Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional characteristics of CYP3A4 allelic variants on the metabolism of loperamide in vitro

Background Cytochrome P450 3A4 (CYP3A4) appears to be genetically polymorphic, which in turn contributes to interindividual variability in response to therapeutic drugs. Loperamide, identified as a CYP3A4 substrate, is prone to misuse and abuse and has high risks of life-threatening cardiotoxicity. Methods Thus, this study is designed to evaluate the enzymatic characteristics of 29 CYP3A4 alleles toward loperamide in vitro, including the 7 novel CYP3A4 variants (*28–*34). The incubation system (containing CYP3A4 enzyme, cytochrome b5, 0.5–20 μM loperamide, potassium phosphate buffer and nicotinamide adenine dinucleotide phosphate) was subject to 40-mins incubation at 37°C and the concentrations of N-demethylated loperamide were quantified by UPLC-MS/MS. Results As a result, CYP3A4.6, . 17, . 20 and . 30 showed extremely low activity or no activity and the rest of CYP3A4 variants presented varying degrees of decrements in catalytical activities when compared with CYP3A4.1. Conclusion As the first study to identify the properties of these CYP3A4 variants toward loperamide metabolism, our investigation may establish the genotype–phenotype relationship for loperamide, predict an individual’s capability in response to loperamide, and provide some guidance of clinical medication and treatment for loperamide.
Influence of Medicinal Plant Extracts on the Growth of Oral Pathogens Streptococcus Mutans and Lactobacillus Acidophilus: An In-Vitro Study

AIM: This study investigated the antibacterial efficacy of five plant extracts, as well as the combinations of the two most effective plant, extracts either with or without commercial varnish (MI varnish) on the in vitro growth of Streptococcus mutans and Lactobacillus acidophilus in comparison to MI varnish using agar disk diffusion and broth dilution methods. METHODS: Methanolic extractions of five plants (Cinnamon, Turmeric, Ginger, Clove and Black seed,) were tested against the growth of the two oral pathogens. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for the two most effective extracts, and their combinations with different ratios were evaluated against the growth of the two oral pathogens, followed by incorporating the two effective plants or each into commercial MI varnish to be assessed against the oral pathogens in comparison to MI varnish. RESULTS: Only Cinnamon and Clove produced inhibition zones against Streptococcus mutans and Lactobacillus acidophilus growth. MIC for the two plants showed equal antimicrobial activity against Streptococcus mutans, while Cinnamon had a higher sensitivity to Lactobacillus acidophilus than Clove. A mixture of Cinnamon and Clove in a ratio 1:2 exhibited the highest antibacterial activity. Integration the mixture of both plants into MI varnish in a ratio of 1:1:1 presented the highest antibacterial activity. Meanwhile, the lowest one was recorded for the MI varnish alone. CONCLUSION: Methanolic extract of Cinnamon and Clove has considerable antimicrobial activity against Streptococcus mutans and Lactobacillus acidophilus and a new tool for minimally invasive and adhesive dentistry avenues.
Right on time: prediction-errors bidirectionally bias time perception

The brain updates internal representation of the environment by using the mismatch between the predicted state/outcome and the actual one, termed prediction-error. In parallel, time perception in the sub-second range is crucial for many behaviors such as movement, learning, memory, attention and speech. Both time-perception and prediction-errors are essential for everyday life function of an organism, and interestingly, the striatum was shown to be independently involved in both functions. We therefore hypothesized that the putative shared circuitry might induce behavioral interaction, namely that prediction-errors might bias time perception. To examine this, participants performed a time-duration discrimination task in the presence of positive and negative prediction-errors that were irrelevant and independent of the main task. We find that positive/negative prediction-errors induce a bias in time perception by increasing/decreasing the perceived time, respectively. Using functional imaging, we identify an interaction in Putamen activity between encoding of prediction-error and performance in the discrimination task. A model that accounts for the behavioral and physiological observations confirms that the interaction in regional activations for prediction-errors and time-estimation underlies the observed bias. Our results demonstrate that these two presumably independent roles of the striatum can actually interfere or aid one another in specific scenarios.
Large Osteochondral Lesions of the Talus Treated With Autologous Bone Graft and Periosteum Transfer

