Miracle-dz/UniFAR-FTUs huggingface dataset:
Phenytoin Reduces Activity of Cardiac Ryanodine Receptor 2; A Potential Mechanism for Its Cardioprotective Action

Phenytoin is a hydantoin derivative that is used clinically for the treatment of epilepsy and has been reported to have antiarrhythmic actions on the heart. In a failing heart, the elevated diastolic Ca2+ leak from the sarcoplasmic reticulum can be normalized by the cardiac ryanodine receptor 2 (RyR2) inhibitor, dantrolene, without inhibiting Ca2+ release during systole or affecting Ca2+ release in normal healthy hearts. Unfortunately, dantrolene is hepatotoxic and unsuitable for chronic long-term administration. Because phenytoin and dantrolene belong to the hydantoin class of compounds, we test the hypothesis that dantrolene and phenytoin have similar inhibitory effects on RyR2 using a single-channel recording of RyR2 activity in artificial lipid bilayers. Phenytoin produced a reversible inhibition of RyR2 channels from sheep and human failing hearts. It followed a hyperbolic dose response with maximal inhibition of ∼50%, Hill coefficient ∼1, and IC50 ranging from 10 to 20 µM. It caused inhibition at diastolic cytoplasmic [Ca2+] but not at Ca2+ levels in the dyadic cleft during systole. Notably, phenytoin inhibits RyR2 from failing human heart but not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans. We conclude that phenytoin could effectively inhibit RyR2-mediated release of Ca2+ in a manner paralleling that of dantrolene. Moreover, the IC50 of phenytoin in RyR2 is at least threefold lower than for other ion channels and clinically used serum levels, pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrythmias. SIGNIFICANCE STATEMENT We show that phenytoin, a Na channel blocker used clinically for treatment of epilepsy, is a diastolic inhibitor of cardiac calcium release channels [cardiac ryanodine receptor 2 (RyR2)] at doses threefold lower than its current therapeutic levels. Phenytoin inhibits RyR2 from failing human heart and not from healthy heart, indicating that phenytoin may selectively target defective RyR2 channels in humans and pointing to phenytoin as a more human-safe alternative to dantrolene for therapies against heart failure and cardiac arrhythmias.
Change in Soil Particle Size Distribution and Erodibility with Latitude and Vegetation Restoration Chronosequence on the Loess Plateau, China

Analyzing the dynamics of soil particle size distribution (PSD) and erodibility is important for understanding the changes of soil texture and quality after cropland abandonment. This study aimed to determine how restoration age and latitude affect soil erodibility and the multifractal dimensions of PSD during natural recovery. We collected soil samples from grassland, shrubland, and forests with different restoration ages in the steppe zone (SZ), forest-steppe zone (FSZ), and forest zone (FZ). Various analyses were conducted on the samples, including multifractal analysis and erodibility analysis. Our results showed that restoration age had no significant effect on the multifractal dimensions of PSD (capacity dimension (D0), information dimension (D1), information dimension/capacity dimension ratio (D1/D0), correlation dimension (D2)), and soil erodibility. Multifractal dimensions tended to increase, while soil erodibility tended to decrease, with restoration age. Latitude was negatively correlated with fractal dimensions (D0, D2) and positively correlated with K and D1/D0. During vegetation restoration, restoration age, precipitation, and temperature affect the development of vegetation, resulting in differences in soil organic carbon, total nitrogen, soil texture, and soil enzyme activity, and by affecting soil structure to change the soil stability. This study revealed the impact of restoration age and latitude on soil erosion in the Loess Plateau.
Atypical Salmonella enterica Serovars in Murine and Human Macrophage Infection Models

