Miracle-dz/UniFAR-FTUs huggingface dataset:
Prothrombotic mutations, family history and the risk of thrombosis in postmenopausal women: implications for hormone replacement therapy

Objective Hormone replacement therapy (HRT) is acknowledged as the gold standard for the alleviation of climacteric vasomotor symptoms. Prothrombotic genetic variants have been suggested to increase thrombotic risk among HRT users. The aim of the study was to determine whether a positive family history may identify a genetic predisposition for thrombosis in women before prescribing HRT. Methods From January 2005 to May 2009, we consecutively enrolled 145 asymptomatic women (mean age 51.2 ± 5.4 years) without previous episodes of venous and/or arterial thrombosis referred to our Genetics Research Unit before starting HRT. A detailed family history was reconstructed and we identified 48 women (33.1%%) with a positive family history, defined as venous thromboembolism and/or stroke or heart attack, in first-degree relatives before 60 years for men and 65 years for women. A group of 121 women (mean age 54.0 ± 9.1 years) with an episode of venous and/or arterial thrombosis was also included. Genetic screening for factor V Leiden, prothrombin G20210A and methylenetetrahydrofolate reductase C677T polymorphisms was performed. Results The frequency of factor V Leiden or prothrombin G20210A mutations was significantly higher both in asymptomatic women with a positive family history (16.7%% vs. 2.1%%, p == 0.001) and in patients with thrombosis (12.4%% vs. 2.1%%; p == 0.005) compared with asymptomatic women without a family history. Multivariate regression analysis showed a synergic effect between the presence of one prothrombotic mutation and family history on the risk of thrombosis (odds ratio 3.7, 95%% confidence interval 1.9–7.2). Conclusions A positive family history of thrombosis is a sensitive indicator for selected genetic testing in high-risk women before starting HRT.
A Theory of Aggregate Demand Fluctuations and Asset Bubbles

We look at the financial markets as represented by a network of agents similar to bond percolation models in physics or epidemiology models. We aim to figure out how an agent based network model can cause perturbations that can cause failures of the traditional economic theory, specifically the AD-AS model of New Keynesian Theory. This model is utilized for its dual uses of having an inbuilt correction mechanism that is similar to what markets display and real world correlations in micro behaviour. We analyse the threshold conditions that result in boundaries beyond which an idea can spread throughout the network and look at the various factors that contribute towards such information percolation. It allows us a look into the micro-behaviour of agents involved in the markets and helps us look at a specific role of the market as a provider of feedback on actions taken. It further gives us a good insight into the roles needed to be played by policymakers and market regulators and gives a few modest proposals that could serve as a warning mechanism against future bubbles and Great Depressions. We look into such a system here to model how bubbles form in economic systems as a consequence of its current architecture and information transmission.
Fabrication of three-dimensional scaffolds using precision extrusion deposition with an assisted cooling device

In the field of biofabrication, tissue engineering and regenerative medicine, there are many methodologies to fabricate a building block (scaffold) which is unique to the target tissue or organ that facilitates cell growth, attachment, proliferation and/or differentiation. Currently, there are many techniques that fabricate three-dimensional scaffolds; however, there are advantages, limitations and specific tissue focuses of each fabrication technique. The focus of this initiative is to utilize an existing technique and expand the library of biomaterials which can be utilized to fabricate three-dimensional scaffolds rather than focusing on a new fabrication technique. An expanded library of biomaterials will enable the precision extrusion deposition (PED) device to construct three-dimensional scaffolds with enhanced biological, chemical and mechanical cues that will benefit tissue generation. Computer-aided motion and extrusion drive the PED to precisely fabricate micro-scaled scaffolds with biologically inspired, porosity, interconnectivity and internal and external architectures. The high printing resolution, precision and controllability of the PED allow for closer mimicry of tissues and organs. The PED expands its library of biopolymers by introducing an assisting cooling (AC) device which increases the working extrusion temperature from 120 to 250 °C. This paper investigates the PED with the integrated AC's capabilities to fabricate three-dimensional scaffolds that support cell growth, attachment and proliferation. Studies carried out in this paper utilized a biopolymer whose melting point is established to be 200 °C. This polymer was selected to illustrate the newly developed device's ability to fabricate three-dimensional scaffolds from a new library of biopolymers. Three-dimensional scaffolds fabricated with the integrated AC device should illustrate structural integrity and ability to support cell attachment and proliferation.
Gamma Interferon (IFN-γ) Receptor Restricts Systemic Dengue Virus Replication and Prevents Paralysis in IFN-α/β Receptor-Deficient Mice

