Miracle-dz/UniFAR-FTUs huggingface dataset:
Mathematical modeling of tumor-tumor distant interactions supports a systemic control of tumor growth

Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition and proliferation inhibition) have been proposed but precise determinants of the phenomenon remain poorly understood. Here we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15, p<0.05). The competition model had to be rejected while the angiogenesis inhibition and proliferation inhibition models were able to describe the data. Additional models including a theory based on distant cytotoxic log-kill effects were unable to fit the data. The proliferation inhibition model was identifiable and minimal (4 parameters), and its descriptive power was validated against the data, including consistency in predictions of single tumor growth when no secondary tumor was present. This theory may also shed new light on single cancer growth insofar as it offers a biologically translatable picture of how local and global action may combine to control local tumor growth, and in particular, the role of tumor-tumor inhibition. This model offers a depiction of concomitant resistance that provides an improved theoretical basis for tumor growth control and may also find utility in therapeutic planning to avoid post-surgery metastatic acceleration.
In vitro assessment of quality of citrate‐phosphate‐dextrose‐adenine‐1 preserved feline blood collected by a commercial closed system

Background Optimal procedure for storage of feline blood is needed. Open‐collection systems have been employed in feline medicine, thus limiting the possibility for storage. Objectives To evaluate indicators of quality of feline blood stored for 35 days at +4°C in a closed‐collection system specifically designed for cats. Animals Eight healthy adult European domestic shorthair cats with a weight of 5‐6.8 kg. Methods This is a case series study. A bacteriological test, CBC, blood smear, pH, osmotic fragility, 2,3‐diphosphoglycerate (2,3‐DPG), and adenosine triphosphate (ATP) measurement were performed weekly on whole blood (WB) units from day 1 to day 35 after donation. The hemolysis index, lactate and potassium concentrations, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen were measured on plasma aliquots. Results One out of eight blood units (BUs) had bacterial growth (Serratia marcescens) at day 35. No significant differences were found regarding CBC, morphology, pH, and osmotic fragility. Despite high inter‐individual variability and low starting levels, significant decreases in the mean concentrations of 2,3‐DPG (T0 1.99 mmol/g Hb, SD 0.52, T35 1.25 mmol/g Hb, SD 1.43; P = .003) and ATP (T0 1.45 mmol/g Hb, SD 0.71, T35 0.62 mmol/g Hb, SD 0.51; P < .001) were detected during the study, as opposed to an increase in hemolysis (T0 0.11 mmol/L, SD 0.07, T35 0.84 mmol/L, SD 0.19; P < .001), lactate (T0 3.30 mmol/L, SD 0.86, T35 13.36 mmol/L, SD 2.90; P < .001), and potassium (T0 3.10 mmol/L, SD 0.21, T35 4.12 mmol/L, SD 0.35; P < .001) concentrations. Conclusions and Clinical Importance The commercial BU kit is appropriate for blood collection and conservation of WB in cats. The maintenance of WB quality indicators during storage is essential for future improvements of feline transfusion medicine.
Safety, Tolerability, and Pharmacokinetics of MEDI4893, an Investigational, Extended-Half-Life, Anti-Staphylococcus aureus Alpha-Toxin Human Monoclonal Antibody, in Healthy Adults

