Miracle-dz/UniFAR-FTUs huggingface dataset:
Secretion of a malarial histidine-rich protein (Pf HRP II) from Plasmodium falciparum-infected erythrocytes

Plasmodium falciparum-infected erythrocytes (IRBCs) synthesize several histidine-rich proteins (HRPs) that accumulate high levels of [3H]histidine but very low levels of amino acids such as [3H]isoleucine or [35S]methionine. We prepared a monoclonal antibody which reacts specifically with one of these HRPs (Pf HRP II) and studied the location and synthesis of this protein during the parasite's intracellular growth. With the knob-positive Malayan Camp strain of P. falciparum, the monoclonal antibody identified a multiplet of protein bands with major species at Mr 72,000 and 69,000. Pf HRP II synthesis began with immature parasites (rings) and continued through the trophozoite stage. The Mr 72,000 band of Pf HRP II, but not the faster moving bands of the multiplet, was recovered as a water-soluble protein from the culture supernatant of intact IRBCs. Approximately 50% of the total [3H]histidine radioactivity incorporated into the Mr 72,000 band was extracellular between 2 and 24 h of culture. Immunofluorescence and cryothin-section immunoelectron microscopy localized Pf HRP II to several cell compartments including the parasite cytoplasm, as concentrated "packets" in the host erythrocyte cytoplasm and at the IRBC membrane. Our results provide evidence for an intracellular route of transport for a secreted malarial protein from the parasite through several membranes and the host cell cytoplasm.
The Treatment of Patients With Disseminated Malignant Melanoma by Vaccination With Autologous Cell Hybrids of Tumor Cells and Dendritic Cells

Malignant melanoma has been shown to be susceptible to T cell-mediated immunity and, therefore, is a candidate for vaccination approaches. Clinical trials using dendritic cells (DC) loaded with peptides corresponding to tumor antigens are ongoing in several institutions, and some promising results have already been published. However, every single peptide-based vaccine can only be used in a patient with a given single HLA type, and this strategy is not appropriate for patients with rare HLA types or with tumors without defined antigens. A clinical pilot study in patients with disseminated melanoma refractory to standard therapy was initiated using a different approach. The authors generated autologous monocyte-derived DC and fused these DC with gamma-irradiated primary autologous tumor cells by incubation in polyethylene glycol. In previous experiments, the authors had shown that these fused cell products are potent inducers of a T-cell response in a mixed lymphocyte tumor cell culture. Seventeen patients were immunized with the cell product by s.c. injection in monthly intervals without any serious side effects. Of these patients, one had a partial response with decrease in size of all evaluable tumor manifestations. In one patient, some of the metastases were regressing despite an overall progressive disease, and one patient achieved disease stabilization for six months. In the responding patient, in parallel to tumor regression, circumscript hair depigmentation occurred. These data show, that a hybrid vaccine of DC and tumor cells can be safely applied and can induce tumor regressions, however, the clinical efficacy of the approach in its present form is insufficient.
Collagen matrix duraplasty for posterior fossa surgery: evaluation of surgical technique in 52 adult patients. Clinical article.

OBJECT Complete dural closure is not always possible following posterior fossa surgery, often requiring a graft to secure complete closure. The authors report their experience of using a collagen matrix as an onlay dural graft for repair of a posterior fossa dural defect. METHODS A retrospective analysis was performed in 52 adult patients who had undergone collagen matrix duraplasty for the posterior fossa. Complications directly related to the dural graft, the presence or absence of hydrocephalus, and the role of closed suction wound drainage in relation to postsurgical pseudomeningoceles were analyzed. RESULTS The indication for posterior fossa surgery was tumors in 32 patients, vascular abnormalities in 9 patients, and spontaneous cerebellar hemorrhage in 11 patients. Closed suction wound drainage was used in 23 patients (44.2%). Forty-eight (92.3%) of 52 patients had a dural defect > 2 cm. Nine (81.8%) of 11 patients with hydrocephalus required ventriculoperitoneal shunts. Complications of the surgery included pseudomeningoceles in 2 patients (3.8%; no closed suction wound drainage); superficial wound infections in 1 patient (1.9%; with closed suction wound drainage); and unexplained eosinophilia in 1 patient. CONCLUSIONS Duraplasty using a collagen matrix is safe and effective in the posterior fossa, and is easy to use and time efficient. Meticulous layered wound closure, the detection and effective control of hydrocephalus, and the use of closed suction wound drainage reduces complications related to collagen matrix duraplasty for the posterior fossa.
Dexmedetomidine versus midazolam for conscious sedation in endoscopic retrograde cholangiopancreatography: An open-label randomised controlled trial