ABSTRACT We previously reported that mice lacking alpha/beta and gamma interferon receptors (IFN-α/βR and -γR) uniformly exhibit paralysis following infection with the dengue virus (DENV) clinical isolate PL046, while only a subset of mice lacking the IFN-γR alone and virtually no mice lacking the IFN-α/βR alone develop paralysis. Here, using a mouse-passaged variant of PL046, strain S221, we show that in the absence of the IFN-α/βR, signaling through the IFN-γR confers approximately 140-fold greater resistance against systemic vascular leakage-associated dengue disease and virtually complete protection from dengue-induced paralysis. Viral replication in the spleen was assessed by immunohistochemistry and flow cytometry, which revealed a reduction in the number of infected cells due to IFN-γR signaling by 2 days after infection, coincident with elevated levels of IFN-γ in the spleen and serum. By 4 days after infection, IFN-γR signaling was found to restrict DENV replication systemically. Clearance of DENV, on the other hand, occurred in the absence of IFN-γR, except in the central nervous system (CNS) (brain and spinal cord), where clearance relied on IFN-γ from CD8+ T cells. These results demonstrate the roles of IFN-γR signaling in protection from initial systemic and subsequent CNS disease following DENV infection and demonstrate the importance of CD8+ T cells in preventing DENV-induced CNS disease.
Mechanistic studies of cyclohexanone monooxygenase: chemical properties of intermediates involved in catalysis.

Cyclohexanone monooxygenase (CHMO), a bacterial flavoenzyme, carries out an oxygen insertion reaction on cyclohexanone to form a seven-membered cyclic product, epsilon-caprolactone. The reaction catalyzed involves the four-electron reduction of O2 at the expense of a two-electron oxidation of NADPH and a two-electron oxidation of cyclohexanone to form epsilon-caprolactone. Previous studies suggested the participation of either a flavin C4a-hydroperoxide or a flavin C4a-peroxide intermediate during the enzymatic catalysis [Ryerson, C. C. , Ballou, D. P., and Walsh, C. (1982) Biochemistry 21, 2644-2655]. However, there was no kinetic or spectral evidence to distinguish between these two possibilities. In the present work we used double-mixing stopped-flow techniques to show that the C4a-flavin-oxygen adduct, which is formed rapidly from the reaction of oxygen with reduced enzyme in the presence of NADP, can exist in two states. When the reaction is carried out at pH 7.2, the first intermediate is a flavin C4a-peroxide with maximum absorbance at 366 nm; this intermediate becomes protonated at about 3 s(-1) to form what is believed to be the flavin C4a-hydroperoxide with maximum absorbance at 383 nm. These two intermediates can be interconverted by altering the pH, with a pK(a) of 8.4. Thus, at pH 9.0 the flavin C4a-peroxide persists mainly in the deprotonated form. Further kinetic studies also demonstrated that only the flavin C4a-peroxide intermediate could oxygenate the substrate, cyclohexanone. The requirement in catalysis of the deprotonated flavin C4a-peroxide, a nucleophile, is consistent with a Baeyer-Villiger rearrangement mechanism for the enzymatic oxygenation of cyclohexanone. In the course of these studies, the Kd for cyclohexanone to the C4a-peroxyflavin form of CHMO was determined to be approximately 1 microM. The rate-determining step in catalysis was shown to be the release of NADP from the oxidized enzyme.
Riboprinting: A Tool for the Study of Genetic Diversity in Microorganisms 1