ABSTRACT MEDI4893 is an investigational immunoglobulin G1(κ) monoclonal antibody that specifically binds to and neutralizes alpha-toxin, a key Staphylococcus aureus virulence factor. A triple-amino-acid substitution, M252Y/S254T/T256E, was engineered into the MEDI4893 Fc region to extend its serum half-life. A phase 1, double-blind, dose escalation study was designed to evaluate the safety, tolerability, pharmacokinetics, anti-alpha-toxin-neutralizing activity, and antidrug antibody (ADA) response of MEDI4893 following a single intravenous infusion in healthy adults 18 to 65 years of age. Thirty-three subjects were randomly assigned to receive MEDI4893 at 225 mg (n = 3), 750 mg (n = 3), 2,250 mg (n = 8), or 5,000 mg (n = 12) or placebo (n = 7) and were followed for 360 days. Adverse events were mild or moderate in severity; none were serious. The MEDI4893 peak serum concentration increased dose proportionally from 77.2 μg/ml (225-mg dose) to 1,784 μg/ml (5,000-mg dose). The area under the concentration-time curve from 0 to 360 days also increased dose proportionally, from 4,840 μg · day/ml (225-mg dose) to 91,493 μg · day/ml (5,000-mg dose), indicating linear pharmacokinetics. MEDI4893's terminal half-life was estimated to be 80 to 112 days, which is approximately 4-fold longer than the half-lives of other human immunoglobulin G antibodies. The alpha-toxin-neutralizing activity in serum correlated highly with the MEDI4893 concentrations in serum. Three adults transiently tested positive for ADA on day 151, but this did not have an impact on MEDI4893 serum concentrations or the MEDI4893 safety profile; no subjects exhibited serum ADA at the study end. These data support the continued development of MEDI4893 for the prevention of S. aureus-mediated pneumonia. (This study has been registered at ClinicalTrials.gov under identifier NCT02296320.)
The 96th Amino Acid of the Coat Protein of Cucumber Green Mottle Mosaic Virus Affects Virus Infectivity

Cucumber green mottle mosaic virus (CGMMV) is one of the most devastating viruses infecting members of the family Cucurbitaceae. The assembly initiation site of CGMMV is located in the coding region of the coat protein, which is not only involved in virion assembly but is also a key factor determining the long-distance movement of the virus. To understand the effect of assembly initiation site and the adjacent region on CGMMV infectivity, we created a GTT deletion mutation in the GAGGTTG assembly initiation site of the infectious clone of CGMMV, which we termed V97 (deletion mutation at residue 97 of coat protein), followed by the construction of the V94A and T104A mutants. We observed that these three mutations caused mosaic after Agrobacterium-mediated transformation in Nicotiana benthamiana, albeit with a significant delay compared to the wild type clone. The mutants also had a common spontaneous E96K mutation in the coat protein. These results indicated that the initial assembly site and the sequence of the adjacent region affected the infectivity of the virus and that E96 might play an essential role in this process. We constructed two single point mutants—E96A and E96K—and three double mutants—V94A-E96K, V97-E96K and T104A-E96K—to further understand the role of E96 in CGMMV pathogenesis. After inoculation in N. benthamiana, E96A showed delayed systemic symptoms, but the E96K and three double mutants exhibited typical symptoms of mosaic at seven days post-infection. Then, sap from CGMMV-infected N. benthamiana leaves was mechanically inoculated on watermelon plants. We confirmed that E96 affected CGMMV infection using double antibody sandwich-enzyme-linked immunosorbent assay (DAS-ELISA), reverse transcription-polymerase chain reaction (RT-PCR), and sequencing, which further confirmed the successful infection of the related mutants, and that E96K can compensate the effect of the V94, V97, and T104 mutations on virus infectivity. In addition, Northern blotting showed that the accumulation of viral RNA corroborated the severity of the symptoms.
EPIZOOTIOLOGIC INVESTIGATIONS OF SELECTED INFECTIOUS DISEASE AGENTS IN FREE-RANGING EURASIAN LYNX FROM SWEDEN

Serum samples from 106 Eurasian lynx (Lynx lynx) from across Sweden, found dead or shot by hunters in 1993–99, were investigated for presence of antibodies to feline parvovirus (FPV), feline coronavirus, feline calicivirus, feline herpesvirus, feline immunodeficiency virus, Francisella tularensis, and Anaplasma phagocytophila, and for feline leukemia virus antigen. In addition, tissue samples from 22 lynx submitted in 1999 were analyzed by real-time polymerase chain reaction (PCR) to detect nucleic acids specific for viral agents and A. phagocytophila. Except for FPV antibodies in one lynx and A. phagocytophila in four lynx, all serology was negative. All PCR results also were negative. It was concluded that free-ranging Swedish lynx do not have frequent contact with the infectious agents considered in this study.
Effect of Microneedle Type on Transdermal Permeation of Rizatriptan

