Miracle-dz/UniFAR-FTUs huggingface dataset:
Disposition and Metabolism of Darapladib , a Lipoprotein-Associated Phospholipase A 2 Inhibitor , in Humans

The absorption, metabolism, and excretion of darapladib, a novel inhibitor of lipoprotein-associated phospholipase A2, was investigated in healthy male subjects using [C]-radiolabeled material in a bespoke study design. Disposition of darapladib was compared following single i.v. and both single and repeated oral administrations. The anticipated presence of low circulating concentrations of drug-related material required the use of accelerator mass spectrometry as a sensitive radiodetector. Blood, urine, and feces were collected up to 21 days post radioactive dose, and analyzed for drug-related material. The principal circulating drug-related component was unchanged darapladib. No notable metabolites were observed in plasma post-i.v. dosing; however, metabolites resulting from hydroxylation (M3) and N-deethylation (M4) were observed (at 4%–6% of plasma radioactivity) following oral dosing, indicative of some first-pass metabolism. In addition, an acidcatalyzed degradant (M10) resulting from presystemic hydrolysis was also detected in plasma at similar levels of ∼5% of radioactivity post oral dosing. Systemic exposure to radioactive material was reduced within the repeat dose regimen, consistent with the notion of time-dependent pharmacokinetics resulting from enhanced clearance or reduced absorption. Elimination of drug-related material occurred predominantly via the feces, with unchanged darapladib representing 43%–53% of the radioactive dose, and metabolites M3 and M4 also notably accounting for ∼9% and 19% of the dose, respectively. The enhanced study design has provided an increased understanding of the absorption, distribution, metabolism and excretion (ADME) properties of darapladib in humans, and substantially influenced future work on the compound.
Evaluation of functional dynamics during osseointegration and regeneration associated with oral implants.

OBJECTIVES The aim of this paper is to review current investigations on functional assessments of osseointegration and assess correlations to the peri-implant structure. MATERIAL AND METHODS The literature was electronically searched for studies of promoting dental implant osseointegration, functional assessments of implant stability, and finite element (FE) analyses in the field of implant dentistry, and any references regarding biological events during osseointegration were also cited as background information. RESULTS Osseointegration involves a cascade of protein and cell apposition, vascular invasion, de novo bone formation and maturation to achieve the primary and secondary dental implant stability. This process may be accelerated by alteration of the implant surface roughness, developing a biomimetric interface, or local delivery of growth-promoting factors. The current available pre-clinical and clinical biomechanical assessments demonstrated a variety of correlations to the peri-implant structural parameters, and functionally integrated peri-implant structure through FE optimization can offer strong correlation to the interfacial biomechanics. CONCLUSIONS The progression of osseointegration may be accelerated by alteration of the implant interface as well as growth factor applications, and functional integration of peri-implant structure may be feasible to predict the implant function during osseointegration. More research in this field is still needed.
Beyond Antiangiogenesis: Intratumorally Injected Bevacizumab Plays a Cisplatin-Sensitizing Role in Squamous Cell Carcinomas in Mice

Background: The anticancer mechanism of bevacizumab beyond antiangiogenesis remains unclear. Here, we investigated whether intratumorally injected bevacizumab could serve as an effective cisplatin sensitizer in squamous cell carcinoma (SCC) in vivo. Methods: Hela and SCC-VII experimental SCC models were established to investigate the anticancer effect of bevacizumab plus cisplatin and the underlying mechanism using immunostaining, TUNEL, and Western blot assays. Results: Bevacizumab-cisplatin therapy markedly inhibited tumor growth and significantly increased survival in both Hela- and SCC-VII-bearing mice compared with single-agent treatments and the untreated control, respectively. Immunostaining of CD34 showed that intratumorally injected bevacizumab significantly reduced microvessel density in bevacizumab-cisplatin and bevacizumab-alone groups of Hela xenografts. TUNEL assay showed that bevacizumab-cisplatin significantly promoted tumor cell apoptosis compared with single-agent treatments and untreated controls in these 2 models. Western blot showed that upregulation of cleaved caspase-3 and downregulation of Bcl-2 and p-Erk expressions are part of the molecular mechanisms beyond angiogenesis which contribute to the cooperative effect of bevacizumab plus cisplatin in the 2 SCC models. Conclusions: Bevacizumab functions not only as an angiogenesis inhibitor but also as a chemosensitizer which enhances the cytotoxicity of cisplatin and promotes apoptosis of SCC cells.
Inducible expression of a gene encoding an L41 ribosomal protein responsible for the cycloheximide-resistant phenotype in the yeast Candida maltosa