ABSTRACT. Classical morphology‐based methods of taxonomic and phylogenetic analysis are inadequate in many groups of structurally simple eukaryotes. Molecular methods can generate data independently of the complexity of the organisms’ morphology. Riboprinting is one such technique, and involves restriction enzyme analysis of polymerase chain reaction amplified small subunit ribosomal RNA genes. The utility of the method is illustrated with examples from several genera of intestinal and bloodstream parasites. Among the applications of riboprinting are the detection of cryptic genetic variation within species, organism misidentifications and culture mix‐ups, independent verification of DNA sequences, and the rapid generation of data useful in phylogenetic analyses.
Albumin Stimulates the Accumulation of Extracellular Matrix in Renal Tubular Epithelial Cells

The accumulation of a large amount of plasma proteins in the urine, previously regarded as a marker of glomerular damage, is now recognized as a mediator of tubulointerstitial damage. Using an in vitro approach, several key extracellular matrix (ECM) proteins were analyzed after treatment of primary human renal proximal tubular epithelial cells with fatty acid free human albumin. We demonstrate that human albumin stimulates the accumulation of ECM proteins by proximal tubular epithelial cells through a post-transcriptional mechanism. Albumin induced a significant increase in tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2. Taken together, our data suggest that ECM protein accumulation in response to albumin resulted partly from inhibition of ECM degradation. Addition of transforming growth factor beta (TGF-β)-specific neutralizing antibody failed to alter ECM protein levels after albumin treatment, indicating that the albumin-induced increase in ECM is TGF-β independent. In conclusion, we have shown that exposure of cultured human proximal tubular cell to albumin leads to the TGF-β-independent accumulation of ECM proteins, suggesting that albumin may be a contributing factor to the progression of kidney fibrosis in proteinuric states.
Postpartum Outcome of Cervical Intraepithelial Neoplasia in Pregnant Women Determined by Route of Delivery

Cervical intraepithelial neoplasia (CIN) has its highest incidence during women’s reproductive years. During 2 sequential 7-year periods, 1994 to 2000 and 2001 to 2007, 3695 and 3894 deliveries were performed, respectively, at Osaka University Hospital. CIN was detected in 21 cases (0.57%) during 1994-2000 and in 43 cases (1.1%) during 2001-2007. By comparison, cervical intraepithelial neoplasia—complicated pregnancies increased significantly in the latter period (P = .015 by Fisher exact test, Odds ratio = 1.95; 95%CI: 1.16-3.30). We observed CIN regression in 34 (76%) of 45 cases of vaginal delivery and in 6 (50%) of 12 cases of cesarean delivery, indicating that the outcome of an initially diagnosed CIN and the delivery routes appeared not to be significantly related. However, a different result was obtained when only those patients whose CIN lesions persisted until the delivery were analyzed. Among the 35 such cases in the vaginal delivery group, 24 cases (69%) regressed after the delivery; in 8 such cases from the cesarean delivery group, only 2 cases (25%) regressed afterward. Our study clearly shows that pregnancy complicated with CIN is increasing rapidly in Japan. We also find that there is a significantly more frequent postpartum regression of biopsy-proven CIN lesions following a vaginal delivery compared to cesarean section (P = .042 by Fisher exact test, Odds ratio = 6.55; 95% CI: 1.13-37.8).
Endothelial function and hypertension

Purpose of review Endothelial dysfunction, in particular a reduced vascular availability of endothelium-derived nitric oxide, has been analysed in numerous experimental and clinical studies as a potential mechanism mediating the adverse vascular effects of hypertension. This paper outlines some notable studies in this dynamic field published recently. Recent findings The understanding of mechanisms underlying endothelial dysfunction in hypertension has been substantially advanced recently. Increased oxidant stress is thought to represent a major mechanism leading to reduced vascular availability of endothelium-derived nitric oxide. Vascular nicotinamide adenine dinucleotide phosphate oxidases, uncoupled nitric oxide synthase and xanthine oxidase have been identified as major sources of reactive oxygen species in hypertension. Endothelial dysfunction has been implicated in the macrovascular complications of hypertension, such as stroke or myocardial infarction, coronary microvascular dysfunction and increased arterial stiffness, probably at least partly resulting from loss of the antiatherogenic and vasculoprotective effects of endothelium-derived nitric oxide. Summary Recent research on endothelial dysfunction supports its clinical significance in hypertension, and has led to important insights into the pathophysiology of the disease. These observations suggest that targeting endothelial dysfunction, in particular reduced nitric oxide availability, would exert beneficial effects in hypertensive patients. This concept needs further evaluation in clinical studies.
A NOTE ON SOME RELIABILITY BOUNDS FOR MULTISTATE SYSTEMS

