Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanistic Investigation of the Preclinical Pharmacokinetics and Interspecies Scaling of PF-05231023, a Fibroblast Growth Factor 21–Antibody Protein Conjugate

PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analog, was generated by covalently conjugating two engineered [des-His1, Ala129Cys]FGF21 molecules to a nontargeting human IgG1κ scaffold. The pharmacokinetics (PK) of PF-05231023 after i.v. and s.c. administration was evaluated in rats and monkeys using two enzyme-linked immunosorbent assays with high specificity for biologically relevant intact N termini (NT) and C termini (CT) of FGF21. Intact CT of FGF21 displayed approximately 5-fold faster systemic plasma clearance (CL), an approximately 2-fold lower steady-state volume of distribution, and at least 5-fold lower bioavailability compared with NT. In vitro serum stability studies in monkeys and humans suggested that the principal CL mechanism for PF-05231023 was degradation by serum proteases. Direct scaling of in vitro serum degradation rates for intact CT of FGF21 underestimated in vivo CL 5-fold, 1.4-fold, and 2-fold in rats, monkeys, and humans, respectively. The reduced steady-state volume of distribution and the bioavailability for intact CT relative to NT in rats and monkeys were compatible with proteolytic degradation occurring outside the plasma compartment via an unidentified mechanism. Human CL and PK profiles for intact NT and CT of FGF21 were well predicted using monkey single-species allometric and Dedrick scaling. Physiologically based pharmacokinetic models incorporating serum stability data and an extravascular extraction term based on differential bioavailability of intact NT and CT of FGF21 in monkeys improved accuracy of human PK predictions relative to Dedrick scaling. Mechanistic physiologically based pharmacokinetic models of this nature may be highly valuable for predicting human PK of fusion proteins, synthetically conjugated proteins, and other complex biologics.
Feature Configuration Modulates Effective Connectivity

Editor's Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to mimic the journal clubs that exist in your own departments or institutions. For more information on the format and purpose of the Journal Club, please see Dynamic stimulus-dependent correlated spiking activity (on a millisecond scale) has been observed in several regions of the visual system, but dependencies have typically been limited to relatively simple in-tegrative rules such as continuity and collinearity (Singer, 1999). Continuity is when features extend across multiple receptive fields (RFs) without interruption and collinearity is when features extend across aligned RFs. The notion that correlated firing might play a role in integrating visual features and solving the binding problem has been a controversial topic in neuroscience [an entire issue of Neuron (Vol. 24, Issue 1, 1999) was devoted to this debate]. The massive amount of physiological and anatomical data on the primary visual cortex (V1), as well as the accessibility to this area, have allowed researchers to characterize systematically stimulus-dependent correlated spiking activity in that structure. These data, together with retinotopic organization and the dependence of spike correlation on simple grouping rules, provide an intuitive idea about how this behavior might play a role in early stages of object recognition such as contour integration. Inferior temporal (IT) cortex is viewed as one of the latest stages serving object recognition (Gross, 1992). IT neurons selectively respond to complex objects such as faces and this selectivity can be partially invariant to spatial location and size. IT neurons can respond equally well to individual features isolated from complex objects. Correlated firing among V1 neurons tuned for orientated segments depends on collinearity and continuity among segments , which are ubiquitous configurations in natural scenes. Therefore, correlated firing among IT neurons tuned for complex features should depend on ecologically critical configurations of features such as faces. In a recent article in The Journal of Neuroscience, Hirabayashi and Miyashita (2005) tested this prediction by looking for differences in IT spike correlation between face-like objects (FO) and nonface-like objects (NFO) [Hiraba-yashi and Miyashita (2005), their Fig. 1 The authors demonstrated a clear difference in cross-correlation peaks among IT pairs between FO and NFO stimuli comprised of the same features [Hiraba-yashi and Miyashita (2005), their Fig. 2 Over 75% of the pairs had stronger spike correlation for the FO configuration versus the …
The Evolution Of East Candor Chasma Valles Marineris Mars Proposed Structural Collapse And Sedimentation

