Miracle-dz/UniFAR-FTUs huggingface dataset:
Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis

Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage‐gated, sodium (Na+) channel α‐subunits (Nav1.5). We summarize experimental studies of physiological and clinical consequences of loss‐of‐function Na+ channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a+/− hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Nav1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Nav1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Nav1.5 haploinsufficient males in producing clinical arrhythmia.
Journal of

The COVID-19 pandemic led governments around the world to impose unprecedented restrictions on economic activity. Were these restrictions equally justified in poorer countries with fewer demographic risk factors and less ability to weather economic shocks? We develop and estimate a fully specified model of the macroeconomy with epidemiological dynamics, incorporating subsistence constraints in consumption and allowing preferences over ‘‘lives versus livelihoods’’ to vary with income. Poorer countries’ demography pushes them unambiguously toward laxer policies. But because both infected and susceptible agents near the subsistence constraint will remain economically active in the face of infection risk and even to some extent under government containment policies, optimal policy in poorer countries pushes in the opposite direction. Moreover, for reasonable income-elasticities of the value of a statistical life, the model can fully rationalize equally strict or stricter policies in poorer countries.
Ethics of antenatal screening for Down’s syndrome

Neisseria meningitidis is remarkable for the diversity of interactions that the bacterium has with the human host, ranging from asymptomatic nasopharyngeal colonisation affecting virtually all members of the population; through focal infections of the meninges, joints, or eye; to the devastating and often fatal syndrome of meningococcal septic shock and purpura fulminans.
On SGD's Failure in Practice: Characterizing and Overcoming Stalling

Stochastic Gradient Descent (SGD) is widely used in machine learning problems to efficiently perform empirical risk minimization, yet, in practice, SGD is known to stall before reaching the actual minimizer of the empirical risk. SGD stalling has often been attributed to its sensitivity to the conditioning of the problem; however, as we demonstrate, SGD will stall even when applied to a simple linear regression problem with unity condition number for standard learning rates. Thus, in this work, we numerically demonstrate and mathematically argue that stalling is a crippling and generic limitation of SGD and its variants in practice. Once we have established the problem of stalling, we generalize an existing framework for hedging against its effects, which (1) deters SGD and its variants from stalling, (2) still provides convergence guarantees, and (3) makes SGD and its variants more practical methods for minimization.
ENAMEL SURFACE QUALITY IMPROVEMENT IN WHITE SPOT LESIONS AFTER ORTHODONTIC TREATMENT USING A MICROABRASION TECHNIQUE WITH FLUORIDE OR CALCIUM PHOSPHOPEPTIDE-AMORPHOUS CALCIUM PHOSPHATE APPLICATION

Objectives: White spot lesions after fixed orthodontic treatment will increase bacterial plaque formation due to increased enamel surface roughness. The aim of this study was to analyze the surface roughness of white spot lesions on enamel after a microabrasion technique, a microabrasion technique combined with calcium phosphopeptide-amorphous calcium phosphate (CPP-ACP) application, and a microabrasion technique combined with fluoride application. Methods: Artificially induced white spot lesions on the enamel surfaces of 42 maxillary first premolars were randomly assigned into one of three treatment groups (n=14): (a) A microabrasion technique, (b) a microabrasion technique combined with CPP-ACP application, and (c) a microabrasion technique combined with fluoride application. A Mitutoyo SJ-301 surface roughness tester was used to measure differences in surface roughness before and after treatment, and the after treatment measurements were compared among the three groups. Results: A significant difference in surface roughness was noted for the white spot lesions on enamel before and after treatment in all groups (p<0.05). A significant difference was also found when comparing the after treatment surface roughness in all groups. Conclusion: The combination of the microabrasion technique with CPP-ACP application significantly reduced enamel surface roughness when compared to microabrasion alone or the combination of microabrasion and fluoride application.
Expanding the Helicobacter pylori Genetic Toolbox: Modification of an Endogenous Plasmid for Use as a Transcriptional Reporter and Complementation Vector