Maymin (1987) proved that for binary systems the path-cut lower bound is sharper than the minimax lower bound when the components are all highly reliable, which was originally conjectured by Barlow and Proschan (1981). This motivates us to consider the problem that whether this property for binary systems remains valid for the more general and complicated multistate systems. An example is constructed to illustrate that this is not the case for general multistate systems. However, an a rmative result is obtained under a mild condition we imposed. We show that this condition is satis ed by the Barlow-Wu (1978) and the N2 classes (Natvig (1982)) of multistate systems. Examples, including a power generation system due to Natvig (1986), are given to illustrate the applications of our results.
Neurodevelopmental Outcomes After Assisted Reproductive Technologies.

OBJECTIVE To compare children's cognitive, motor, and language development at 2 years of age after assisted reproductive technologies (ARTs) relative to natural conception. METHODS The 3D-Study (2010-2012) is a prospective cohort study, which sought to improve the understanding among perinatal events, obstetric outcomes, and child development. A total of 2,366 pregnant women were recruited, of whom 278 conceived with ART: ovarian stimulation, intrauterine sperm insemination, in vitro fertilization, intracytoplasmic sperm injection, or in vitro maturation. Natural conception was defined as the unassisted establishment of pregnancy. Cognitive, motor, and language neurodevelopmental outcomes were compared between ART and natural conception groups at 24 months using the Bayley Scales of Infant and Toddler Development, 3rd edition, and the MacArthur-Bates Communicative Development Inventories. Adjusted linear regression models evaluated the effect of ART on neurodevelopmental outcomes using natural conception as a reference. RESULTS A total of 175 children in the ART group (62.9%) and 1,345 children in the natural conception group (64.4%) underwent neurodevelopmental assessment at 24 months postpartum. After adjusting for relevant confounders, children born after ART showed no difference in Bayley scales' cognitive scores (B1 [standard error]=-1.60 [0.9], 95% confidence interval [CI] -3.36 to 0.16), composite motor scores (B1 [standard error]=-1.33 [1.0], 95% CI -3.29 to 0.63), or MacArthur-Bates language scores (B1 [standard error]=-0.28 [2.1], 95% CI -4.39 to 3.83). No difference was observed when independent ART techniques were compared nor when comparing in vivo (ovarian stimulation or intrauterine insemination) or in vitro (in vitro fertilization, intracytoplasmic sperm injection, or in vitro maturation) techniques (P>.05). CONCLUSION Children born after ART had similar cognitive, motor, and language development as children born after natural conception at 2 years of age. These findings may be useful in the clinical counseling of patients undergoing ART.
Effectiveness and safety of sorafenib in the treatment of unresectable and advanced intrahepatic cholangiocarcinoma: a pilot study

Patients with unresectable and advanced intrahepatic cholangiocarcinoma (ICC) usually have short survival due to a lack of effective treatment. This multicenter, single arm, open labeled, prospective study was conducted to evaluate the effectiveness and safety of sorafenib combined with best supportive care (BSC) in these patients. We enrolled 44 patients with unresectable and advanced ICC who were treated with sorafenib (400 mg, twice daily) and BSC. The primary endpoint was disease control rate (DCR) at week 12, and the secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), duration of therapy (DOT), and adverse events (AEs). Our results showed that the DCR was 15.9%, the median TTP was 5.6 months, and the median PFS and OS were 3.2 and 5.7 months (95% confidence interval [CI]: 2.4-4.1 months; 3.7-8.5 months), respectively. The median DOT was 1.8 months (95% CI: 1.9-3.9 months). AEs of grades 1 and 2 events occurred in 75% of patients, and AE of grade 4 (severe) was observed in 1 patient. Therefore, sorafenib in combination with BSC had an acceptable DCR and safety profile in patients with unresectable and advanced ICC.
Changes of Hematological Markers during a Multi-stage Ultra-marathon Competition in the Heat