ii Acknowledgements . iii List of Figures . vii Chapter 1 . vii Chapter 2 . vii Chapter 3 . x Chapter 4 . xiii 1.0 Chapter 1: Introduction . 1 1.1 A brief Overview of the History of Mars . 1 1.2 Obliquity and Climate Change . 2 1.3 Valles Marineris . 3 1.4 Valles Marineris Geologic History . 4 1.5 Composition of Martian Crust Near Valles Marineris . 6 1.6 Interior Layered Deposits . 7 1.7 Evidence of Glaciation in Valles Marineris . 8 1.8 Sulfates . 10 1.9 Interior Layered Deposit Formation Mechanisms . 11 1.10 Subaerial Formation Mechanisms . 12 1.10. 1 Subaqueous Formation Mechanisms . 13 1.10. 2 Volcanic Ash Formation Mechanisms . 14 1.11 Erosional Features of ILDs . 15 1.12 Purpose of study . 15 References . 17 2.0 Chapter 2: ILDs in East Candor Chasma . 22
CRISPR Typing and Subtyping for Improved Laboratory Surveillance of Salmonella Infections

Laboratory surveillance systems for salmonellosis should ideally be based on the rapid serotyping and subtyping of isolates. However, current typing methods are limited in both speed and precision. Using 783 strains and isolates belonging to 130 serotypes, we show here that a new family of DNA repeats named CRISPR (clustered regularly interspaced short palindromic repeats) is highly polymorphic in Salmonella. We found that CRISPR polymorphism was strongly correlated with both serotype and multilocus sequence type. Furthermore, spacer microevolution discriminated between subtypes within prevalent serotypes, making it possible to carry out typing and subtyping in a single step. We developed a high-throughput subtyping assay for the most prevalent serotype, Typhimurium. An open web-accessible database was set up, providing a serotype/spacer dictionary and an international tool for strain tracking based on this innovative, powerful typing and subtyping tool.
Dextran Preserves Native Corneal Structure During Decellularization.

Corneal decellularization has become an increasingly popular technique for generating scaffolds for corneal regeneration. Most decellularization procedures result in tissue swelling, thus limiting their application. Here, the use of a polysaccharide, dextran, to reduce swelling and conserve the native corneal structure during decellularization was investigated. Corneas were treated with 1% Triton X-100, 0.5% sodium dodecyl sulfate, and nucleases under constant rotation followed by extensive washing. To reduce swelling, decellularization solutions were supplemented with 5% dextran either throughout the whole decellularization process or during the washing cycles only. Quantitative analysis of DNA content showed a 96% reduction after decellularization regardless of the addition of dextran. Dextran resulted in a significant reduction in swelling from 3.85 ± 0.43 nm without to 1.94 ± 0.29-2.01 ± 0.37 nm (p < 0.05) remaining at similar dimensions to the native tissue (1.73 ± 0.23 nm). Tissue transparency was restored to all decellularized corneas following submersion in glycerol. Transmission electron microscopy (TEM) analysis found that dextran must be present throughout the decellularization protocol to preserve the native corneal architecture, anisotropy analysis demonstrated comparable results (0.22 ± 0.03) to the native cornea (0.24 ± 0.02), p > 0.05. Dextran can counteract the detrimental effects of decellularizing agents on the biomechanical properties of the tissue resulting in similar compressive moduli (mean before decellularization: 5.40 ± 1.18 kPa; mean after decellularization with dextran: 5.64 ± 1.34 kPa, p > 0.05). Cells remained viable in the presence of decellularized scaffolds. The findings of this study indicate that dextran not only prevents significant corneal swelling during decellularization but also enhances the maintenance of the native corneal ultrastructure.
A geometrical approach for aerial cooperative obstacle mapping using RSSI observations