Background: Traditionally, midazolam has been used for providing conscious sedation in endoscopic retrograde cholangiopancreatography (ERCP). Recently, dexmedetomidine has been tried, but very little evidence exists to support its use. Objective: The primary objective was to compare haemodynamic, respiratory and recovery profile of both drugs. Secondary objective was to compare the degree of comfort experienced by patients and the usefulness of the drug to endoscopist. Study Design: Open-label Randomised Controlled Trial. Methods: Subjects between 18 and 60 years of age with American Society of Anaesthesiologist Grade I-II requiring ERCP were enrolled in two groups (30 each). Both groups received fentanyl 1 μg/kg IV at the beginning of ERCP. Group M received IV midazolam (0.04 mg/kg) and additional 0.5 mg doses until Ramsay Sedation Scale (RSS) score reached 3-4. Group D received dexmedetomidine at loading dose of 1 μg/kg over 10 min followed by 0.5 μg/kg/h infusion until RSS reached 3-4. The vital parameters (heart rate (HR), blood pressure (BP), respiration rate, SpO 2 ), time to achieve RSS 3-4 and facial pain score (FPS) were compared during and after the procedure. In the recovery room, time to reach modified Aldrete score (MAS) 9-10 and patient and surgeon′s satisfaction scores was also recorded and compared. Any complication during or after the procedure were also noted. Results: In Group D, patients had lower HR and FPS at 5, 10 and 15 min following the initiation of sedation (P<0.05). There was no statistically significant difference in BP and respiratory rate. The procedure elicited a gag response in 29 (97%) and 7 (23%) subjects in Group M and Group D respectively (P<0.05). MAS of 9-10 at 5 min during recovery was achieved in 27 (90%) subjects in Group D in contrast to 5 (17%) in Group M (P<0.05). Dexmedetomidine showed higher patient and surgeon satisfaction scores (P<0.05). Conclusion: Dexmedetomidine can be a superior alternative to midazolam for conscious sedation in ERCP.
Investigating superiority of novel bilosomes over niosomes in the transdermal delivery of diacerein: in vitro characterization, ex vivo permeation and in vivo skin deposition study

Abstract Skin is considered the most accessible organ of the body because of its underlying capillary network. However, stratum corneum (SC), the upper most layer of skin, represents major diffusional barrier for most drugs. Hence, the use of edge activators (EAs) in designing novel elastic vesicles is hypothesized to impart their lipid bilayer with ultra-flexibility to trespass SC by high self-optimizing deformability. To confirm this hypothesis, this work aimed at developing novel bilosomes by modulating conventional niosomal composition using different bile salts as EAs and investigating their superiority over niosomes for transdermal delivery of diacerein (DCN), as model drug. Bilosomes were prepared by thin film hydration (TFH) technique according to full 31.22 factorial design to select the optimal formulation using Design-Expert® software. The optimal bilosomes (B6) showed nanosized vesicles (301.65 ± 17.32 nm) and 100.00 ± 0.00 % entrapment efficiency. Ex vivo permeation studies and in vivo evaluation revealed that B6 exhibited superior permeation and drug retention capacity compared to the conventional niosomal formulation and drug suspension. Furthermore, B6 was subjected to in vivo histopathological study using male Wistar rats which ensured its safety for topical application. Overall, the results confirmed the hypothesized superiority of bilosomes over niosomes for enhancing DCN flux across the skin.
Shear stress-induced changes of membrane transporter localization and expression in mouse proximal tubule cells