In a previous paper (S. Kawai, S. Murao, M. Mochizuki, I. Shibuya, K. Yano, and M. Takagi, J. Bacteriol. 174:254-262, 1992), we showed that in each genome of several yeast species, there is one of two types of L41 gene, one for an L41 (Q-type) protein which confers cycloheximide (CYH) resistance or one for an L41 (P-type) protein which does not. These genes have been suggested to be responsible for the CYH response used in taxonomy. For example, Saccharomyces cerevisiae, which is CYH sensitive, has a P-type L41 gene, while Kluyveromyces fragilis and Candida maltosa, which are CYH resistant, have Q-type L41 genes. However, in contrast to K. fragilis, which is constitutively resistant to CYH, C. maltosa is inducibly resistant to CYH. Here, we show that C. maltosa has both types of the L41 gene in its genome and that expression of the Q-type L41 gene is induced by CYH while the P-type L41 gene is constitutively expressed.
Doppler waveform indices of fetal middle cerebral artery in normal 20 to 40 weeks pregnancies.

BACKGROUND One of the main methods for evaluation of fetal well-being is analysis of Doppler flow velocity waveform of fetal vessels. Evaluation of Doppler wave of the middle cerebral artery can predict most of the at-risk fetuses in high-risk pregnancies. In this study, we tried to determine the normal ranges and their trends during pregnancy of Doppler flow velocity indices (resistive index, pulsatility index, systolic-to-diastolic ratio, and peak systolic velocity) of middle cerebral artery in 20 - 40 weeks normal pregnancies in Iranians. METHODS In this cross-sectional study, 1037 women with normal pregnancy and gestational age of 20 to 40 weeks were investigated for fetal middle cerebral artery Doppler examination. RESULTS Resistive index, pulsatility index, and systolic-to-diastolic ratio values of middle cerebral artery decreased in a parabolic pattern while the peak systolic velocity value increased linearly with progression of the gestational age. These changes were statistically significant (P<0.001 for all four variables) and were more characteristic during late weeks of pregnancy. The mean fetal heart rate was also significantly (P<0.001) reduced in correlation with the gestational age. CONCLUSION Doppler waveform indices of fetal middle cerebral artery are useful means for determining fetal well-being. Herewith, the normal ranges of Doppler waveform indices for an Iranian population are presented.
Low Mechanical Index Contrast-Enhanced Ultrasound Better Reflects High Arterial Perfusion of Liver Metastases Than Arterial Phase Computed Tomography

Rationale and Objectives:We investigated whether observing the arterial vascularization of liver metastases by contrast-enhanced ultrasound with low mechanical index (low-MI) imaging offers additional diagnostic information for the characterization of the liver lesions. Methods:Twenty nine patients with untreated liver metastases of different primaries were examined. Measurements were performed using a low frame rate, low-MI pulse inversion technique after injection of 2.4 mL SonoVue. The relative maximum signal intensity of the liver lesions related to the normal liver tissue was quantified. Ultrasound findings were compared with contrast-enhanced, dual-phase computed tomography (CT) using a pattern-based classification scheme. Results:Compared with contrast-enhanced CT, this modality better detects arterial perfusion. Metastases, even those usually considered hypovascularized, often showed homogeneous enhancement (66%) and higher arterial vascularization than normal liver tissue. CT did not show a comparable vascularization pattern (P < 0.001) or any similarly early signal intensity (P < 0.001). Conclusions:Contrast-enhanced CT may not be able to visualize short-lasting but large differences of the arterial perfusion of liver metastases, as does contrast-enhanced low-MI ultrasound. This offers new methods for their characterization and for monitoring of therapeutic effects.
High anticancer efficacy of L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13) in vivo.

