Miracle-dz/UniFAR-FTUs huggingface dataset:
Hodgkin–Huxley revisited: reparametrization and identifiability analysis of the classic action potential model with approximate Bayesian methods

As cardiac cell models become increasingly complex, a correspondingly complex ‘genealogy’ of inherited parameter values has also emerged. The result has been the loss of a direct link between model parameters and experimental data, limiting both reproducibility and the ability to re-fit to new data. We examine the ability of approximate Bayesian computation (ABC) to infer parameter distributions in the seminal action potential model of Hodgkin and Huxley, for which an immediate and documented connection to experimental results exists. The ability of ABC to produce tight posteriors around the reported values for the gating rates of sodium and potassium ion channels validates the precision of this early work, while the highly variable posteriors around certain voltage dependency parameters suggests that voltage clamp experiments alone are insufficient to constrain the full model. Despite this, Hodgkin and Huxley's estimates are shown to be competitive with those produced by ABC, and the variable behaviour of posterior parametrized models under complex voltage protocols suggests that with additional data the model could be fully constrained. This work will provide the starting point for a full identifiability analysis of commonly used cardiac models, as well as a template for informative, data-driven parametrization of newly proposed models.
Diagnostic performance of fecal quantitative real-time polymerase chain reaction for detection of Lawsonia intracellularis–associated proliferative enteropathy in nursery pigs

Quantitative polymerase chain reaction (qPCR) tests for detection and quantification of Lawsonia intracellularis in feces from pigs have been developed. The objective of the current study was to evaluate the diagnostic performance of a fecal qPCR test for detection of nursery pigs with L. intracellularis–associated proliferative enteropathy (PE) under field conditions. Furthermore, the diagnostic performance for different subpopulations of pigs was investigated, including pigs infected or noninfected with Porcine circovirus-2, Brachyspira pilosicoli, and Escherichia coli. The diagnostic performance was evaluated in terms of diagnostic sensitivity and specificity. Data from pigs originating from 20 herds with antibiotic treatment requiring diarrhea outbreaks from a prior study were reused. Before treatment, pigs were randomly selected for histological and immunohistochemical examination of intestinal segments and fecal quantification of L. intracellularis by qPCR. A total of 313 pigs (157 without diarrhea, 156 with diarrhea) were included in the statistical analysis, and 37 pigs (11.8%) were classified as PE positives (defined as proliferative histological lesions in combination with L. intracellularis demonstration by immunohistochemistry). Lawsonia intracellularis was detected by qPCR in feces from 91 pigs (29.1%). A nonparametric receiver operating characteristic (ROC) analysis provided an area under the ROC curve (0.93) and an optimal cutoff value of 4.8 log10 L. intracellularis bacteria/g feces. This cutoff provided a diagnostic sensitivity of 0.84 and diagnostic specificity of 0.93. The diagnostic sensitivity and specificity were significantly different between herds (P < 0.0001). Numerically, diagnostic sensitivity and specificity were different between subpopulations of pigs, but no significant differences were demonstrated.
Cloning of the Saccharomyces cerevisiae gene whose overexpression overcomes the effects of HM-1 killer toxin, which inhibits beta-glucan synthesis

A gene whose overexpression can endow Saccharomyces cerevisiae cells with resistance to HM-1 killer toxin was cloned from an S. cerevisiae genomic library. This gene, designated HKR1 (Hansenula mrakii killer toxin-resistant gene 1), contains a 5.4-kb open reading frame. The predicted amino acid sequence of the protein specified by HKR1 indicates that the protein consists of 1,802 amino acids and is very rich in serine and threonine, which could serve as O-glycosylation sites. The protein also contains two hydrophobic domains at the N-terminal end and in the C-terminal half, which could function as a signal peptide and transmembrane domain, respectively. Hkr1p is found to contain an EF hand motif of the calcium-binding consensus sequence in the C-terminal cytoplasmic domain. Thus, Hkr1p is expected to be a calcium-binding, glycosylated type I membrane protein. Southern and Northern (RNA) analyses demonstrated that there is a single copy of the HKR1 gene in the S. cerevisiae genome, and the transcriptional level of HKR1 is extremely low. Gene disruption followed by tetrad analysis showed that HKR1 is an essential gene. Overexpression of the truncated HKR1 encoding the C-terminal half of Hkr1p made the cells more resistant to HM-1 killer toxin than the full-length HKR1 did, demonstrating that the C-terminal half of Hkr1p is essential for overcoming the effect of HM-1 killer toxin. Furthermore, overexpression of HKR1 increased the beta-glucan content in the cell wall without affecting in vitro beta-glucan synthase activity, suggesting that HKR1 regulates beta-glucan synthesis in vivo.
Mortality among Human Immunodeficiency Virus Type 2-Positive Villagers in Rural Guinea-Bissau Is Correlated with Viral Genotype