Background: The treatment of large osteochondral lesions of the talus (OLTs) is challenging due to the poor intrinsic reparative capability of the damaged articular cartilage. Autologous transfer of bone and periosteum has been used successfully in the treatment of large defects in animals, and therefore it was believed that this technique might show similar results in humans. The purpose of this study was to assess the outcome of an innovative technique for autologous transplantation of cancellous tibial graft with periosteal transfer in large OLTs. Methods: Forty-one patients (22 females, 19 males), with a mean age of 34.9 years (range, 18-72 years), with a large OLT (>200 mm2) were treated with autologous bone graft and periosteum transfer. OLTs averaging 310 mm2 were identified on a preoperative computed tomography scan. The procedure consisted of malleolar osteotomy, curettage of sclerotic bone, autologous bone graft from the proximal tibia, and transfixion of periosteum over the graft. Outcome measures, including the pain visual analog scale (VAS), ankle range of motion (ROM), American Orthopaedic Foot & Ankle Society (AOFAS) score, and Foot & Ankle Disability Index (FADI), were compared between preoperative and 1 and 2 years following surgery. Results: There were significant improvements in VAS pain score from 7.7 before surgery to 1.1 at 1 year after surgery and 0.4 at 2 years or more after surgery. The AOFAS and FADI scores were also significantly improved from 40.3 and 53.3 preoperatively to 95 and 93.2 postoperatively at 1 year and 95 and 93.2 at 2 or more years postoperatively, respectively. Postoperative complications included 2 patients who required removal of medial malleolar osteotomy tension bands due to symptomatic hardware. There were no nonunions or malunions of the osteotomies and no donor site complications. Conclusion: Autologous bone graft and periosteum transfer was an effective treatment for large OLTs leading to significant decreases in pain and improvement in functional scores at more than 2 years after surgery. Level of Evidence: Level IV, retrospective case series.
Sub-surface drip fertigation improves seed cotton yield and monetary returns

Surface flood (SF) method is used to irrigate cotton in India, which results in huge wastage of water besides leaching of nutrients. This necessitates the adoption of efficient management strategies to save scarce water without compromising the yield. Therefore, a 2-year field investigation was conducted under two climatic regimes (Faridkot and Abohar) to study the effect of sub-surface drip fertigation (SSDF) on seed cotton yield (SCY), water productivity, nitrogen use efficiency (NUE), and economic parameters in comparison with SF and surface drip fertigation (SDF). The field experiment had a total of eight treatments arranged in a randomized complete block design. Three levels of sub-surface drip irrigation [(SSDI); i.e., 60%, 80%, and 100% of crop evapotranspiration (ETc)] and two N fertigation levels [100% recommended dose of nitrogen (RDN; i.e., 112.5 kg N ha-1) and 75% RDN] made up six treatments, while SF (Control 1) and SDF at 80% ETc (Control 2), both with 100% of RDN, served as the controls. Among irrigation regimes, the SSDI levels of 80% ETc and 100% ETc recorded 18.7% (3,240 kg ha-1) and 21.1% (3,305 kg ha-1) higher SCY compared with SF (2,728 kg ha-1). Water use efficiency under SF (57.0%) was reduced by 34.2%, 40.8%, and 38.2% compared with SSDI’s 60 (76.5%), 80 (80.3%), and 100% ETc (78.8%), respectively. Among fertigation levels, NUE was higher by 19.2% under 75% (34.1 kg SCY kg-1 N) over 100% RDN (28.6 kg SCY kg-1 N), but later it also registered 11.9% higher SCY, indicating such to be optimum for better productivity. SSDF at 80% ETc along with 112.5 kg N ha-1 recorded 26.6% better SCY (3455 kg ha-1) and 18.5% higher NUE (30.7 kg SCY kg-1 N) over SF. These findings demonstrate that the application of SSDF could save irrigation water, enhance SCY, and improve the farmers’ returns compared with SF. Therefore, in northwestern India, SSDF at 80% ETc along with 112.5 kg N ha-1 could be a novel water-savvy concept which would be immensely helpful in enhancing cotton productivity.
Good timing: evaluating anuran activity and detectability patterns in the Brazilian Atlantic Forest

