Miracle-dz/UniFAR-FTUs huggingface dataset:
An End to Endless Forms: Epistasis, Phenotype Distribution Bias, and Nonuniform Evolution

Studies of the evolution of development characterize the way in which gene regulatory dynamics during ontogeny constructs and channels phenotypic variation. These studies have identified a number of evolutionary regularities: (1) phenotypes occupy only a small subspace of possible phenotypes, (2) the influence of mutation is not uniform and is often canalized, and (3) a great deal of morphological variation evolved early in the history of multicellular life. An important implication of these studies is that diversity is largely the outcome of the evolution of gene regulation rather than the emergence of new, structural genes. Using a simple model that considers a generic property of developmental maps—the interaction between multiple genetic elements and the nonlinearity of gene interaction in shaping phenotypic traits—we are able to recover many of these empirical regularities. We show that visible phenotypes represent only a small fraction of possibilities. Epistasis ensures that phenotypes are highly clustered in morphospace and that the most frequent phenotypes are the most similar. We perform phylogenetic analyses on an evolving, developmental model and find that species become more alike through time, whereas higher-level grades have a tendency to diverge. Ancestral phenotypes, produced by early developmental programs with a low level of gene interaction, are found to span a significantly greater volume of the total phenotypic space than derived taxa. We suggest that early and late evolution have a different character that we classify into micro- and macroevolutionary configurations. These findings complement the view of development as a key component in the production of endless forms and highlight the crucial role of development in constraining biotic diversity and evolutionary trajectories.
Antifungal Activity of Amphotericin B, Fluconazole, and Voriconazole in an In Vitro Model of Candida Catheter-Related Bloodstream Infection

ABSTRACT The activity of five simulated antifungal regimens for eradication of catheter-related bloodstream Candida infection was evaluated with an in vitro pharmacodynamic model. Single-lumen central venous catheters were colonized with Candida species by sequentially incubating central venous catheters in plasma and then in growth medium (RPMI plus morpholinepropanesulfonic acid) containing a standardized suspension (105 CFU/ml) of Candida albicans, Candida glabrata, or slime-producing Candida parapsilosis. Colonized central venous catheters were then placed in a one-compartment pharmacodynamic model where five antifungal regimens (plus control) were simulated: amphotericin B, 1.0 mg/kg every 24 h; amphotericin B, 0.5 mg/kg every 24 h; fluconazole, 400 mg every 24 h; fluconazole, 800 mg every 24 h; and voriconazole, 4 mg/kg every 12 h. During exposure to the simulated clinical regimens, samples were serially removed from the model over 48 h for quantitation of viable organisms. All antifungal regimens suppressed fungal counts by both peripheral and catheter sampling versus control (P = 0.001). Overall, antifungal activity ranked amphotericin B (1 mg/kg) > amphotericin B (0.5 mg/kg) ≥ voriconazole > fluconazole (800 mg) ≥ fluconazole (400 mg). No regimen, however, completely eradicated (by culture and electron microscopy) central venous catheter colonization. Regrowth was noted in the model during therapy against C. glabrata and C. parapsilosis but was not associated with an increase in the MICs for the isolates. Lack of in vitro antifungal activity against biofilm-encased organisms appeared to be the primary reason for mycological failure of antifungal regimens in the model.
Association Between Carotid Bulb Diaphragm and Ischemic Stroke in Young Afro-Caribbean Patients: A Population-Based Case–Control Study