Our previous studies of microperfused single proximal tubule showed that flow-dependent Na+ and HCO3− reabsorption is due to a modulation of both NHE3 and vacuolar H+-ATPase (V-ATPase) activity. An intact actin cytoskeleton was indicated to provide a structural framework for proximal tubule cells to transmit mechanical forces and subsequently modulate cellular functions. In this study, we have used mouse proximal tubule (MPT) cells as a model to study the role of fluid shear stress (FSS) on apical NHE3 and V-ATPase and basolateral Na/K-ATPase trafficking and expression. Our hypothesis is that FSS stimulates both apical and basolateral transporter expression and trafficking, which subsequently mediates salt and volume reabsorption. We exposed MPT cells to 0.2 dynes/cm2 FSS for 3 h and performed confocal microscopy and Western blot analysis to compare the localization and expression of both apical and basolateral transporters in control cells and cells subjected to FSS. Our findings show that FSS leads to an increment in the amount of protein expression, and a translocation of apical NHE3 and V-ATPase from the intracellular compartment to the apical plasma membrane and Na/K-ATPase to the basolateral membrane. Disrupting actin by cytochalasin D blocks the FSS-induced changes in NHE3 and Na/K-ATPase, but not V-ATPase. In contrast, FSS-induced V-ATPase redistribution and expression are largely inhibited by colchicine, an agent that blocks microtubule polymerization. Our findings suggest that the actin cytoskeleton plays an important role in FSS-induced NHE3 and Na/K-ATPase trafficking, and an intact microtubule network is critical in FSS-induced modulation of V-ATPase in proximal tubule cells.
L‐Type Calcium Current Reactivation Contributes to Arrhythmogenesis Associated with Action Potential Triangulation

Introduction: The morphology of the mammalian cardiac action potential (AP) is an important factor in the susceptibility to drug‐induced early afterdepolarizations (EADs) that may initiate Torsade de Pointes (TdP). AP triangulation has been shown to be an important predictor of drug‐induced TdP.
Identification of the Structural and Functional Domains of the Large Serine Recombinase TnpX from Clostridium perfringens*

Members of the large serine resolvase family of site-specific recombinases are responsible for the movement of several mobile genetic elements; however, little is known regarding the structure or function of these proteins. TnpX is a serine recombinase that is responsible for the movement of the chloramphenicol resistance elements of the Tn4451/3 family. We have shown that TnpX binds differentially to its transposon and target sites, suggesting that resolvase-like excision and insertion were two distinct processes. To analyze the structural and functional domains of TnpX and, more specifically, to define the domains involved in protein-DNA and protein-protein interactions, we conducted limited proteolysis studies on the wild-type dimeric TnpX1–707 protein and its functional truncation mutant, TnpX1–597. The results showed that TnpX was organized into three major domains: domain I (amino acids (aa) 1–170), which included the resolvase catalytic domain; domain II (aa 170–266); and domain III (aa 267–707), which contained the dimerization region and two separate regions involved in binding to the DNA target. A small polypeptide (aa 533–587) was shown to bind specifically to the TnpX binding sites providing further evidence that it was the primary DNA binding region. In addition, a previously unidentified DNA binding site was shown to be located between residues 583 and 707. Finally, the DNA binding and multerimization but not the catalytic functions of TnpX could be reconstituted by recombining separate polypeptides that contain the N- and C-terminal regions of the protein. These data provide evidence that TnpX has separate catalytic, DNA binding, and multimerization domains.
Treaty Of Amsterdam Amending The Treaty On European Union The Treaties Establishing The European Communities And Certain Related Acts

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Arming oncolytic viruses to leverage antitumor immunity

Introduction: Over the past decade, the cytolytic capabilities of oncolytic viruses (OVs), exploited to selectively eliminate neoplastic cells, have become secondary to their use to elicit a tumor-directed immune response. Areas covered: Here, based on an NCBI-PubMed literature survey, we review the efforts undertaken to arm OVs in order to improve therapeutic antitumor responses upon administration of these agents. Specifically, we explore the different options to modulate immune suppression in the tumor microenvironment (TME) and to facilitate the generation of effective antitumor responses that have been investigated in conjunction with OVs in recent years. Expert opinion: Their induction of immunogenic tumor cell death and association with pro-inflammatory signals make OVs attractive immunotherapeutic modalities. The first promising clinical results with immunologically armed OVs warrant their further optimization and development. OVs should be modified to avoid detrimental effects of pre-existent anti-OV immunity as well as for increased tumor targeting and selectivity, so as to ultimately allow for systemic administration while achieving local immune potentiation and tumor elimination in the TME. In particular, a combination of trans-genes encoding bispecific T-cell engagers, immune checkpoint blockers and antigen-presenting cell enhancers will remove suppressive hurdles in the TME and allow for optimal antitumor efficacy of armed OVs.
Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets.