Abstract Context. Animal activity patterns throughout the day constitute an important dimension of their ecological niche, and may have ecological and evolutionary implications; for an organism to be active during the day or night period, a series of conditions requiring different anatomical, physiological and behavioural adaptations must be met. Aims. To study the anuran community in an area of Atlantic Forest in Brazil, to evaluate the species activity period as well as the diurnal and nocturnal detection probabilities of anurans, and to relate these activities to environmental variables such as air temperature, relative humidity and precipitation. Methods. The anurans were sampled along 21 plot transects in the diurnal period and during a nocturnal period, with temperature and relative humidity measured in each plot. Species were considered predominantly diurnal or nocturnal if 35% or more individuals were recorded during one of these periods. Anuran detectability was estimated using single-season occupancy models, relating to environmental variables. Key results. Of the individuals recorded, 12% were recorded during diurnal sampling and 88% were recorded during nocturnal sampling, with Ololygon agilis being the only species considered diurnal. The probability of detection was affected by only two variables (period and humidity). Conclusions. The anuran community in the study area was essentially nocturnal, with only one species that could be considered diurnal. Additionally, detectability was higher at night, with humidity being the most important variable affecting species detection. Implications. Surveys can be planned under climatic conditions that positively influence the probabilities of detection to improve the effectiveness of monitoring species and/or anurans community.
On fundamental responsibility

Some psychological states—paradigmatically, beliefs and intentions—are rationally evaluable: they can be rational or irrational, justified or unjustified. Other states—e.g. sensa-tions and gastrointestinal states—aren’t: they’re a-rational. On a familiar but hard-to-make-precise line of thought, at least part of what explains this difference is that we’re somehow responsible for (having/being in) states of the for-mer sort, in a way we’re not for the others. But this responsibility can’t be modeled on the responsibility we have for our (free, intentional) actions. So how should it be understood? In this paper I address that question. The overall shape of my answer is in line with tradition: I take the responsibility to be grounded in certain capacities for reflection and control . Answers in this family have recently been subjected to an interesting challenge. But the version I defend meets that challenge.
Biocompatibility and biocidal effects of modified polylactide composites

Polylactide (PLA) materials treated with antimicrobial fillers represent a suitable alternative to the production of medical devices. Their advantage is that they can prevent the growth of microorganisms and the formation of microbial biofilms on the surface and around composites. The work is focused on the evaluation of biocompatibility and biocide effect of PLA composite films filled with vermiculite and graphene oxide modified with silver (Ag+ and Ag nanoparticles), hexadecylpyridinium (HDP) and hexadecyltrimethylammonium (HDTMA) cations and their degradation leachates monitored at 1–3–6-month intervals. The antimicrobial effect of the leachates was detected by microdilution methods on gram-negative (Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis), gram-positive (Staphylococcus aureus, Streptococcus salivarius) bacteria and yeast (Candida albicans). The biocidal effect of composites on biofilm formation on the surface of composites was monitored by Christensen method and autoaggregation and motility tests. The biocompatibility of the composite and the leachates was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cytotoxicity assay. The evaluation of the antimicrobial effect of the leachates demonstrated that leachates of PLA composite filled with graphene oxide and Ag+ showed a stronger antimicrobial effect than leachates of PLA composite filled with vermiculite and Ag+ and Ag nanoparticles. The leachates of PLA composites containing vermiculite with HDP and HDTMA cations had a higher antimicrobial effect on G+ bacteria and yeast than G– bacteria. Bacterial growth, biofilm formation, autoaggregation and motility of the tested bacteria were most inhibited by the composite with vermiculite and Ag+ and Ag nanoparticles. Even after a 6-month degradation of this composite, bacterial growth and biofilm formation continued to be strongly inhibited up to 42 and 91%, respectively. The cytotoxic effect was proved only in the leachate of the composite with vermiculite containing HDP after 6 months of its degradation. Tests evaluating the biocompatibility of materials have shown that the vermiculite is the most preferred carrier and can be used in the future to bind other compounds. The study confirmed that PLA composite filled with vermiculite and Ag+ and Ag nanoparticles was the most stable and effective composite with the best biocompatible and biocidal properties. Graphical Abstract
Visual over auditory superiority in sensorimotor timing under optimized condition