The effect of an obstacle on signal strength attenuation is the most important reason that affects the performance of distance estimation based on Received Signal Strength Indication (RSSI) observations. Consequently, in this paper, a novel approach for estimation of the location and height of an obstacle between two UAVs using RSSI observations is proposed which would help to better estimate the location of a radio frequency (RF) source. The long-term goal of developing this approach is to improve the localization of an RF source by removing the effect of obstacle(s) on the signal attenuation. This approach is based on path planning of the UAVs to estimate the tip of the obstacle between them. The change in the diffraction loss observations are used to find the Line Of Sight (LOS) positions of the UAVs. These LOS lines, constructed by connecting the UAVs in LOS situation, are the locus of the tip of the obstacle and used in an iterative geometrical approach for estimation of the location of the tip of the obstacle. Due to the uncertainty in determining the LOS position which is created because of the radius of the Fresnel zone, the motion steps of UAVs, and the non-modeled dynamics in signal attenuation, an EKF filter is used to estimate the tip of the obstacle. The approach has been simulated and the results show that the approach provides better accuracy in RF source localization compared to the basic approach which does not consider the obstacles in the localization process.
Trends in chronic myeloid leukemia incidence and survival in the United States from 1975 to 2009

Abstract The use of interferon-α and allogeneic stem cell transplant and more recently of tyrosine kinase inhibitors (TKIs) have improved the outcome of patients with chronic myeloid leukemia (CML). We performed a population-based study of CML to evaluate relative survival (RS) trend by treatment eras. All instances of CML diagnosed between 1975 and 2009 reported in the Surveillance, Epidemiology and End Results databases were reviewed. The incidence of CML was 1.75/100 000 persons per year and increased with age. The incidence was highest in Detroit and lowest among Asians. The 5-year RS ratios increased from 0.26 in patients diagnosed in 1975–1989 to 0.36 in 1990–2000 and 0.56 in 2001–2009. There was a significant improvement in 5-year RS ratios in the 2005–2009 calendar period compared to the 2001–2004 period (p < 0.05), corresponding to the introduction of second-generation TKIs. Age was the most important prognostic factor for RS, but the improvement in 5-year RS ratios was observed in all age groups except the group aged < 15 years (p > 0.05), including adolescents and young adults and elderly patient groups. There are ethnic and geographic variations in the incidence of CML. The RS improved with each treatment era, with the greatest improvement in all age groups occurring during the TKI era.
Opportunistic relay selection with outdated CSI: outage probability and diversity analysis

In this paper, we analyze the outage probability and diversity order of opportunistic relay selection in a scenario based on decode and forward and where the available channel state information (CSI) is outdated. The study is conducted analytically by obtaining a closed-form expression for the outage probability, which is defined as the probability that the instantaneous capacity is below a target value. We derive high-SNR approximations for the outage probability. By doing so, we demonstrate that the diversity order of the system is reduced to 1 when CSI is outdated, being this behavior independent of the level of CSI accuracy. A physical explanation for this extreme loss of diversity is provided along with numerical results to support the analytical study.
Ovarian Stem Cell Niche and Follicular Renewal in Mammals

Stem cell niche consists of perivascular compartment, which connects the stem cells to the immune and vascular systems. During embryonic period, extragonadal primordial germ cells colonize coelomic epithelium of developing gonads. Subsequently, ovarian stem cells (OSC) produce secondary germ cells under the influence of OSC niche, including immune system‐related cells and hormonal signaling. The OSC in fetal and adult human ovaries serve as a source of germ and granulosa cells. Lack of either granulosa or germ cell niche will result in premature ovarian failure in spite of the presence of OSC. During perinatal period, the OSC transdifferentiate into fibroblast‐like cells forming the ovarian tunica albuginea resistant to environmental threats. They represent mesenchymal precursors of epithelial OSC during adulthood. The follicular renewal during the prime reproductive period (PRP) ensures that there are fresh eggs available for a healthy progeny. End of PRP is followed by exponentially growing fetal genetic abnormalities. The OSC are present in adult, aging, and postmenopausal ovaries, and differentiate in vitro into new oocytes. During in vitro development of large isolated oocytes reaching 200 μm in diameter, an ancestral mechanism of premeiotic nurse cells, which operates during oogenesis in developing ovaries from invertebrates to mammalian species, is utilized. In vitro developed eggs could be used for autologous IVF treatment of premature ovarian failure. Such eggs are also capable to produce parthenogenetic embryos like some cultured follicular oocytes. The parthenotes produce embryonic stem cells derived from inner cell mass, and these cells can serve as autologous pluripotent stem cells. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.
Acute gastrointestinal illness in adults in Germany: a population-based telephone survey