The present study was aimed to investigate the effect of salient microneedle (MN) geometry parameters like length, density, shape and type on transdermal permeation of rizatriptan (RIZ). Studies were carried out using two types of MN devices viz. AdminPatch® arrays (ADM) (0.6, 0.9, 1.2 and 1.5 mm lengths) and laboratory-fabricated polymeric MNs (PMs) of 0.6 mm length. In the case of the PMs, arrays were applied three times at different places within a 1.77-cm2 skin area (PM-3) to maintain the MN density closer to 0.6 mm ADM. Histological studies revealed that PM, owing to their geometry/design, formed wider and deeper microconduits when compared to ADM of similar length. Approximately 4.9- and 4.2-fold increases in the RIZ steady-state flux values were observed with 1.5 mm ADM and PM-3 applications when compared to the passive studies. A good correlation between different dimensionless parameters like the amount of RIZ permeated (Ct/Cs), thickness (h/L) and surface area (Sa/L2) of the skin was observed with scaling analyses. Numerical simulations provided further information regarding the distribution of RIZ in MN-treated skin after application of different MNs. Overall, the study suggests that MN application enhances the RIZ transdermal permeation and the geometrical parameters of MNs play an important role in the degree enhancement.
Nanoparticle-Cell Lipid Membrane Biophysical Interaction and its Role in Developing Tumor Targeted Nanoparticles

Tumor targeted nanoparticles could improve drug delivery of the encapsulated cancer therapeutics to the tumor while reducing their non-specific side effects. However, complex conjugation chemistry, weak antibody-nanoparticle binding, and finite number of receptors available for nanoparticle binding could limit the efficacy of tumor targeted nanoparticles. Therefore, there is need for a new approach to improve nanoparticle localization in tumors. Physical properties of nanoparticles particularly their surface properties have shown to influence in vitro cellular uptake, in vivo biodistribution and tumor localization of nanoparticles. Apart from physical characteristics of nanoparticles, their uptake has also been shown to depend on the cell type. Additionally, progression of disease such as cancer can cause changes in the cell membrane lipid composition, and thereby influence nanoparticle-cell membrane interactions and cellular uptake of nanoparticles. The research described in this thesis explores an interesting approach that explores the differences in the cell membrane lipid composition as well as modification in nanoparticle surface characteristics to design nanoparticles that would preferentially target tumors.
Characteristics of attrition among children receiving trauma-focused treatment.

OBJECTIVES Identifying the factors related to premature termination from trauma-focused child therapy is an important first step in ultimately preventing attrition in at-risk families. The primary aim of the present study was to investigate whether demographic factors and pretreatment symptom levels were associated with premature termination among children who received trauma-focused treatment. Because different definitions of attrition may influence results, candidate factors were examined in relation to 2 operational definitions of attrition. METHOD Four hundred and sixty-six children (ages 2-18 years; M = 9.23, SD = 3.78; 66.1% females) who were referred to a Child Advocacy Center (CAC) for trauma-focused therapy were included in the study. Demographic and family variables, characteristics of the traumatic event, and caregiver- and child-reported pretreatment symptoms levels were assessed in relation to both clinician-rated treatment status and whether the child received an adequate dose of treatment (i.e., ≥12 sessions). RESULTS Several demographic factors (e.g., child's age, minority status, household income, maternal years of education), Child Protective Services (CPS) involvement, type of treatment received, number of traumatic events, and caregiver-rated pretreatment symptom levels were related to clinician-rated treatment status. Relatively fewer factors were associated with the adequate dose operationalization of attrition. Children's symptom reports were unrelated to either attrition definition. CONCLUSIONS Demographic and family factors, trauma characteristics, and level of caregiver-reported symptoms may help identify families at risk for premature termination. Efforts to understand the interactions between attrition factors, as well the use of different operational definitions in relation to premature termination, are warranted. (PsycINFO Database Record
Time manages interference in visual short-term memory