Auditory over visual advantage in temporal processing is generally appreciated, such as the well-established auditory superiority in sensorimotor timing. To test for a possible visual superiority in temporal processing, here, we present a data set composed of a large 60 subjects sample and a data set including eight smaller samples of approximately 15 subjects, showing that synchronization to a temporally regular sequence was more stable for a visual bouncing ball (VB) than for auditory tones (ATs). The results demonstrate that vision can be superior over audition in sensorimotor timing under optimized conditions, challenging the generally believed auditory superiority in temporal processing. In contrast to the auditory-specific biological substrates of timing in sensorimotor interaction, the present finding points to tight visual-motor cortical coupling in sensorimotor timing.
Influence of spermine and nitrogen deficiency on growth and secondary metabolites accumulation in Castilleja tenuiflora Benth. cultured in a RITA® temporary immersion system

The effect of exogenous spermine (SPM) on Castilleja tenuiflora shoots developing under nitrogen deficiency (ND) stress was evaluated. Shoots cultivated in a temporary immersion system were subjected to four experimental treatments: (1) control; (2) exogenous SPM; (3) ND; and (4) ND+SPM. Shoots were longer in the ND+SPM treatment (6.3 ± 0.5 cm) than in the ND treatment (4.2 ± 0.5 cm). The total chlorophyll content was similar in the control and SPM treatments (0.41 µg mg−1 FM) and the highest values of total phenolic content were detected at 21 days in the ND+SPM treatment (84.1 ± 0.05 GAE g−1 DM). In the ND+SPM treatment, the phenylalanine ammonia lyase activity increased earlier than in ND treatment, and reached its maximum at day 21 (3.9 ± 0.2 µmol E‐CIN h−1 mg−1 protein). Compared with the control, the ND and ND+SPM treatments resulted in increased secondary metabolites contents in both root and aerial parts. The strongest effect was in the roots, where the SPM and ND+SPM treatments both resulted in increased quercetin content (4.3‐fold that in the control). Our results showed that SPM partially counteract the damage caused by ND and results in increased contents of valuable bioactive compounds.
Vasoplegia After Cardiac Surgery Is Associated With Endothelial Glycocalyx Alterations.

OBJECTIVE To assess endothelial glycocalyx (EG) alteration in vasoplegic syndrome after cardiac surgery with cardiopulmonary bypass. DESIGN Prospective analysis SETTING: Single university hospitals. PARTICIPANTS Patients undergoing elective cardiac surgery under cardiopulmonary bypass. INTERVENTIONS Observational study METHODS: Heparan sulfate and syndecan-1 levels were assessed in plasma before surgery, on intensive care unit admission, and on the first postoperative day. The primary outcome was comparisons of heparan sulfate and syndecan-1 levels in patients with and without vasoplegic syndrome. RESULTS A total of 46 patients were analyzed. Only syndecan-1 was modified by cardiac surgery (p < 0.05). Plasma syndecan-1 levels were lower in patients with vasoplegic syndrome at the 3 time-points and were associated with the cumulative norepinephrine dose. Baseline plasma syndecan-1 predicted the development of vasoplegic syndrome with an area under the curve of 0.7 (confidence interval 95%: 0.51-0.85, p = 0.045). Heparan sulfate levels were not modified by cardiac surgery. CONCLUSION Patients with vasoplegic syndrome after cardiac surgery present a different pattern of EG components. Lower syndecan-1 levels were associated with vasoplegic syndrome. These preliminary results suggest a specific phenotype that may reflect endothelial activation leading to alteration of the EG.
Formic acid, an organic acid food preservative, induces viable-but-non-culturable state, and triggers new Antimicrobial Resistance traits in Acinetobacter baumannii and Klebsiella pneumoniae