Abstract This study examined the changes in resting hematological variables in ultra-endurance runners throughout a multi-stage ultra-marathon competition, and compared athletes that completed all stages with those that failed to complete at least one stage within the cut-off time of competition. 19 ultra-endurance runners competing in a 230 km multi-stage ultra-marathon, conducted over 5 consecutive days in hot ambient conditions (32–40°C Tmax), volunteered to participate in the study. Each day, whole blood samples were collected prior to stage commencement and analyzed for full cell counts by Coulter counter. Linear increases were observed for leukocytes, monocytes and lymphocytes; with increases until Stage 3 and a decrease thereafter. Granulocytes showed a cubic growth exponent, indicating decrements to baseline after the significant increments until Stage 3. Hemoglobin and hematocrit showed linear decrements throughout the multi-stage ultra-marathon. No changes in erythrocytes and platelets were observed throughout the multi-stage ultra-marathon. Granulocytes, erythrocytes, hemoglobin and hematocrit changes along the multi-stage ultra-marathon differed in runners that completed all stages compared to those who failed to complete at least one stage within the cut-off time. Multi-stage ultra-marathon in the heat has a large impact on hematological responses of ultra-endurance runners associated with altered performance.
Single-cell molecular biology: implications for the diagnosis and treatment of neurological disease.

The normal functioning of the central nervous system (CNS) requires complex interactions among numerous biological components. The pathophysiology of perturbations in this system is as complex as that of neurological disease. Many methods exist to examine the biological output of dysfunctional cells from a diseased system (e.g., immunohistochemical analysis, electrophysiology, and microdialysis), with one goal being to understand the mechanisms of cell death. This understanding may allow the design of therapeutic strategies to prevent cell death and ensuing behavioral abnormalities. Analysis of messenger RNA (mRNA) levels for various genes in CNS tissue may enhance understanding of neurological disease, since cells differ in the complement and abundance of genes they express. One popular method for detecting changes in gene expression is the Northern blot technique, in which total RNA from a sample is extracted and the RNA molecules are separated by size on a denaturing gel and transferred or "blotted" onto nylon membranes that are then probed with radiolabeled DNA for subsequent autoradiograpic detection of gene expression.
Nonsmooth optimization for joint multicast beamforming and user scheduling in massive MIMO systems

Wireless multicast is a key enabling technology for efficient distribution of high-rate multimedia services in future wireless communication systems. When there are a massive number of users in the system, it is impractical or inefficient to serve all users with a single multicast beamformer and within a single channel. We therefore study the joint multicast beamforming and user scheduling problem, with the objective of minimizing the total transmitting power across multiple channels by jointly assigning each user to appropriate channel and designing multicast beamformer for each channel. The problem of interest is first formulated as a mixed binary quadratically constrained quadratic program, and then reformulated as a highly structured nonsmooth optimization problem. We propose a sequential approximation scheme for the nonsmooth formulation to yield a series of parallel smooth convex subproblems, and devise a dual fast gradient projection method for the subproblem. The overall algorithm is an efficient matrix-free algorithm, which is based solely on matrix-vector multiplications and comparison operations and costs O(MK) arithmetic operations per iteration with M being the number of antennas and K being the number of users, and therefore is well suited for massive MIMO systems with a large number of users. The proposed algorithm is guaranteed to converge to a critical point to the nonsmooth formulation problem. Finally, simulation results demonstrate the advantage of the proposed co-design scheme over conventional fixed scheduling and random scheduling.