Background and Purpose— Carotid bulb diaphragm (CBD) has been described in young carotid ischemic stroke (CIS) patients, especially in blacks. However, the prevalence of CBD in CIS patients is unknown, and whether CBD is a risk factor for CIS remains unclear. We assessed the association between CBD and incident CIS in a population-based study. Methods— We selected all young (<55 years) CIS patients from a 1-year population-based cohort study in the Afro-Caribbean population of Martinique in 2012. All patients had a comprehensive work-up including a computed tomographic angiography. We calculated CIS associated with ipsilateral CBD incidence with 95% confidence intervals using Poisson distribution. We then selected age- and sex-matched controls among young (<55 years) Afro-Caribbean stroke-free patients admitted for a road crash who routinely had computed tomographic angiography. Odds ratio (ORs) were calculated by conditional logistic regression adjusted for hypertension, dyslipidemia, diabetes and smoking. Results— CIS associated with ipsilateral CBD incidence was 3.8 per 100 000 person-years (95% confidence interval, 1.4–6.1). Prevalence of ipsilateral CBD was 23% in all CIS and 37% in undetermined CIS patients. When restricted to undetermined CIS, CBD prevalence was 24 times higher than that in controls (adjusted OR, 24.1; 95% confidence interval, 1.8–325.6). Conclusions— CBD is associated with an increased risk of ipsilateral CIS in young Afro-Caribbean population.
Comparative study of therapeutic antibody candidates derived from mini‐pool and clonal cell lines

The long journey of developing a drug from initial discovery target identification to regulatory approval often leaves many patients with missed window of opportunities. Both regulatory agencies and biopharmaceutical industry continue to develop creative approaches to shorten the time of new drug development in order to deliver life‐saving medicine to patients. Generally, drug substance materials to support the toxicology and early phase clinical study can only be manufactured after creating the final Master Cell Bank (MCB) of the clonally derived cell line, which normally takes 1–2 years. With recent advances in cell line development, cell culture process and analytical technologies, generating more homogeneous bulk/mini‐pool population with higher productivity and acceptable quality attributes has become a norm, thereby making it possible to shorten the timeline to initiate First in Human (FIH) trial by using bulk/mini‐pool generated materials to support toxicology and FIH studies. In this study, two monoclonal antibodies of different subclasses (IgG1 and IgG4) were expressed from the mini‐pool cells as well as clonally derived cell lines generated from the same mini‐pool. Cell growth, productivity, and product quality were compared between the materials generated from the mini‐pool and clonally derived cell line. The results demonstrate the similarity of the antibody products generated from mini‐pool cells and clonally derived cell lines from the same mini‐pool, and strongly support the concept and feasibility of using antibody materials produced from mini‐pool cultures for toxicology and FIH studies. The strategy to potentially shorten the FIH timeline is discussed. © 2017 American Institute of Chemical Engineers Biotechnol. Prog. , 33:1456–1462, 2017
Recent Origin and Cultural Reversion of a Hunter–Gatherer Group

Contemporary hunter–gatherer groups are often thought to serve as models of an ancient lifestyle that was typical of human populations prior to the development of agriculture. Patterns of genetic variation in hunter–gatherer groups such as the ! Kung and African Pygmies are consistent with this view, as they exhibit low genetic diversity coupled with high frequencies of divergent mtDNA types not found in surrounding agricultural groups, suggesting long-term isolation and small population sizes. We report here genetic evidence concerning the origins of the Mlabri, an enigmatic hunter–gatherer group from northern Thailand. The Mlabri have no mtDNA diversity, and the genetic diversity at Y-chromosome and autosomal loci are also extraordinarily reduced in the Mlabri. Genetic, linguistic, and cultural data all suggest that the Mlabri were recently founded, 500–800 y ago, from a very small number of individuals. Moreover, the Mlabri appear to have originated from an agricultural group and then adopted a hunting–gathering subsistence mode. This example of cultural reversion from agriculture to a hunting–gathering lifestyle indicates that contemporary hunter–gatherer groups do not necessarily reflect a pre-agricultural lifestyle.
Finite-SNR Diversity-Multiplexing Tradeoff for Two-Way Multi-Antenna Relay Fading Channels

In this paper, we study the diversity-multiplexing tradeoff (DMT) of two-way relay channels (TWRC) with multi-antenna relay at finite signal-to-noise ratio (SNR). A two-phase decode-and-forward (DF) relay protocol and Rayleigh fading environment are considered. We first derive upper and lower bounds on the outage probability. These bounds are very tight for all practical SNR regions. Based on these bounds, the estimates of finite-SNR DMT (f-DMT) are then obtained. Our analysis shows that the multiplexing gain approaches one when SNR decreases to zero. On the other hand, the diversity gain approaches the number of relay antennas when SNR increases to infinity. Furthermore, the impact of time sharing, rate allocation and relay location on the outage and f-DMT is also discussed through numerical examples.
The Short Physical Performance Battery is a discriminative tool for identifying patients with COPD at risk of disability