Numerous human pathogens, especially Gram-negative bacteria, are able to enter the viable-but-non-culturable (VBNC) state when they are exposed to environmental stressors and pose the risk of being resuscitated and causing infection after the removal of the trigger. Widely used food preservatives like weak organic acids are potential VBNC inducers in food processing and packaging facilities but have only been reported for food-borne pathogens. In the present study, it is demonstrated for the first time that one such agent, formic acid (FA), can induce a VBNC state at food processing, storage, and distribution temperatures (4, 25, and 37°C) with a varied time of treatment (days 4–10) in pathogenic Gram-negative bacteria Acinetobacter baumannii and Klebsiella pneumoniae. The use of hospital-associated pathogens is critical based on the earlier reports that demonstrated the presence of these bacteria in hospital kitchens and commonly consumed foods. VBNC induction was validated by multiple parameters, e.g., non-culturability, metabolic activity as energy production, respiratory markers, and membrane integrity. Furthermore, it was demonstrated that the removal of FA was able to resuscitate VBNC with an increased expression of multiple virulence and Antimicrobial Resistance (AMR) genes in both pathogens. Since food additives/preservatives are significantly used in most food manufacturing facilities supplying to hospitals, contamination of these packaged foods with pathogenic bacteria and the consequence of exposure to food additives emerge as pertinent issues for infection control, and control of antimicrobial resistance in the hospital setting.
Manipulation of diacylglycerol and ERK-mediated signaling differentially controls CD8+ T cell responses during chronic viral infection

Introduction Activation of T cell receptor (TCR) signaling is critical for clonal expansion of CD8+ T cells. However, the effects of augmenting TCR signaling during chronic antigen exposure is less understood. Here, we investigated the role of diacylglycerol (DAG)-mediated signaling downstream of the TCR during chronic lymphocytic choriomeningitis virus clone 13 (LCMV CL13) infection by blocking DAG kinase zeta (DGKζ), a negative regulator of DAG. Methods We examined the activation, survival, expansion, and phenotype of virus-specific T cell in the acute and chronic phases of LCMV CL13-infected in mice after DGKζ blockade or selective activation of ERK. Results Upon LCMV CL13 infection, DGKζ deficiency promoted early short-lived effector cell (SLEC) differentiation of LCMV-specific CD8+ T cells, but this was followed by abrupt cell death. Short-term inhibition of DGKζ with ASP1570, a DGKζ-selective pharmacological inhibitor, augmented CD8+ T cell activation without causing cell death, which reduced virus titers both in the acute and chronic phases of LCMV CL13 infection. Unexpectedly, the selective enhancement of ERK, one key signaling pathway downstream of DAG, lowered viral titers and promoted expansion, survival, and a memory phenotype of LCMV-specific CD8+ T cells in the acute phase with fewer exhausted T cells in the chronic phase. The difference seen between DGKζ deficiency and selective ERK enhancement could be potentially explained by the activation of the AKT/mTOR pathway by DGKζ deficiency, since the mTOR inhibitor rapamycin rescued the abrupt cell death seen in virus-specific DGKζ KO CD8+ T cells. Discussion Thus, while ERK is downstream of DAG signaling, the two pathways lead to distinct outcomes in the context of chronic CD8+ T cell activation, whereby DAG promotes SLEC differentiation and ERK promotes a memory phenotype.
Effects of sugar sources and doses on fermentation dynamics, carbohydrates changes, in vitro digestibility and gas production of rice straw silage

Abstract To elucidate the differences of various sugar sources and doses on rice straw silage, the effect of molasses (M, direct substrate) and fibrolytic enzyme (E, indirect substrate) with four doses on fermentation dynamics, carbohydrates and in vitro digestibility was evaluated. Molasses (0, 2, 3 and 4% of fresh weight) or fibrolytic enzyme (0, 0.02, 0.04 and 0.06%) were applied to fresh rice straw ensiling for 3, 6, 9, 15, 30 and 60 days. All additives increased lactic acid content and lactic/acetic acid, reduced pH, NH3-N content of resulting silage (p < .05). The highest lactic acids, residual sugar and fibre degradation were observed in 0.06%E (p < .05). M-treated silage had higher dry matter (DM) content, in vitro digestibility of DM and neutral detergent fibre, and less DM loss, acetic acid, butyric acid and in vitro gas production (GP) than other treatments. Both sugar sources effectively improved fermentation quality. Fibrolytic enzyme induced free sugar release from fibre, especially from hemicellulose, while molasses showed a potential dose effect to decrease ruminal energy waste by increasing digestibility and decreasing GP in vitro. 3%M, 4%M and 0.04%E produced moderate silage based on V-score, and 4%M is recommended for rice straw silage, indicated by intermediate fermentation quality and higher in vitro digestibility. Highlights Low WSC limited fermentation Sugar sources reduced fibre with various mechanisms Molasses decreased in vitro gas production with a dose effect