The ability of methyl-deficient, amino acid-defined diets to produce liver tumors was studied in rats treated both with and without initiating doses of diethylnitrosamine (DENA). Male, weanling F344 rats were fed a complete, amino acid-defined diet for one week. They were then injected once i.p. with one of 3 doses of DENA (20, 70 or 200 mg/kg body weight) and fed the complete diet for an additional week. Thirty animals from each dose group were then maintained for 76 weeks on the complete diet (Diet 1) or one of 4 methyl-deficient diets: Diet 2, devoid of methionine and choline; Diet 3, devoid of methionine only; Diet 4, devoid of choline only and Diet 5, devoid of methionine, choline, folic acid and vitamin B12. In Diets 2, 3 and 5 methionine was replaced by equimolar amounts of its metabolic precursor DL-homocystine. Control rats were injected i.p. with the saline vehicle and maintained for the 76-week period on Diets 1 and 2. Forty percent of the rats fed Diet 2, but receiving no DENA, developed hepatocellular carcinomas or cholangiomas. A 90-100% incidence of hepatocellular carcinomas was seen in all groups initiated with DENA and fed Diet 2. No malignant liver tumors developed in Diet 1 rats that had received 0 or 20 mg/kg DENA; however, hepatocellular carcinomas were noted in one-half of such animals receiving the 70 and 200 mg/kg doses. Liver metastases grew in the lungs of 60% of the tumor-bearing rats fed Diet 2; none were seen in the Diet 1-fed rats. The singly deficient Diets 3 and 4 enhanced liver tumor formation to DENA-initiated rats to a significantly lesser extent than did Diet 2. All DENA-initiated rats fed the severely deficient Diet 5, died within 23 experimental weeks with livers containing hepatocytes of atypical appearance and, particularly at the 2 higher dosages, a cirrhotic pseudonodular architecture. No hepatocellular carcinomas or cholangiomas were observed in Diet 5-fed rats. None of the diets tested appeared to enhance tumor formation in extrahepatic tissues. In fact, significant decreases were noted in the formation of spontaneous testicular interstitial cell tumors in Diet 2-fed rats and of pancreatic acinar tumors in rats fed Diets 2 and 3. Diet 2, devoid of both methionine and choline, also induced metaplasia of pancreatic acinar cells to hepatocyte-like cells and was associated with moderate to severe hyperplasia of the transitional epithelium lining the renal pelvis. (ABSTRACT TRUNCATED AT 400 WORDS)
The Effects of a Central Bank's Inflation Forecasts on Private Sector Forecasts: Recent Evidence from Japan

How central banks can best communicate to the market is an increasingly important topic in the central banking literature. With ever greater frequency, central banks communicate to the market through the forecasts of prices and output with the purposes of reducing uncertainty; at the same time, central banks generally rely on a publicly stated medium-term inflation target to help anchor expectations. This paper aims to document how much the release of the forecasts of one major central bank, the Bank of Japan (BOJ), has influenced private sector expectations of inflation, and whether the degree of influence depends to any degree on the adoption of an inflation target (IT). Consistent with earlier studies, we find the central bank's forecasts to be quite influential on private sector forecasts. In the case of next year forecasts, their impact continues into the IT regime. Thus, the difficulties of aiming at an inflation target from below do not necessarily diminish the influence of the central bank's inflation forecasts.
Melatonin and Light Induce Phase Shifts of Circadian Activity Rhythms in the C3H/HeN Mouse