ABSTRACT We present the results of a 6-year study of 131 human immunodeficiency virus (HIV) type 2 (HIV-2)-infected individuals from a rural population in Guinea-Bissau. Proviral DNA sequences 1.3 kb in length were obtained from each individual and, together with clinical data, including proviral load and CD4 and CD8 levels, were used to assess whether viral genotype influences clinical outcome. With a phylogenetic model, a correlation was found between viral genotype and mortality; this correlation was not due to confounding factors, such as age-specific viral strains or cohabitation of patients. The data provide strong evidence for the involvement of viral genetic factors in determining HIV disease progression in vivo. The pattern of association found suggests that virulence factors are multiple and scattered throughout the HIV-2 genome and can be rapidly gained or lost by the virus through a combination of mutation and recombination. These findings may lead to the identification of viral determinants of HIV disease progression.
The C-Terminal SH3 Domain Contributes to the Intramolecular Inhibition of Vav Family Proteins

An intramolecular double-lock system prevents spurious activation of a protein involved in lymphocyte development and cancer. Double Lock for Safety Members of the Vav family of guanine nucleotide exchange factors activate Rho family guanosine triphosphatases to mediate processes such as lymphocyte development; however, they are also implicated in pathologies such as cancer. Interactions between N-terminal regions of Vav with its central catalytic core contribute to the formation of an autoinhibited conformation. Phosphorylation of specific N-terminal tyrosines disrupts this interaction and leads to Vav activation. Through mutational analysis and nucleotide exchange assays, Barreira et al. showed that there is a second inhibitory interaction with the catalytic core that is mediated by a C-terminal Src homology 3 (CSH3) domain of Vav1. Furthermore, phosphorylation of distinct tyrosines disrupted this interaction. Thus, both sets of inhibitory interactions constitute a double-lock system that prevents spurious activation of Vav1 by requiring multiple phosphorylation events to relieve autoinhibition. Vav proteins are phosphorylation-dependent guanine nucleotide exchange factors (GEFs) that catalyze the activation of members of the Rho family of guanosine triphosphatases (GTPases). The current regulatory model holds that the nonphosphorylated, catalytically inactive state of these GEFs is maintained by intramolecular interactions among the amino-terminal domains and the central catalytic core, which block the binding of Vav proteins to GTPases. We showed that this autoinhibition is mechanistically more complex, also involving the bivalent association of the carboxyl-terminal Src homology 3 (SH3) region of Vav with its catalytic and pleckstrin homology (PH) domains. Such interactions occurred through proline-rich region–independent mechanisms. Full release from this double-locked state required synergistic weakening effects from multiple phosphorylated tyrosine residues, thus providing an optimized system to generate gradients of Vav GEF activity depending on upstream signaling inputs. This mechanism is shared by mammalian and Drosophila melanogaster Vav proteins, suggesting that it may be a common regulatory feature for this protein family.
A simple thermodynamic description of the combined Einstein and elastic models

A simple application of the Einstein model combined with an elastic description of the solid state is developed. The frequency of quantum oscillators has been assumed as volume dependent and elastic energy terms with a static character have been included to complete the description. Such an extension enables us to construct the complete thermodynamics. In particular, the model yields a practical equation of state and describes the thermal expansion coefficient as well as the isothermal compressibility of solids. The thermodynamic properties resulting from the Gibbs free-energy analysis have been calculated and are illustrated in figures. Some comparisons of the theoretical results with experimental data for solid argon have been made.
Valdecoxib Recovers the Lipid Composition, Order and Dynamics in Colon Cancer Cell Lines Independent of COX-2 Expression: An ATR-FTIR Spectroscopy Study

Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenases (COXs). Aberrant expression of the inducible isoform COX-2 plays a significant role in colon cancer initiation and progression. In this study, we have hypothesized that COX-2 specific inhibitors such as Valdecoxib (VLX), being highly hydrophobic, may alter biophysical properties of cellular lipids. In this study, COX-2 expressing (HT29) and COX-2 non-expressing (SW620) colon cancer cell lines were treated with VLX and examined using attenuated total reflection infrared spectroscopy. The results revealed that VLX treatment decreased lipid fluidity in the cells irrespective of COX-2 expression status and affected order parameters of the lipids in both cell lines. Cluster analysis also indicated that the spectral differences between the two cell lines are profound and could be successfully differentiated. Valdecoxib treatment could enhance the composition, order and dynamics of the lipids of colon cancer cells independently of its COX-2 inhibitory mechanism. Valdecoxib has therapeutic effects upon colon cancer, therefore it can be used as an adjuvant and/or chemopreventive agent for colon cancer.
Arachnids Submitted as Suspected Brown Recluse Spiders (Araneae: Sicariidae): Loxosceles Spiders Are Virtually Restricted to Their Known Distributions but Are Perceived to Exist Throughout the United States

Abstract An Internet offer was made to identify any spider in the United States perceived to be a brown recluse spider, Loxosceles reclusa Gertsch & Mulaik (Sicariidae). In total, 1,773 arachnids from 49 states represented three orders (Araneae, Solifugae, and Opiliones) and the identifiable spiders (Araneae) consisted of 38 families, 88 genera, and 158 recognizable species. Participants from states at least half within the known brown recluse distribution submitted Loxosceles spiders 32–89% of the time, except Louisiana and Mississippi with no submissions. From 25 of 29 states completely or almost completely outside of the range of Loxosceles spiders, no recluse spiders were submitted. Only two discoveries of brown recluses and two of the worldwide tramp species Loxosceles rufescens (Dufour) were submitted from nonendemic Loxosceles areas. States on distribution margins of brown recluse or other native Loxosceles spiders were intermediate in their Loxosceles submissions. This study showed that 1) the general public perceives brown recluses to occur over wide-ranging areas of the United States; and 2) brown recluses are frequently submitted from endemic states and almost never from nonendemic states, and therefore are virtually limited to their known distributions. This study corroborates opinions that diagnosis of brown recluse spider bites is best restricted to areas historically supporting proven, widespread populations of Loxosceles spiders.
Within-Epitope Interactions Can Bias CTL Escape Estimation in Early HIV Infection

As human immunodeficiency virus (HIV) begins to replicate within hosts, immune responses are elicited against it. Escape mutations in viral epitopes—immunogenic peptide parts presented on the surface of infected cells—allow HIV to partially evade these responses, and thus rapidly go to fixation. The faster they go to fixation, i.e., the higher their escape rate, the larger the selective pressure exerted by the immune system is assumed to be. This relation underpins the rationale for using escapes to assess the strength of immune responses. However, escape rate estimates are often obtained by employing an aggregation procedure, where several mutations that affect the same epitope are aggregated into a single, composite epitope mutation. The aggregation procedure thus rests upon the assumption that all within-epitope mutations have indistinguishable effects on immune recognition. In this study, we investigate how violation of this assumption affects escape rate estimates. To this end, we extend a previously developed simulation model of HIV that accounts for mutation, selection, and recombination to include different distributions of fitness effects (DFEs) and inter-mutational genomic distances. We use this discrete time Wright–Fisher based model to simulate early within-host evolution of HIV for DFEs and apply standard estimation methods to infer the escape rates. We then compare true with estimated escape rate values. We also compare escape rate values obtained by applying the aggregation procedure with values estimated without use of that procedure. We find that across the DFEs analyzed, the aggregation procedure alters the detectability of escape mutations: large-effect mutations are overrepresented while small-effect mutations are concealed. The effect of the aggregation procedure is similar to extracting the largest-effect mutation appearing within an epitope. Furthermore, the more pronounced the over-exponential decay of the DFEs, the more severely true escape rates are underestimated. We conclude that the aggregation procedure has two main consequences. On the one hand, it leads to a misrepresentation of the DFE of fixed mutations. On the other hand, it conceals within-epitope interactions that may generate irregularities in mutation frequency trajectories that are thus left unexplained.
Analysis of the Echinococcus granulosus Laminated Layer Carbohydrates by Lectin Blotting