Background Limited mobility is a risk factor for developing chronic obstructive pulmonary disease (COPD)-related disabilities. Little is known about the validity of the Short Physical Performance Battery (SPPB) for identifying mobility limitations in patients with COPD. Objective To determine the clinical validity of the SPPB summary score and its three components (standing balance, 4-meter gait speed, and five-repetition sit-to-stand) for identifying mobility limitations in patients with COPD. Methods This cross-sectional study included 137 patients with COPD, recruited from a hospital in Spain. Muscle strength tests and SPPB were measured; then, patients were surveyed for self-reported mobility limitations. The validity of SPPB scores was analyzed by developing receiver operating characteristic curves to analyze the sensitivity and specificity for identifying patients with mobility limitations; by examining group differences in SPPB scores across categories of mobility activities; and by correlating SPPB scores to strength tests. Results Only the SPPB summary score and the five-repetition sit-to-stand components showed good discriminative capabilities; both showed areas under the receiver operating characteristic curves greater than 0.7. Patients with limitations had significantly lower SPPB scores than patients without limitations in nine different mobility activities. SPPB scores were moderately correlated with the quadriceps test (r>0.40), and less correlated with the handgrip test (r<0.30), which reinforced convergent and divergent validities. A SPPB summary score cutoff of 10 provided the best accuracy for identifying mobility limitations. Conclusion This study provided evidence for the validity of the SPPB summary score and the five-repetition sit-to-stand test for assessing mobility in patients with COPD. These tests also showed potential as a screening test for identifying patients with COPD that have mobility limitations.
Evaluating the Sample Registration System using indirect estimates of fertility and mortality. Occasional Paper No. 3 of 1992.

The authors attempt to evaluate the quality of mortality and fertility estimates obtained from the Indian Sample Registration System by using a number of indirect estimation techniques. Three fertility estimation techniques were used: the Palmore method the Gunasekaran-Palmore method and the Rele method. The four mortality estimation methods used were the Swanson-Palmore method an extension of this method that allows for estimating life expectancy at birth for each sex separately the Gunasekaran-Palmore-Gardner method and a new method under development based on the Rele-Palmore method. "The overall conclusion from our evaluation of the SRS is that both the fertility and mortality estimates are remarkably good. " (EXCERPT)
Cyclooxygenase 2 expression in pterygium

Purpose Following the recent discovery of an abnormal expression of the p53 gene in the epithelium in pterygium, some researchers felt that pterygium is a tumor rather than a degenerative disease. Ultraviolet (UV) radiation has been reported to be associated with pterygium formation, however the mechanism whereby UV induces uncontrolled proliferation in pterygial cells is unclear. Because cyclooxygenase 2 (COX 2) was reported to exist and play an important role in UV-related cutaneous carcinogenesis, it is logical to suspect that COX 2 existed in pterygium. This study was designed to investigate the expression of COX 2 in pterygium. Methods Immunohistochemical staining using a monoclonal antibody to COX 2 was performed on 90 pterygial specimens, 40 normal conjunctiva, and 5 normal limbus. Results In the pterygium group, 75 (83.3%) specimens stained positive for COX 2. The staining was limited to the cytoplasm of the epithelial layer and predominantly over the basal epithelial layer. No substantial staining was visible in the subepithelial fibrovascular layers. All specimens were negative in the normal conjunctiva and limbus group. Conclusions The present study showed COX 2 existed in pterygium. Given the role of COX 2 in cutaneous tumor carcinogenesis, we suggest COX 2 may also play a role in pterygium formation. This study could be used as the basis for future surveys of the causal relationship between COX 2 and pterygium as well as the effect of COX 2 inhibitor in preventing primary or recurrent pterygium.
Cholestasis in Neonates with Red Cell Alloimmune Hemolytic Disease: Incidence, Risk Factors and Outcome