ABSTRACT Helicobacter pylori is an important human pathogen. However, the study of this organism is often limited by a relative shortage of genetic tools. In an effort to expand the methods available for genetic study, an endogenous H. pylori plasmid was modified for use as a transcriptional reporter and as a complementation vector. This was accomplished by addition of an Escherichia coli origin of replication, a kanamycin resistance cassette, a promoterless gfpmut3 gene, and a functional multiple cloning site to form pTM117. The promoters of amiE and pfr, two well-characterized Fur-regulated promoters, were fused to the promoterless gfpmut3, and green fluorescent protein (GFP) expression of the fusions in wild-type and Δfur strains was analyzed by flow cytometry under iron-replete and iron-depleted conditions. GFP expression was altered as expected based on current knowledge of Fur regulation of these promoters. RNase protection assays were used to determine the ability of this plasmid to serve as a complementation vector by analyzing amiE, pfr, and fur expression in wild-type and Δfur strains carrying a wild-type copy of fur on the plasmid. Proper regulation of these genes was restored in the Δfur background under high- and low-iron conditions, signifying complementation of both iron-bound and apo Fur regulation. These studies show the potential of pTM117 as a molecular tool for genetic analysis of H. pylori.
Staphylococcus aureus Capsular Polysaccharides

SUMMARY Serotype 5 and 8 capsular polysaccharides predominate among clinical isolates of Staphylococcus aureus. The results of experiments in animal models of infection have revealed that staphylococcal capsules are important in the pathogenesis of S. aureus infections. The capsule enhances staphylococcal virulence by impeding phagocytosis, resulting in bacterial persistence in the bloodstream of infected hosts. S. aureus capsules also promote abscess formation in rats. Although the capsule has been shown to modulate S. aureus adherence to endothelial surfaces in vitro, animal studies suggest that it also promotes bacterial colonization and persistence on mucosal surfaces. S. aureus capsular antigens are surface associated, limited in antigenic specificity, and highly conserved among clinical isolates. With the emergence of vancomycin-resistant S. aureus in the United States in 2002, new strategies are needed to combat staphylococcal infections. Purified serotype 5 and 8 capsular polysaccharides offer promise as target antigens for a vaccine to prevent staphylococcal infections, although the inclusion of other antigens is likely to be essential in the development of an effective S. aureus vaccine. The genetics and mechanisms of capsule biosynthesis are complex, and much work remains to enhance our understanding of capsule biosynthesis and its regulation.
On the Importance of Pivot Language Selection for Asian Language Translation

Recent research on multilingual statistical machine translation focuses on the usage of pivot languages in order to overcome resource limitations for certain language pairs. Due to the richness of available language resources, English is in general the pivot language of choice. In this paper, we investigate the appropriateness of Asian languages as pivot languages. Experimental results using state-of-the-art statistical machine translation techniques to translate between eight Asian languages revealed that the translation quality of 73% of the language pairs improved when a non-English pivot language was chosen.
Osthole Ameliorates Renal Ischemia-Reperfusion Injury by Inhibiting Inflammatory Response

Introduction: Renal ischemia-reperfusion (I/R) injury is a primary cause of acute renal failure that results in high mortality. This study aimed to investigate the effect of osthole, a natural coumarin derivative, on renal I/R injury in a rat model. Materials and Methods: Rats were randomly allocated to the sham operation + vehicle, I/R + vehicle, and I/R + osthole groups. Renal I/R injury was induced by clamping the left renal artery for 45 min followed by 12 h of reperfusion and a contralateral nephrectomy. Osthole (40 mg/kg) was intraperitoneally injected 30 min before inducing I/R. Renal function and histological damage were determined subsequently. Myeloperoxidase activity, monocyte/macrophage infiltration, as well as tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys were also assessed. Results: Osthole treatment significantly ameliorated I/R-induced renal functional and morphological injuries. Moreover, osthole treatment attenuated myeloperoxidase activity, monocyte/macrophage infiltration, and tumor necrosis factor-α, IL-1β, and activated p38 mitogen-activated protein kinase expression in kidneys. Conclusions: Osthole treatment ameliorates renal I/R injury by inhibiting inflammatory responses in kidneys. Thus, osthole may represent a novel practical strategy to prevent renal I/R injury.
Enhancement of ropivacaine caudal analgesia using dexamethasone or magnesium in children undergoing inguinal hernia repair