Cystic hydatid disease is caused by cystic larval (metacestode) stages of Echinococcus granulosus. This parasite can potentially occur all over the world especially in Mediterranean and Middle East countries and some parts of Africa, Latin America and China which have major foci of human infections. The cyst wall of metacestodes consists of inner, middle and external layers. To date, little attention has been paid to the immunological studies of the laminated (middle) layer. Because of the presence of diagnostic carbohydrate antigens, this layer is important. In this report, the characterisation of the laminated layer carbohydrate of the E. granulosus was investigated by peroxidase-labelled lectin conjugate blots. The comparison of SDS-PAGE and Western blot analysis confirms that many laminated layer bands are glycoproteins, especially 50-66 kDa and 25-29 kDa bands. These glycoproteins contain -Methyl-Dmannoside, N-Acetyl--D-glucosamine, -L-Fucose and N-Acetyl - -D-galactosamine. Iran. Biomed. J. 5 (1): 47-51, 2001
A novel F420-dependent anti-oxidant mechanism protects Mycobacterium tuberculosis against oxidative stress and bactericidal agents

Mycobacterium tuberculosis (Mtb) is an aerobic bacterium that persists intracellularly in host macrophages and has evolved diverse mechanisms to combat and survive oxidative stress. Here we show a novel F420‐dependent anti‐oxidant mechanism that protects Mtb against oxidative stress. Inactivation of the fbiC gene in Mtb results in a cofactor F420‐deficient mutant that is hypersensitive to oxidative stress and exhibits a reduction in NADH/NAD+ ratios upon treatment with menadione. In agreement with the recent hypothesis on oxidative stress being an important component of the pathway resulting in cell death by bactericidal agents, F420− mutants are hypersensitive to mycobactericidal agents such as isoniazid, moxifloxacin and clofazimine that elevate oxidative stress. The Mtb deazaflavin‐dependent nitroreductase (Ddn) and its two homologues Rv1261c and Rv1558 encode for an F420H2‐dependent quinone reductase (Fqr) function leading to dihydroquinones. We hypothesize that Fqr proteins catalyse an F420H2‐specific obligate two‐electron reduction of endogenous quinones, thereby competing with the one‐electron reduction pathway and preventing the formation of harmful cytotoxic semiquinones, thus protecting mycobacteria against oxidative stress and bactericidal agents. These findings open up an avenue for the inhibition of the F420 biosynthesis pathway or Fqr‐class proteins as a mechanism to potentiate the action of bactericidal agents.
Impact of Corticosteroids on Mortality in Patients with Acute Respiratory Distress Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE The impact of corticosteroids on acute respiratory distress syndrome (ARDS) mortality remains controversial following the publication of numerous trials, observational studies and meta-analyses. An updated meta-analysis is warranted, as a few original studies on this topic have been published since the last meta-analysis. METHODS We searched for eligible articles using four databases. In particular, we included full-length original articles providing sufficient data for evaluating the impact of corticosteroid treatment on adult ARDS mortality in the form of odds ratios. A fixed model with the confidence interval method was used. An assessment of publication bias and sensitivity analyses were also conducted. RESULTS We included 11 of 185 articles. The pooled odds ratio for corticosteroids with respect to all-cause mortality involving 949 patients was 0.77 [95% confidence interval (CI): 0.58-1.03, p=0.079] with strong heterogeneity(I2=70%, p<0.001). The results of the sensitivity analysis, Begg-Kendall test (τ=0.53, p=0.024)and funnel plot consistently suggested the existence of strong publication bias. After six potentially unpublished cohorts were filled using Duval's trim and fill method, the pooled odds ratio shifted to 1.11 (95% CI0.86-1.44, p=0.427). In addition, the sensitivity analyses suggested that corticosteroid treatment has a different impact on mortality depending on the comorbidities and trigger events. CONCLUSION We were unable to confirm, based on the data of published studies, the favorable impact of corticosteroid therapy on mortality in overall ARDS cases. Published articles exhibit strong publication bias,and previous meta-analyses may be affected by this publication bias. Further research focusing on pathophysiology- or trigger event-specific ARDS is anticipated.
Structural Analysis of the Proximal Region of the Microtubule‐Associated Protein 1B Promoter