The anticancer efficacy of the new anticancer tripeptide, L-proline-m-bis (2-chloroethyl) amino-L-phenylalanyl-L-norvaline ethyl ester hydrochloride (MF13), was investigated in mice. MF13 showed a therapeutic effect in liquid tumors and induced complete remission even in late stage malignancies. MF13 also inhibited human colon cancer growth in nude mice by more than 85% (volume, p<0.001). It acted in a dose-dependent manner and induced a complete regression of tumor in 20% of the mice when the initial dose was high (15 mg/kg, i.p.). Human melanoma exhibited a response to MF13 similar to colon cancer. Activity of MF13 in murine hepatoma in vivo was stronger than its precursor m-sarcolysin (p<0.001). Tumor cells in peritoneal cavities of the MF13 treated (s.c.) mice underwent an irreversible apoptosis. Side effects of MF13 were the transient depression of hemopoiesis and loss of body weight, which vanished within 9-10 days. LD50 of MF13 of a single i.p. injection was 27 mg/kg (94 mg/m2), 11 times higher than the therapeutic dose of a single injection.
Vinegar for Decreasing Catheter-Associated Bacteriuria in Long-Term Catheterized Patients

Purpose: The purpose of this study was to evaluate the effect of rice vinegar administered via nasogastric feeding tube on catheter-associated bacteriuria in patients with long-term urinary catheterization. Method: The authors conducted a randomized controlled trial (n = 60) to compare treatment with dilute vinegar and usual care. The authors recruited patients with chronic catheters from a long-term care facility in northern Taiwan. The experimental group received 100 ml of diluted rice vinegar each day for 4 weeks, whereas the control group received 100 ml of water. The authors analyzed urine weekly and cultured it on Day 28. Results: The generalized estimating equation results showed significant between-group differences in urinary pH, bacterial titer, and turbidity. No patient in the experimental group, but three in the control group, exhibited symptomatic urinary tract infection (UTI). Rice vinegar may decrease bacteriuria. Medicinal use of vinegar may decrease the risk of symptomatic UTI, but further study is needed to determine the effects of ingesting vinegar for a longer period and with a larger sample size.
Low-Frequency Noise in Amorphous Indium–Gallium–Zinc-Oxide Thin-Film Transistors

We have investigated the low-frequency noise (LFN) properties of amorphous indium-gallium-zinc-oxide (a-IGZO) thin-film transistors (TFTs) as a function of frequency, bias, and channel length of devices. The measured noise power spectral density of drain current (<i>S</i> <sub>iD</sub>) shows that the low-frequency noise in a-IGZO TFTs obeys the classical 1/<i>f</i> noise theory, i.e., it fits well to a 1/<i>f</i> <sup>gamma</sup> power law with gamma ~ 1 in the frequency range of 10 Hz to 1 kHz. From the dependence of normalized noise power spectral density (<i>S</i> <sub>iD</sub>/<i>ID</i> <sup>2</sup>) on the gate voltage, mobility fluctuation is considered as a dominant LFN mechanism in a-IGZO TFTs. The magnitude of <i>S</i> <sub>iD</sub>/<i>ID</i> <sup>2</sup> is inversely proportional to the channel length of devices, which indicates that contact noise is insignificant in a-IGZO TFTs.
Toxic shock syndrome associated with Staphylococcus aureus sinusitis in children.