Background: Caudal analgesia is the most commonly used technique providing intra- and postoperative analgesia for various pediatric infraumbilical surgical procedures but with the disadvantage of short duration of action after single injection. Caudal dexamethasone and magnesium could offer significant analgesic benefits. We compared the analgesic effects and side-effects of dexamethasone or magnesium added to caudal ropivacaine in pediatric patients undergoing inguinal hernia repair. Materials and Methods: A total of 105 (1-6 years) were randomly assigned into three groups in a double-blinded manner. After a standardized sevoflurane in oxygen anesthesia, each patient received a single caudal dose of ropivacaine 0.15% 1.5 mL/kg combined with either magnesium 50 mg in normal saline 1 mL (group RM), dexamethasone 0.1 mg/kg in normal saline 1 mL (group RD), or corresponding volume of normal saline (group R) according to group assignment. Postoperative analgesia, use of analgesics, and side-effects were assessed during the first 24 h. Results: Addition of magnesium or dexamethasone to caudal ropivacaine significantly prolonged analgesia duration 8 (5-11) h and 12 (8-16) h, respectively compared with 4 (3-5) h with the use of ropivacaine alone. The incidence of postoperative rescue analgesia was significantly higher in group R compared with groups RM and RD. The time to 1st analgesic dose was significantly longer in groups RM and RD (500 ± 190 and 730 ± 260 min) respectively compared with group R (260 ± 65 min). Group R patients achieved significantly higher Children's Hospital of Eastern Ontario Pain Scale and Faces Legs Activity Cry Consolability scores (4th hourly) compared with groups RM and RD patients (8th and 12th hourly, respectively). Conclusion: The addition of dexamethasone or magnesium to caudal ropivacaine significantly prolonged the duration of postoperative analgesia in children undergoing inguinal hernia repair. Also the time to 1st analgesic dose was longer and the need for rescue postoperative analgesic was reduced and without increase in incidence of side effects.
Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus

The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open‐label, nonrandomized, single‐sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100‐mg oral dose, followed by a minimum 8‐day washout period, and subsequent coadministration of a single 10‐mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady‐state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2‐mg oral dose, followed by a minimum 14‐day washout period, and subsequent coadministration of a single 0.5‐mg dose of tacrolimus with steady‐state telaprevir (750 mg q8h). Coadministration with steady‐state telaprevir increased cyclosporine dose‐normalized (DN) exposure (DN_AUC0‐∞) by approximately 4.6‐fold and increased tacrolimus DN_AUC0‐∞ by approximately 70‐fold. Coadministration with telaprevir increased the terminal elimination half‐life (t½) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t½ of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours. Conclusion: In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life‐threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained. (HEPATOLOGY 2011;)
B Cells: The Old New Players in Reproductive Immunology

Reproductive immunology research has long focused on T cell responses to paternal antigens and tolerance mechanisms supporting fetal well-being. The participation of B cells herein was not widely studied. Because of the fascinating immunological uniqueness of pregnancy, it is however to be expected that such pleiotropic cells play a considerable role. In fact, on the one hand B cells contribute toward pregnancy tolerance by secreting the immunomodulatory cytokine IL-10 but on the other hand can seriously harm pregnancy because of their capacity of producing autoantibodies. As for protective B cells, new evidences in mouse models arise suggesting that IL-10 producing B cells, the so-called B10 cells, help in maintaining tolerance toward semi-allogenic fetal antigens. They may be also important to fight danger signals at the fetal-maternal interface as, e.g., in the case of infections with the aim to restore the disrupted fetal tolerance. In human pregnancies, IL-10 producing B cells increase with pregnancy onset but not in the case of spontaneous abortions. In vitro, they are able to suppress TNF-α production by T cells from pregnant individuals. Their generation and functionality will be discussed throughout this review article. B cells can be deleterious to pregnancy as well. Aberrant B cell compartment is associated with obstetric pathologies. In particular, the capacity of B2 cells to produce specific autoantibodies or of B-1a B cells to secrete natural autoantibodies that can turn autoreactive will be discussed herein.
Spatial Heterogeneity of Low-Grade Gliomas at the Capillary Level: A PET Study on Tumor Blood Flow and Amino Acid Uptake