Background: Etiology of cholestatic liver disease in neonates with hemolytic disease of the newborn (HDN) has been associated with iron overload due to intrauterine red cell transfusions (IUTs). Data on the incidence and severity of cholestasis in neonates with HDN are scarce, and little is known about pathogenesis, risk factors, neonatal management and outcome. Objective: To evaluate incidence, risk factors, management and outcome of cholestasis in neonates with red cell alloimmune hemolytic disease. Methods: All (near-) term neonates with HDN due to red cell alloimmunization admitted to our center between January 2000 and July 2010 were included in this observational study. Liver function tests (including conjugated bilirubin) were routinely performed in the neonatal period. We recorded the presence of cholestasis, investigated several potential risk factors and evaluated the management and outcome in affected neonates. Results: A total of 313 infants with red cell alloimmune hemolytic disease treated with or without IUTs were included. The incidence of cholestasis was 13% (41/313). Two risk factors were independently associated with cholestasis: treatment with at least one IUT (OR 5.81, 95% CI 1.70–19.80, p = 0.005) and rhesus D type of alloimmunization (OR 4.66, 95% CI 1.05–20.57, p = 0.042). Additional diagnostic tests to investigate possible causes of cholestasis were all negative. In 5 infants (12%), supportive medical and nutritional therapy was started, and one neonate required iron chelation therapy. Conclusion: Cholestasis occurs in 13% of neonates with HDN due to red cell alloimmunization, and it is independently associated with IUT treatment and rhesus D type of alloimmunization.
AAV-mediated expression targeting of rod and cone photoreceptors with a human rhodopsin kinase promoter.

PURPOSE Gene therapy for retinal degeneration requires well-defined promoters that drive expression in rod and cone photoreceptors. This study was undertaken to develop short, active derivatives of the human rhodopsin kinase (RK) gene promoter for targeting transgene expression in rods and cones. RK, also known as G protein-coupled receptor kinase 1 (GRK1), is a component of the light adaptation pathway expressed in rods and cones. METHODS Human RK (hRK) promoter and its concatemers or derivatives extending into the conserved 5' untranslated region (5'-UTR) were assayed for promoter activity in WERI retinoblastoma or Crx/Sp1-supplemented HEK-293 cells. The derivative displaying the highest activity was linked to a GFP reporter and packaged in a pseudotyped adenoassociated viral vector (AAV2/5). The AAV vector was tested in vivo by subretinal injections in wild-type mice, in the all-cone Nrl(-/-) mice, and in the cone-rich diurnal Nile grass rat (Arvicanthis niloticus). Control eyes received a similar AAV2/5 vector carrying a mouse rod opsin (mOps) promoter-controlled GFP reporter. RESULTS The hRK promoter with the full 5' untranslated sequence (-112 to +180) was the most active in cell culture. Delivered by the AAV2/5 vector, RK promoter drove GFP expression specifically in photoreceptors. In rods, hRK promoter-mediated expression was as efficient as, but appeared more uniform than, mOps promoter-mediated expression. In cones, the hRK promoter drove expression, whereas the mOps promoter did not. CONCLUSIONS The hRK promoter is active and specific for rod and cone photoreceptors. Because of its small size and proven activity in cones, it is a promoter of choice for somatic gene transfer and gene therapy targeting rods and cones.
Factors Influencing Secondary Alveolar Bone Grafting in Cleft Lip and Palate Patients: Prospective Analysis Using CT Image Analyzer

Objective: To examine the effect of migration of the germ of the lateral incisor into the bone for eruption factors on bone bridge resorption. Methods: Twenty-five subjects who underwent secondary alveolar bone graft were enrolled. The volume of the alveolar bone grafts immediately after the operation (V1), bone bridge formation 6 months postoperatively (V2), and tooth (teeth) migration into the bone bridge (Vt) were measured using a computed tomography (CT) image analyzer. Based upon these measurements, the following points were examined: (1) the correlation between the tooth-occupied ratio (Rt = Vt/V2 × 100) and the ratio of bone bridge resorption (Rv = (V1 − V2)/ V1 × 100); and (2) comparison of the tooth-occupied ratio (Rt) and the ratio of bone bridge resorption (Rv) between the groups with and without the germ of the lateral incisor. Results: A significant negative correlation was found between Rv and Rt (p < .001). Comparison of Rv and Rt between the groups with and without a germ of the lateral incisor revealed that both indices were significantly higher in the former group than the latter one (p < .05). Conclusion: In cleft lip and palate patients with a germ of the lateral incisor, it is beneficial to carry out secondary bone grafting to the alveolar cleft at the age of 5 to 7 years, preceding eruption of the canine, in order to form a good bone bridge that will facilitate eruption of the lateral incisor and subsequent normal dentition and occlusion.
Effects of Alcohol Reduction on Blood Pressure: A Meta-Analysis of Randomized Controlled Trials