SUMMARY Population-based estimates of incidence and risk factors for acute gastrointestinal illness (AGI) are important for infectious disease surveillance and healthcare planning. We conducted a nationwide representative cross-sectional telephone survey of 21 262 adults over a 12-month period during 2008–2009 in Germany. Participants were asked if they had either AGI-related diarrhoea or vomiting in a 4-week recall period. We estimated 0·95 episodes/person per year (95% confidence interval 0·90–0·99), corresponding to 64·9 million episodes of AGI annually in adults, which results in 24·5 million outpatient visits, 19·9 million hospital days and 63·2 million days of work lost. We observed an overall declining trend of AGI with increasing age. Diarrhoea was more often reported than vomiting. The mean duration of illness was 3·8 days and did not differ between age groups. Social factors seemed to be weak predictors compared to state of health and health behaviour characteristics. This study allows international comparisons and contributes to the estimation of the global burden of AGI.
Factors Affecting Occupational Exposure to Needlestick and Sharps Injuries among Dentists in Taiwan: A Nationwide Survey

Background Although the risks of needlestick and sharps injuries (NSIs) for dentists are well recognized, most papers published only described the frequency of occupational exposure to NSIs. Less has been reported assessing factors contributing to exposure to NSIs. The purpose of this study was to update the epidemiology of NSIs among dentists in Taiwan and identify factors affecting NSIs in order to find preventive strategies. Methodology/Principal Findings A nationwide survey was conducted in dentists at 60 hospitals and 340 clinics in Taiwan. The survey included questions about factors supposedly affecting exposure to NSIs, such as dentist and facility characteristics, knowledge and attitudes about infectious diseases, and practices related to infection control. Univariate and multivariate logistic regression analyses were conducted to determine the association between risk factors and exposure to NSIs. In total, 434 (74.8%) of 580 dentists returned the survey questionnaires, and 100 (23.0%) reported that they had experienced more than one NSI per week. Our data showed that the risk of occupational NSIs is similarly heightened by an older age (odds ratio [OR], 3.18; 95% confidence interval [CI], 1.62–6.25), more years in practice (OR, 2.57; 95% CI, 1.41–4.69), working in clinics (OR, 1.73; 95% CI, 1.08–2.77), exhibiting less compliance with infection-control procedures (OR, 1.82; 95% CI, 1.04–3.18), having insufficient knowledge of blood-borne pathogens (OR, 1.67; 95% CI, 1.04–2.67), and being more worried about being infected by blood-borne pathogens (OR, 1.82; 95% CI, 1.05–3.13). Conclusions/Significance High rates of NSIs and low compliance with infection-control procedures highly contribute to the chance of acquiring a blood-borne pathogen infection and threaten occupational safety. This study reveals the possible affecting factors and helps in designing prevention strategies for occupational exposure to NSIs.
School connectedness and daily smoking among boys and girls: the influence of parental smoking norms.

BACKGROUND The objective was to test whether an association between school connectedness and smoking exists among Danish school children, and if so, to examine whether parental smoking attitude and parental smoking behaviour influenced this association. METHODS Data were collected by the Danish contribution to the cross-national study Health Behaviour in School-Aged Children (HBSC) 1998. Analyses were performed on questionnaire-based data from 1537 students at grade nine from a random sample of schools in Denmark. RESULTS An independent inverse association was found between school connectedness and smoking among both boys and girls. Parents' attitude to their children's smoking significantly modified this association among boys. Among girls the modifying effect was less marked. Neither among boys nor girls did parental smoking behaviour significantly modify the association between school connectedness and smoking, although a modifying tendency was observed among girls. CONCLUSIONS The smoking behaviour of Danish adolescents may be influenced by complicated interactions of varying sets of experienced smoking norms, and any research project or preventive programme focusing on the influence of school life on adolescent smoking behaviour needs to consider the family smoking norms. Additionally, the results stress the important role of gender by indicating that the smoking behaviour of girls may be more sensitive to restricting social influences than the smoking behaviour of boys.
Correct folding of alpha-lytic protease is required for its extracellular secretion from Escherichia coli