Many low-grade gliomas (World Health Organization grade II) respond to chemotherapy. Cerebral blood flow (CBF) and microvessel density may be critical for drug delivery. We used PET with 18F-fluoro-ethyl-l-tyrosine (FET) to measure the spatial distribution of the amino acid carrier, which is located at the brain capillaries, and 15O-H2O to measure tumor CBF. Methods: Seventeen patients with low-grade glioma were studied. Region-of-interest (ROI) analysis was used to quantify tumor tracer uptake, which was normalized to cerebellar uptake (tumor-to-cerebellum ratio). “Active” tumor was defined as tumor having a radioactivity concentration that was at least 110% of the cerebellar activity. This threshold provided measures of active tumor volume, global and peak tumor CBF, and 18F-FET uptake. Trace ROIs were applied to create voxelwise profiles of CBF and 18F-FET uptake across tumor and brain. Standard MRI sequences were used for spatial correlations. Results: Fourteen of 17 tumors showed increased global CBF and 18F-FET uptake. Active tumor volumes ranged between 3 and 270 cm3 for 18F-FET and between 1 and 41 cm3 for CBF. Global 18F-FET uptake in tumors corresponded to CBF increases (Spearman rank ρ = 0.771, P < 0.01). The volumes of increased CBF and 18F-FET uptake spatially coincided and were also correlated (ρ = 0.944, P < 0.01). Trace ROIs showed that irrespective of increased 18F-FET uptake at the tumor periphery, CBF increases were more confined to the tumor center. Within individual tumors, spatial heterogeneity was present. Particular tumors infiltrating the corpus callosum showed low CBF and 18F-FET uptake in this tumor region. The patterns observed with PET were not reflected on MRI of the tumors, all of which presented as homogeneous non–gadolinium-enhancing lesions. Conclusion: Low-grade gliomas are heterogeneous tumors with regard to the distribution of amino acid uptake and CBF. Both are coupled in the tumor center. At the tumor periphery, where tumor infiltration of surrounding brain occurs, CBF may be low irrespective of increased 18F-FET uptake. An ongoing study is investigating the effect of chemotherapy on these observations.
Stochasticity and traffic jams in the transcription of ribosomal RNA: Intriguing role of termination and antitermination

In fast-growing bacteria, ribosomal RNA (rRNA) is required to be transcribed at very high rates to sustain the high cellular demand on ribosome synthesis. This results in dense traffic of RNA polymerases (RNAP). We developed a stochastic model, integrating results of single-molecule and quantitative in vivo studies of Escherichia coli, to evaluate the quantitative effect of pausing, termination, and antitermination (AT) on rRNA transcription. Our calculations reveal that in dense RNAP traffic, spontaneous pausing of RNAP can lead to severe “traffic jams,” as manifested in the broad distribution of inter-RNAP distances and can be a major factor limiting transcription and hence growth. Our results suggest the suppression of these pauses by the ribosomal AT complex to be essential at fast growth. Moreover, unsuppressed pausing by even a few nonantiterminated RNAPs can already reduce transcription drastically under dense traffic. However, the termination factor Rho can remove the nonantiterminated RNAPs and restore fast transcription. The results thus suggest an intriguing role by Rho to enhance rather than attenuate rRNA transcription.
Amyloid β-Protein Assembly and Alzheimer Disease*

The biochemistry of amyloid proteins has been a fascinating and important area of research because of its contribution to our understanding of protein folding dynamics and assembly and of the pathogenetic mechanisms of human disease. One such disease is AD,2 the most common neurodegenerative disorder of aging. In AD, Aβ (Fig. 1A), which is expressed normally and ubiquitously throughout life as a 40–42-residue peptide, forms fibrils that deposit in the brain as “amyloid plaques. ” This pathologic deposition process led researchers to investigate fibril formation as a target for therapeutic intervention. In doing so, an increasing number of fibril precursors and non-fibrillar Aβ assemblies have been identified, the majority of which are neurotoxic. These findings have altered prevailing fibril-centered views of the pathobiology of amyloid diseases (1) and intensified efforts to understand the early folding and assembly dynamics of Aβ. In the discussion that follows, we seek to introduce the reader to the complex world of Aβ assembly and biological activity, a goal we hope will provide a conceptual framework upon which further knowledge or experimentation may be built. FIGURE 1. Aβ assembly. A, the sequence of Aβ42 is shown in one-letter amino acid code. The side chain charge at neutral pH is color-coded (red, negative; blue, positive). B, nucleation-dependent polymerization, reflecting the unfavorable self-association .
Architecture, design, and performance of Application System/400 (AS/400) multiprocessors

The architecture, design, and performance of multiprocessors in the Application System/400® (AS/400®) family are discussed. The paper describes how this multitasking system, originally designed as a uniprocessor system, was modified to form a multiprocessor system. The unique approach, using relatively atomic Instructions, required a minimum of change while providing significant performance gains.
Scalp Melanoma Diagnosed by Fine Needle Aspiration Cytology in a Tertiary Health Center

Melanoma is one of the most aggressive malignant skin neoplasms worldwide with more than 20% of world melanoma seen in black Africa and Asia. Late presentation due to ignorance, poverty, and lack of adequate health facility in Nigeria is always the norms. We present this case report because of precision in diagnosis, using fine needle aspiration cytology (FNAC) to reemphasize that the technique is cheap, cost effective, and quick that can reduce the burden of incisional biopsy before definitive surgery and improve early detection of the disease especially in developing countries.