Abstract: Microtubule‐associated protein 1B (MAP1B) is a major cytoskeletal protein expressed early during development of the nervous system. Previous analysis of the MAP1B gene has identified two alternative promoters that can independently regulate neuron‐specific expression of MAP1B. To further characterize the MAP1B promoters, we performed DNase I hypersensitivity assays in vivo over a range of 8.5 kb surrounding the transcription initiation sites. These studies identified a DNase I‐hypersensitive site that was present in brain but not liver nuclei at the proximal region of the MAP1B promoter, located between the two transcription initiation sites. Fine mapping by S1 nuclease sensitivity localized two adjacent sites in the proximal promoter region that contained three symmetrical inverted repeats. Electrophoresis mobility shift assays showed that proteins present in nuclear extracts can bind two consensus regulatory elements present within the proximal promoter region, Sp1 and cyclic AMP response element. In addition, there was a specific nuclear protein binding activity with two common sequences, a “neuronal motif” and a TCC repeat motif. This binding activity was much more abundant in liver than in brain nuclear extracts, suggesting that it may represent a negative control element in the tissue‐specific expression of the MAP1B gene.
Health status in patients with sub-clinical hypothyroidism.

OBJECTIVE Sub-clinical hypothyroidism (SCH) is a common disorder. People with this condition may have symptoms which could affect their perception of health. Therefore, the perceived health status of people with SCH was assessed and compared with population-matched norms. DESIGN A prospective cross-sectional survey. METHODS Seventy-one adults with SCH, age range 18-64 years were studied. Perceived health status was measured by the Short Form-36 (SF-36) version 2 questionaire, which has been validated in a UK population setting. The SF-36 has eight scales measuring physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health. Their SF-36 scores were compared with UK normative data after matching for age and sex and are reported as z-scores. RESULTS Scores of all eight SF-36 scales were significantly lower in people with SCH compared with the normative population. A negative score (compared with zero of the normative population) indicates worse health status. The most significantly impaired aspects of health status were vitality and role limitations due to physical problems (role physical scale) with z-scores (95% confidence intervals) of -1.01 (-0.74 to -1.29) and -0.73 (-0.43 to -1.04) respectively. Thyroid autoimmunity did not influence the results. CONCLUSION Perceived health status is significantly impaired in people with SCH when compared with UK normative population scores. This needs to be taken into consideration by clinicians when managing patients with this disease.
Analyses of the Recycling Receptor, FcRn, in Live Cells Reveal Novel Pathways for Lysosomal Delivery

Lysosomes play a central role in the degradation of proteins and other macromolecules. The mechanisms by which receptors are transferred to lysosomes for constitutive degradation are poorly understood. We have analyzed the processes that lead to the lysosomal delivery of the Fc receptor, FcRn. These studies provide support for a novel pathway for receptor delivery. Specifically, unlike other receptors that enter intraluminal vesicles in late endosomes, FcRn is transferred from the limiting membrane of such endosomes to lysosomes, and is rapidly internalized into the lysosomal lumen. By contrast, LAMP‐1 persists on the limiting membrane. Receptor transfer is mediated by tubular extensions from late endosomes to lysosomes, or by interactions of the two participating organelles in kiss‐and‐linger‐like processes, whereas full fusion is rarely observed. The persistence of FcRn on the late endosomal limiting membrane, together with selective transfer to lysosomes, allows this receptor to undergo recycling or degradation. Consequently, late endosomes have functional plasticity, consistent with the presence of the Rab5 GTPase in discrete domains on these compartments.