alpha-Lytic protease is a bacterial serine protease of the trypsin family that is synthesized as a 39-kD preproenzyme (Silen, J. L., C. N. McGrath, K. R. Smith, and D. A. Agard. 1988. Gene (Amst.). 69: 237- 244). The 198-amino acid mature protease is secreted into the culture medium by the native host, Lysobacter enzymogenes (Whitaker, D. R. 1970. Methods Enzymol. 19:599-613). Expression experiments in Escherichia coli revealed that the 166-amino acid pro region is transiently required either in cis (Silen, J. L., D. Frank, A. Fujishige, R. Bone, and D. A. Agard. 1989. J. Bacteriol. 171:1320-1325) or in trans (Silen, J. L., and D. A. Agard. 1989. Nature (Lond.). 341:462-464) for the proper folding and extracellular accumulation of the enzyme. The maturation process is temperature sensitive in E. coli; unprocessed precursor accumulates in the cells at temperatures above 30 degrees C (Silen, J. L., D. Frank, A. Fujishige, R. Bone, and D. A. Agard. 1989. J. Bacteriol. 171:1320-1325). Here we show that full- length precursor produced at nonpermissive temperatures is tightly associated with the E. coli outer membrane. The active site mutant Ser 195----Ala (SA195), which is incapable of self-processing, also accumulates as a precursor in the outer membrane, even when expressed at permissive temperatures. When the protease domain is expressed in the absence of the pro region, the misfolded, inactive protease also cofractionates with the outer membrane. However, when the folding requirement for either wild-type or mutant protease domains is provided by expressing the pro region in trans, both are efficiently secreted into the extracellular medium. Attempts to separate folding and secretion functions by extensive deletion mutagenesis within the pro region were unsuccessful. Taken together, these results suggest that only properly folded and processed forms of alpha-lytic protease are efficiently transported to the medium.
Gait Planning Research for an Electrically Driven Large-Load-Ratio Six-Legged Robot

Gait planning is an important basis for the walking of a legged robot. To improve the walking stability of multi-legged robots and to reduce the impact force between the foot and the ground, gait planning strategies are presented for an electrically driven large-load-ratio six-legged robot. First, the configuration and walking gait of the electrically driven large-load-ratio six-legged robot are designed. The higher-stable swing sequences of legs and typical walking modes are respectively obtained. Based on the Denavit–Hartenberg (D–H) method, the analyses of the forward and inverse kinematics are implemented. The mathematical models of the articulated rotation angles are respectively established. In view of the buffer device installed at the end of shin to decrease the impact force between the foot and the ground, an initial lift height of the leg is brought into gait planning when the support phase changes into the transfer phase. The mathematical models of foot trajectories are established. Finally, a prototype of the electrically driven large-load-ratio six-legged robot is developed. The experiments of the prototype are carried out regarding the aspects of the walking speed and surmounting obstacle. Then, the reasonableness of gait planning is verified based on the experimental results. The proposed strategies of gait planning lay the foundation for effectively reducing the foot–ground impact force and can provide a reference for other large-load-ratio multi-legged robots.
Activity-regulated RNA editing in select neuronal subfields in hippocampus

RNA editing by adensosine deaminases is a widespread mechanism to alter genetic information in metazoa. In addition to modifications in non-coding regions, editing contributes to diversification of protein function, in analogy to alternative splicing. However, although splicing programs respond to external signals, facilitating fine tuning and homeostasis of cellular functions, a similar regulation has not been described for RNA editing. Here, we show that the AMPA receptor R/G editing site is dynamically regulated in the hippocampus in response to activity. These changes are bi-directional, reversible and correlate with levels of the editase Adar2. This regulation is observed in the CA1 hippocampal subfield but not in CA3 and is thus subfield/celltype-specific. Moreover, alternative splicing of the flip/flop cassette downstream of the R/G site is closely linked to the editing state, which is regulated by Ca2+. Our data show that A-to-I RNA editing has the capacity to tune protein function in response to external stimuli.