Toxic shock syndrome (TSS) is a severe, acute, multisystem illness associated with rash and shock. It is usually associated with a focal infection (e.g., during menstruation associated with tampon use, abscess, surgical wound infection) caused by certain Staphylococcus aureus strains. Identification and drainage of the focus of infection may be important in therapy. Occasionally, a focus of infection is not obvious, requiring additional diagnostic procedures. Three cases of children with TSS associated with sinusitis and no other focus of S. aureus infection are presented, demonstrating the important consideration of the perinasal sinuses as a cryptic focus of S. aureus infection causing TSS.
Disturbance of Circadian Rhythms in Analgosedated Intensive Care Unit Patients with and without Craniocerebral Injury

Melatonin, cortisol, heart rate, blood pressure, spontaneous motor activity, and body temperature follow stable circadian rhythms in healthy individuals. These circadian rhythms may be influenced or impaired by the loss of external zeitgebers during analgosedation, critical illness, continuous therapeutic intervention in the intensive care unit (ICU), and cerebral injury. This prospective, observational, clinical study examined 24 critically ill analgo‐sedated patients, 13 patients following surgery, trauma, or acute respiratory distress (ICU), and 11 patients with acute severe brain injury following trauma or cerebral hemorrhage (CCI). Blood samples for the determination of melatonin and cortisol were obtained from each patient at 2 h intervals for 24 h beginning at 18:00 h on day 1 and ending 16:00 h on day 2. Blood pressure, heart rate, body temperature, and spontaneous motor activity were monitored continuously. Level of sedation was assessed using the Ramsey Sedation Scale. The severity of illness was assessed using the APACHE‐II‐score. The time series data were analyzed by rhythm analysis with the Chronos‐Fit program, using partial Fourier series with up to six harmonics. The 24 h profiles of all parameters from both groups of patients were greatly disturbed/abolished compared to the well‐known rhythmic 24 h patterns in healthy controls. These rhythm disturbances were more pronounced in patients with brain injury. The results of this study provide evidence for a pronounced disturbance of the physiological temporal organization in ICU patients. The relative contribution of analgosedation and/or brain injury, however, is a point of future investigation.
The Meaning of Utterance-Final Even

This article takes up a relatively understudied phenomenon in English wherein the additive scalar focus particle even occurs following its focus, typically in utterance-final (UF) position. We show that this UF incarnation of even is not a simple variant of its prefocal (PF) counterpart. Four distinct functions of UF-EVEN are identified: (1) the mirative, (2) the elaborative, (3) the simple additive, and (4) the simple corrective. Building on Traugott’s theory of semantic change, the authors present an analysis that outlines the developmental path of UF-EVEN: all its functions are claimed to originate from PF-EVEN’s meaning, although some are less directly related to it. In addition, the authors demonstrate that UF-EVEN shares some of its developmental paths with discourse markers like actually and in fact, suggesting that it has taken on the function of a sentential adverb. The article ends with discussing repercussions for the theory of meaning change and its conventionalization.
The effects of violations of assumptions underlying the test.

As psychologists who perform in a research capacity are well aware, psychological data too frequently have an exasperating tendency to manifest themselves in a form which violates one or more of the assumptions underlying the usual statistical tests of significance. Faced with the problem of analyzing such data, the researcher usually attempts to transform them in such a way that the assumptions are tenable, or he may look elsewhere for a statistical test. The latter alternative has become popular because of the proliferation of the so-called nonparametric or distribution-free methods. These techniques quite generally, however, couple their freedom from restricting assumptions with a disdain for much of the information contained within the data. For example, by classifying scores into groups above and below the median one ignores the fact that there are intracategory differences between the individual scores. As a result, tests which make no assumptions about the distribution from which one is sampling will tend not to reject the null hypothesis when it is actually false as often as will those tests which do make assumptions. This lack of power of the nonpara-
On extracting design principles from biology: II. Case study—the effect of knee direction on bipedal robot running efficiency

