromatography. The resulting fraction had a specific activity of 1260 Wilbur-Anderson units/mg protein and was inhibited by acetazolamide (50% inhibition concentration, 12 nM). Final purification was accomplished by the specific absorption of the enzyme to a Centricon-10 microconcentrator filter. A single, 29.5-kD polypeptide was eluted from the filter with sodium dodecyl sulfate-polyacrylamide gel electrophoresis sample buffer, and a 1.5 M ammonium sulfate eluate contained CA activity. In comparison with human CA isoenzyme II, the N-terminal and internal amino acid sequences from the 29.5-kD polypeptide were 40% identical with the N-terminal region and 67% identical with an internal conserved region. Based on this evidence, we postulate that the 29.5-kD polypeptide is an internal CA in C. reinhardtii and that the enzyme is closely related to the [alpha]-type CAs observed in animal species.
Design and Sample Size Considerations for Simultaneous Global Drug Development Program

Due to the potential impact of ethnic factors on clinical outcomes, the global registration of a new treatment is challenging. China and Japan often require local trials in addition to a multiregional clinical trial (MRCT) to support the efficacy and safety claim of the treatment. The impact of ethnic factors on the treatment effect has been intensively investigated and discussed from different perspectives. However, most current methods are focusing on the assessment of the consistency or similarity of the treatment effect between different ethnic groups in exploratory nature. In this article, we propose a new method for the design and sample size consideration for a simultaneous global drug development program (SGDDP) using weighted z-tests. In the proposed method, to test the efficacy of a new treatment for the targeted ethnic (TE) group, a weighted test that combines the information collected from both the TE group and the nontargeted ethnic (NTE) group is used. The influence of ethnic factors and local medical practice on the treatment effect is accounted for by down-weighting the information collected from NTE group in the combined test statistic. This design controls rigorously the overall false positive rate for the program at a given level. The sample sizes needed for the TE group in an SGDDP for three most commonly used efficacy endpoints, continuous, binary, and time-to-event, are then calculated.
Report on the Cooperative Study of Intracranial Aneurysms and Subarachnoid Hemorrhage * SECTION VII PART I Evaluation of the Conservative Management of Ruptured Intracranial Aneurysmst

T hE prognosis of subarachnoid hemorrhage as reported in the li terature has been reviewed in Section I (Sahs et al. '66). The reports of such authors as Hyland '50 and Walton '55 contained a mixture of cases of aneurysms, arteriovenous malformations, hypertensive hemorrhages, and miscellaneous conditions giving rise to subarachnoid hemorrhage. No specific breakdown of the prognosis for the various etiological types was available in the early l i terature because angiography was not utilized routinely. Thus in Hyland ' s 191 cases, 55 came to autopsy and of these, 44 had aneurysms. In the series of Ask-Upmark and Ingvar '50, 47 were autopsied with the disclosure of e9 aneurysms. I t is not clear exactly what these autopsy findings mean in terms of the etiological distributions in the remaining cases. On the basis of these two series in which e8% of 10e patients showed no aneurysm, one cannot assume tha t the same proport ion of the living patients have no aneurysm, for those with aneurysm may have had a greater tendency to die.
Antioxidant Compounds from Algerian Convolvulus tricolor (Convolvulaceae) Seed Husks

Seed husk extracts of Convolvulus tricolor L. (Convolvulaceae) afforded six compounds, identified for the first time from this plant: isorhamnetin 3-O-β-D-galactopyranoside (1), isorhamnetin 3-O-β-D-(6″-acetyl)-galactopyranoside (2), isorhamnetin 3-O-robinobioside (3), 3,4-di-O-caffeoylquinic acid (4), gentisic acid 5-O-glucoside (5), and scopoletin (6). Separation of compounds was carried out by CC and CPC. Structural elucidations were performed by HPLC-UV-DAD, HPLC-ESI/MS (negative mode) and NMR.
Toll-Like Receptors 4 and 5 Induce Distinct Types of Vasculitis

Large vessel vasculitides, such as Takayasu arteritis and giant cell arteritis, affect vital arteries and cause clinical complications by either luminal occlusion or vessel wall destruction. Inflammatory infiltrates, often with granulomatous arrangements, are distributed as a panarteritis throughout all of the artery’s wall layers or cluster in the adventitia as a perivasculitis. Factors determining the architecture and compartmentalization of vasculitis are unknown. Human macrovessels are populated by indigenous dendritic cells (DCs) positioned in the adventitia. Herein, we report that these vascular DCs sense bacterial pathogens and regulate the patterning of the emerging arteritis. In human temporal artery–SCID chimeras, lipopolysaccharides stimulating Toll-like receptor (TLR)4 and flagellin stimulating TLR5 trigger vascular DCs and induce T-cell recruitment and activation. However, the architecture of the evolving inflammation is ligand-specific; TLR4 ligands cause transmural panarteritis and TLR5 ligands promote adventitial perivasculitis. Underlying mechanisms involve selective recruitment of functional T cell subsets. Specifically, TLR4-mediated DC stimulation markedly enhances production of the chemokine CCL20, biasing recruitment toward CCL20-responsive CCR6+ T cells. In adoptive transfer experiments, CCR6+ T cells produce an arteritis pattern with media-invasive T cells damaging vascular smooth muscle cells. Also, CCR6+ T cells dominate the vasculitic infiltrates in patients with panarteritic giant cell arteritis. Thus, depending on the original danger signal, vascular DCs edit the emerging immune response by differentially recruiting specialized T effector cells and direct the disease process toward distinct types of vasculitis.
Small GTPase and Regulation of Inflammation Response in Atherogenesis

Abstract: Small GTPases are key signal transducers from extracellular stimuli to the nucleus that regulate a variety of cellular responses, including changes in gene expression and cell adhesion and migration. Accumulating data have demonstrated that abnormal activation of these small GTPases plays a critical role in the atherosclerosis characterized by vascular abnormalities, especially endothelial dysfunction and inflammation. Here, we discuss the linkage between small GTPases, inflammation, and atherogenesis. First, small GTPases affect gene expression of inflammatory cytokines through proinflammatory signaling pathways, such as nuclear factor-&kgr;B, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interlukin-8, and monocyte chemoattractant protein-1. Then, these molecules regulate the vascular inflammation through cell adhesion and migration. In turn, small GTPases are also regulated by extracellular stimuli, such as L-selectin, thrombin, oxidized phospholipids, and interleukins. Thus, these inflammatory cytokines generate a vicious cycle for small GTPases and inflammatory responses in the atherogenesis.