This study examines the effect of light pulses and administration of the pineal hormone melatonin on the circadian activity rhythm of C3H/HeN mice. Mice were housed in constant dark in cages equipped with running wheels. Phase shifts in the circadian rhythm of wheel-running activity were measured following treatment with a 15-min pulse of light (300 lux) or administration of vehicle (ethanol/saline) or melatonin (90 μg, sc). Light treatment induced phase changes in circadian activity rhythms; specifically, delays during early subjective night (circadian time [CT] 12.5 to CT 18.5) and advances during late subjective night (CT 0.5). A single dose of melatonin administered at various CTs had no consistent effect on free-running circadian activity rhythms. By contrast, melatonin administration for 3 consecutive days at the same clock time induced advances in circadian activity rhythms by more than 1 h when the first dose was administered at CT 10 and induced delays in circadian activity rhythms by up to 1 h when the first dose was administered between CT 24 and CT 2. With the caveat that multi- ple melatonin treatments are required to induce phase shifts, the results suggest that the circadian timing system controlling the rhythm of wheel-running activity in the C3H/HeN mouse is responsive to both light and melatonin.
Maternal Outcomes in Pregnancies Complicated by Obesity

OBJECTIVE: To investigate the relationship between prepregnancy obesity and maternal outcomes. METHODS: A 15-year, population-based cohort study using the Nova Scotia Atlee Perinatal Database compared maternal outcomes in obese and nonobese women. Prepregnancy weight of 55–75 kg was considered nonobese, and weight greater than 90 kg was considered obese. Obese women were categorized into moderate obesity (90–120 kg) and severe obesity (> 120 kg) groups. Univariate and multivariable logistic regression analysis was performed, and odds ratios (ORs), adjusted ORs, and 95% confidence intervals (CIs) were calculated. P < . 05 was considered statistically significant. RESULTS: In 142,404 singleton pregnancies, 10,134 (7.2%) women were identified as obese (moderate obesity 92.3%, severe obesity 7.7%). The proportion of women in the obese categories increased from 3.2% in 1988 to 10.2% in 2002. Moderately obese women had an increased risk of pregnancy-induced hypertension (PIH) (adjusted OR 2.38, 95% CI 2.24–2.52), antepartum venous thromboembolism (adjusted OR 2.17, 95% CI 1.30–3.63), labor induction (adjusted OR 1.94, 95% CI 1.86–2.04), cesarean delivery (adjusted OR 1.60, 95% CI 1.53–1.67), and wound infection (adjusted OR 1.67, 95% CI 1.38–2.00). Severely obese women had an increased risk of PIH (adjusted OR 3.00, 95% CI 2.49–3.62), antepartum venous thromboembolism (adjusted OR 4.13, 95% CI 1.26–13.54), induction of labor (adjusted OR 2.77, 95% CI 2.39–3.21), cesarean delivery (adjusted OR 2.46, 95% CI 2.15–2.81), anesthesia complications (adjusted OR 2.01, 95% CI 1.33–3.06), and wound infection (adjusted OR 4.79, 95% CI 3.30–6.95). This implies that, relative to nonobese women, there was 1 excess case of PIH per 10 moderately obese women and 1 per 7 severely obese women. For antepartum venous thromboembolism, there was 1 excess case per 857 moderately obese women and 1 per 321 severely obese women. CONCLUSION: Prepregnancy maternal obesity increases the risk of PIH, antepartum venous thromboembolism, labor induction, cesarean delivery, and wound infection. LEVEL OF EVIDENCE: II-2
Quorum Sensing-Controlled Biofilm Development in Serratia liquefaciens MG1

ABSTRACT Serratia liquefaciens MG1 contains an N-acylhomoserine lactone-mediated quorum-sensing system that is known to regulate swarming motility colonization. In this study, we describe for S. liquefaciens MG1 the development of a novel biofilm consisting of cell aggregates and differentiated cell types, such as cell chains and long filamentous cells. Furthermore, quorum sensing is shown to be crucial for normal biofilm development and for elaborate differentiation. A mutant of S. liquefaciens MG1 that was incapable of synthesizing extracellular signal formed a thin and nonmature biofilm lacking cell aggregates and differentiated cell chains. Signal-based complementation of this mutant resulted in a biofilm with the wild-type architecture. Two quorum-sensing-regulated genes (bsmA and bsmB) involved in biofilm development were identified, and we propose that these genes are engaged in fine-tuning the formation of cell aggregates at a specific point in biofilm development.