Comparing the leg of an ostrich to that of a human suggests an important question to legged robot designers: should a robot's leg joint bend in the direction of running (‘forwards’) or opposite (‘backwards’)? Biological studies cannot answer this question for engineers due to significant differences between the biological and engineering domains. Instead, we investigated the inherent effect of joint bending direction on bipedal robot running efficiency by comparing energetically optimal gaits of a wide variety of robot designs sampled at random from a design space. We found that the great majority of robot designs have several locally optimal gaits with the knee bending backwards that are more efficient than the most efficient gait with the knee bending forwards. The most efficient backwards gaits do not exhibit lower touchdown losses than the most efficient forward gaits; rather, the improved efficiency of backwards gaits stems from lower torque and reduced motion at the hip. The reduced hip use of backwards gaits is enabled by the ability of the backwards knee, acting alone, to (1) propel the robot upwards and forwards simultaneously and (2) lift and protract the foot simultaneously. In the absence of other information, designers interested in building efficient bipedal robots with two-segment legs driven by electric motors should design the knee to bend backwards rather than forwards. Compared to common practices for choosing robot knee direction, application of this principle would have a strong tendency to improve robot efficiency and save design resources.
BtsT, a Novel and Specific Pyruvate/H+ Symporter in Escherichia coli

ABSTRACT The peptide transporter carbon starvation (CstA) family (transporter classification [TC] 2.A.114) belongs to the second largest superfamily of secondary transporters, the amino acid/polyamine/organocation (APC) superfamily. No representative of the CstA family has previously been characterized either biochemically or structurally, but we have now identified the function of one of its members, the transport protein YjiY of Escherichia coli. Expression of the yjiY gene is regulated by the LytS-like histidine kinase BtsS, a sensor of extracellular pyruvate, together with the LytTR-like response regulator BtsR. YjiY consists of 716 amino acids, which form 18 putative transmembrane helices. Transport studies with intact cells provided evidence that YjiY is a specific and high-affinity transporter for pyruvate (Km, 16 μM). Furthermore, reconstitution of the purified YjiY into proteoliposomes revealed that YjiY is a pyruvate/H+ symporter. It has long been assumed that E. coli possesses a transporter(s) for pyruvate, but the present study is the first to definitively identify such a protein. Based on its function, we propose to change the name of the uncharacterized gene yjiY to btsT for Brenztraubensäure (the German word for pyruvate) transporter. IMPORTANCE BtsT (formerly known as YjiY) is found in many commensal and pathogenic representatives of the Enterobacteriaceae. This study for the first time characterizes a pyruvate transporter in E. coli, BtsT, as a specific pyruvate/H+ symporter. When nutrients are limiting, BtsT takes up pyruvate from the medium, thus enabling it to be used as a carbon source for the growth and survival of E. coli.
In vitro sensitivity of oral, gram-negative, facultative bacteria to the bactericidal activity of human neutrophil defensins

Neutrophils play a major role in defending the periodontium against infection by oral, gram-negative, facultative bacteria, such as Actinobacillus actinomycetemcomitans, Eikenella corrodens, and Capnocytophaga spp. We examined the sensitivity of these bacteria to a mixture of low-molecular-weight peptides and highly purified individual defensin peptides (HNP-1, HNP-2, and HNP-3) isolated from human neutrophils. Whereas the Capnocytophaga spp. strains were killed significantly by the mixed human neutrophil peptides, the A. actinomycetemcomitans and E. corrodens strains were resistant. Killing was attributable to the defensins. The bactericidal activities of purified defensins HNP-1 and HNP-2 were equal, and both of these activities were greater than HNP-3 activity against strains of Capnocytophaga sputigena and Capnocytophaga gingivalis. The strain of Capnocytophaga ochracea was more sensitive to defensin-mediated bactericidal activity than either C. sputigena or C. gingivalis was. The three human defensins were equipotent in killing C. ochracea. C. ochracea was killed under aerobic and anaerobic conditions and over a broad pH range. Killing was most effective under hypotonic conditions but also occurred at physiologic salt concentrations. We concluded that Capnocytophaga spp. are sensitive to oxygen-independent killing by human defensins. Additional studies will be required to identify other components that may equip human neutrophils to kill A. actinomycetemcomitans, E. corrodens, and other oral gram-negative bacteria.