ABSTRACT Emerging evidence suggests that age-related declines in memory may reflect a failure in pattern separation, a process that is believed to reduce the encoding overlap between similar stimulus representations during memory encoding. Indeed, behavioural pattern separation may be indexed by a visual continuous recognition task in which items are presented in sequence and observers report for each whether it is novel, previously viewed (old), or whether it shares features with a previously viewed item (similar). In comparison to young adults, older adults show a decreased pattern separation when the number of items between “old” and “similar” items is increased. Yet the mechanisms of forgetting underpinning this type of recognition task are yet to be explored in a cognitively homogenous group, with careful control over the parameters of the task, including elapsing time (a critical variable in models of forgetting). By extending the inter-item intervals, number of intervening items and overall decay interval, we observed in a young adult sample (N = 35, Mage = 19.56 years) that the critical factor governing performance was inter-item interval. We argue that tasks using behavioural continuous recognition to index pattern separation in immediate memory will benefit from generous inter-item spacing, offering protection from inter-item interference.
First Report on a Randomized Investigation of Antimicrobial Resistance in Fecal Indicator Bacteria from Livestock, Poultry, and Humans in Tanzania.

This study provides an estimate of antimicrobial resistance in intestinal indicator bacteria from humans (n = 97) and food animals (n = 388) in Tanzania. More than 70% of all fecal samples contained tetracycline (TE), sulfamethoxazole (STX), and ampicillin (AMP)-resistant coliforms, while cefotaxime (CTX)-resistant coliforms were observed in 40% of all samples. The average Log10 colony forming units/g of CTX-resistant coliforms in samples from humans were 2.20. Of 390 Escherichia coli tested, 66.4% were resistant to TE, 54.9% to STX, 54.9% to streptomycin, and 36.4% to CTX. Isolates were commonly (65.1%) multiresistant. All CTX-resistant isolates contained blaCTX-M gene type. AMP- and vancomycin-resistant enterococci were rare, and the average concentrations in positive samples were low (log10 0.9 and 0.4, respectively). A low-to-moderate resistance (2.1-15%) was detected in 240 enterococci isolates to the drugs tested, except for rifampicin resistance (75.2% of isolates). The average number of sulII gene copies varied between Log10 5.37 and 5.68 with no significant difference between sample source, while cattle had significantly higher number of tetW genes than humans. These findings, based on randomly obtained samples, will be instrumental in designing antimicrobial resistance (AMR) intervention strategies for Tanzania.
Feral Swine in the United States Have Been Exposed to both Avian and Swine Influenza A Viruses

ABSTRACT Influenza A viruses (IAVs) in swine can cause sporadic infections and pandemic outbreaks among humans, but how avian IAV emerges in swine is still unclear. Unlike domestic swine, feral swine are free ranging and have many opportunities for IAV exposure through contacts with various habitats and animals, including migratory waterfowl, a natural reservoir for IAVs. During the period from 2010 to 2013, 8,239 serum samples were collected from feral swine across 35 U.S. states and tested against 45 contemporary antigenic variants of avian, swine, and human IAVs; of these, 406 (4.9%) samples were IAV antibody positive. Among 294 serum samples selected for antigenic characterization, 271 cross-reacted with ≥1 tested virus, whereas the other 23 did not cross-react with any tested virus. Of the 271 IAV-positive samples, 236 cross-reacted with swine IAVs, 1 with avian IAVs, and 16 with avian and swine IAVs, indicating that feral swine had been exposed to both swine and avian IAVs but predominantly to swine IAVs. Our findings suggest that feral swine could potentially be infected with both avian and swine IAVs, generating novel IAVs by hosting and reassorting IAVs from wild birds and domestic swine and facilitating adaptation of avian IAVs to other hosts, including humans, before their spillover. Continued surveillance to monitor the distribution and antigenic diversities of IAVs in feral swine is necessary to increase our understanding of the natural history of IAVs. IMPORTANCE There are more than 5 million feral swine distributed across at least 35 states in the United States. In contrast to domestic swine, feral swine are free ranging and have unique opportunities for contact with wildlife, livestock, and their habitats. Our serological results indicate that feral swine in the United States have been exposed to influenza A viruses (IAVs) consistent with those found in both domestic swine and wild birds, with the predominant infections consisting of swine-adapted IAVs. Our findings suggest that feral swine have been infected with IAVs at low levels and could serve as hosts for the generation of novel IAVs at the interface of feral swine, wild birds, domestic swine, and humans.
Resilient deconstructible columns for accelerated bridge construction in seismically active areas