Alcohol drinking has been associated with increased blood pressure in epidemiological studies. We conducted a meta-analysis of randomized controlled trials to assess the effects of alcohol reduction on blood pressure. We included 15 randomized control trials (total of 2234 participants) published before June 1999 in which alcohol reduction was the only intervention difference between active and control treatment groups. Using a standard protocol, information on sample size, participant characteristics, study design, intervention methods, duration, and treatment results was abstracted independently by 3 investigators. By means of a fixed-effects model, findings from individual trials were pooled after results for each trial were weighted by the inverse of its variance. Overall, alcohol reduction was associated with a significant reduction in mean (95% confidence interval) systolic and diastolic blood pressures of −3.31 mm Hg (−2.52 to −4.10 mm Hg) and −2.04 mm Hg (−1.49 to −2.58 mm Hg), respectively. A dose-response relationship was observed between mean percentage of alcohol reduction and mean blood pressure reduction. Effects of intervention were enhanced in those with higher baseline blood pressure. Our study suggests that alcohol reduction should be recommended as an important component of lifestyle modification for the prevention and treatment of hypertension among heavy drinkers.
The size of a revised knowledge base

In this paper we address a specific computational aspect of belief revision: the size of the propositional formula obtained by means of the revision of a formula with a new one. In particular, we focus on the size of the smallest formula which is logically equivalent to the revised knowledge base. The main result of this paper is that not all formalizations of belief revision are equal from this point of view. For some of them we show that the revised knowledge base can be represented by a polynomial-size formula (we call these results “compactability” results). On the other hand, for other ones the revised knowledge base does not always admit a polynomial-space representation, unless the polynomial hierarchy collapses at a sufficiently low level (“non-compactability” results). We also show that the time complexity of query answering for the revised knowledge base has definitely an impact on being able to represent the result of the revision compactly. Nevertheless, formalisms with the same complexity may have different compactability properties. We also study compactability properties for a weaker form of equivalence, called query equivalence, which allows to introduce new propositional symbols. Moreover, we extend our analysis to the special case in which the new formula has constant size and to the case of sequences of revisions (i.e., iterated belief revision). A complete analysis along these four coordinates is shown. ∗An extended abstract of this paper appeared as [5]. †Current address: Politecnico di Bari, Dipartimento di Elettrotecnica ed Elettronica, Via E. Orabona 4, I-70125 Bari, Italy.
Collusion-Resistant Video Fingerprinting for Large User Group

Digital fingerprinting protects multimedia content from illegal redistribution by uniquely marking copies of the content distributed to users. Most existing multimedia fingerprinting schemes consider a user set on the scale of thousands. However, in such real-world applications as video-on-demand distribution, the number of potential users can be as many as 10-100 million. This large user size demands not only strong collusion resistance but also high efficiency in fingerprint construction, and detection, which makes most existing schemes incapable of being applied to these applications. A recently proposed joint coding and embedding fingerprinting framework provides a promising balance between collusion resistance, efficient construction, and detection, but several issues remain unsolved for applications involving a large group of users. In this paper, we explore how to employ the joint coding and embedding framework and develop practical algorithms to fingerprint video in such challenging settings as to accommodate more than ten million users and resist hundreds of users' collusion. We investigate the proper code structure for large-scale fingerprinting and propose a trimming detection technique that can reduce the decoding computational complexity by more than three orders of magnitude at the cost of less than 0.5% loss in detection probability under moderate to high watermark-to-noise ratios. Both analytic and experimental results show a high potential of joint coding and embedding to meet the needs of real-world large-scale fingerprinting applications.