This article presents an unprecedented concept for resilient bridge columns comprising precast modules designed for disassembly. Resiliency is provided by superelastic shape memory alloys that minimize permanent drift and engineered cementitious composite that minimizes damage, while keeping the rest of the column elastic. The precast modules consist of prefabricated plastic hinges and prefabricated concrete-filled fiber–reinforced polymer tubes. The columns are very desirable candidates for accelerated bridge construction. Two ¼-scale column models with engineered cementitious composite plastic hinges incorporating two types of shape memory alloy bars, one made of nickel–titanium and the other of copper–aluminum–manganese, were designed and tested under simulated earthquakes. To assess the influence of reusing column components, each of the models was first tested under a series of ground motions, and then the models were disassembled, inspected, reassembled, and subsequently retested. The reassembled models reached the same capacity as the original models but were more flexible. A simple modeling method was able to match the global measured response of the models with a reasonable accuracy.
Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib: a real-world study

A recent study reported long-term safety outcomes of tofacitinib for rheumatoid arthritis (RA) in global clinical trials1; the safety profile of tofacitinib exposure through 8.5 years appeared stable over time, with no new detectable safety signals. However, since most tofacitinib studies excluded patients with chronic hepatitis B (HBV) infection,1 2 the risk of HBV reactivation among tofacitinib-treated patients remains unknown. More than two billion people globally have been infected by HBV,3 and a substantial number of patients with RA outside North America and Western Europe have coexisting HBV infection.4 HBV reactivation is a critical challenge in patients with RA receiving biological therapy5; consequently, HBV screening is recommended before initiating biologics.3 Janus kinase inhibition may counteract the suppressive effects of interferon α on viral replication6; therefore, we assessed the risk of HBV reactivation in patients receiving tofacitinib. We established a retrospective cohort of 116 Taiwanese patients with RA who received tofacitinib at a single medical centre between April 2015 …
Minimising the Kullback–Leibler Divergence for Model Selection in Distributed Nonlinear Systems

The Kullback–Leibler (KL) divergence is a fundamental measure of information geometry that is used in a variety of contexts in artificial intelligence. We show that, when system dynamics are given by distributed nonlinear systems, this measure can be decomposed as a function of two information-theoretic measures, transfer entropy and stochastic interaction. More specifically, these measures are applicable when selecting a candidate model for a distributed system, where individual subsystems are coupled via latent variables and observed through a filter. We represent this model as a directed acyclic graph (DAG) that characterises the unidirectional coupling between subsystems. Standard approaches to structure learning are not applicable in this framework due to the hidden variables; however, we can exploit the properties of certain dynamical systems to formulate exact methods based on differential topology. We approach the problem by using reconstruction theorems to derive an analytical expression for the KL divergence of a candidate DAG from the observed dataset. Using this result, we present a scoring function based on transfer entropy to be used as a subroutine in a structure learning algorithm. We then demonstrate its use in recovering the structure of coupled Lorenz and Rössler systems.