Nontyphoidal Salmonella species are globally disseminated pathogens and are the predominant cause of gastroenteritis. The pathogenesis of salmonellosis has been extensively studied using in vivo murine models and cell lines, typically challenged with Salmonella enterica serovar Typhimurium. Although S. enterica serovars Enteritidis and Typhimurium are responsible for most of the human infections reported to the Centers for Disease Control and Prevention (CDC), several other serovars also contribute to clinical cases of salmonellosis. ABSTRACT Nontyphoidal Salmonella species are globally disseminated pathogens and are the predominant cause of gastroenteritis. The pathogenesis of salmonellosis has been extensively studied using in vivo murine models and cell lines, typically challenged with Salmonella enterica serovar Typhimurium. Although S. enterica serovars Enteritidis and Typhimurium are responsible for most of the human infections reported to the Centers for Disease Control and Prevention (CDC), several other serovars also contribute to clinical cases of salmonellosis. Despite their epidemiological importance, little is known about their infection phenotypes. Here, we report the virulence characteristics and genomes of 10 atypical S. enterica serovars linked to multistate foodborne outbreaks in the United States. We show that the murine RAW 264.7 macrophage model of infection is unsuitable for inferring human-relevant differences in nontyphoidal Salmonella infections, whereas differentiated human THP-1 macrophages allowed these isolates to be further characterized in a more human-relevant context.
Aedes cadherin receptor that mediates Bacillus thuringiensis Cry11A toxicity is essential for mosquito development

Aedes cadherin (AaeCad, AAEL024535) has been characterized as a receptor for Bacillus thuringiensis subsp. israelensis (Bti) Cry11A toxins. However, its role in development is still unknown. In this study, we modified the cadherin gene using ZFN and TALEN. Even though we obtained heterozygous deletions, no homozygous mutants were viable. Because ZFN and TALEN have lower off-targets than CRISPR/Cas9, we conclude the cadherin gene is essential for Aedes development. In contrast, in lepidopteran insects loss of a homologous cadherin does not appear to be lethal, since homozygous mutants are viable. To analyze the role of AaeCad in vivo, we tagged this protein with EGFP using CRISPR-Cas9-mediated homologous recombination and obtained a homozygous AaeCad-EGFP line. Addition of Aedes Rad51 mRNA enhanced the rate of recombination. We then examined AaeCad protein expression in most tissues and protein dynamics during mosquito development. We observe that AaeCad is expressed in larval and adult midgut-specific manner and its expression pattern changed during the mosquito development. Confocal images showed AaeCad has high expression in larval caecae and posterior midgut, and also in adult midgut. Expression of AaeCad is observed primarily in the apical membranes of epithelial cells, and not in cell-cell junctions. The expression pattern observed suggests AaeCad does not appear to play a role in these junctions. However, we cannot exclude its role beyond cell-cell adhesion in the midgut. We also observed that Cry11A bound to the apical side of larval gastric caecae and posterior midgut cells exactly where AaeCad-EGFP was expressed. Their co-localization suggests that AaeCad is indeed a receptor for the Cry11A toxin. Using this mosquito line we also observed that low doses of Cry11A toxin caused the cells to slough off membranes, which likely represents a defense mechanism, to limit cell damage from Cry11A toxin pores formed in the cell membrane.
Comparative analysis of taxol‐derived fluorescent probes to assess microtubule networks in a complex live three‐dimensional tissue

Drosophila oogenesis is an excellent in vivo model for investigating cytoskeletal dynamics because of the rapid cytoskeletal remodeling that occurs at the end of stage 10; however, there are few robust tools for detecting microtubules in live complex tissues. The recent development of membrane permeable taxol‐based fluorescent probes to label microtubules is significant technical progress, but the effectiveness of these probes and the potential stabilizing effects of the taxol derivative have not been well characterized in vivo. Here, we compared three commercially available taxol‐derived microtubule labels to determine their efficacy and potential artifacts. We found that all three probes labeled microtubules with differences in permeability, brightness, and signal to noise ratio. Like taxol, however, all of the probes disrupted the F‐actin cytoskeleton at higher concentrations. We also found that the efflux pump inhibitor, verapamil, increased the intensity of the label and modestly increased the severity of the F‐actin defects. Of the three probes, Tubulin Tracker (ThermoScientific) was the most permeable and was brightest, with the highest signal to noise ratio. Furthermore, washing out the probe after a 30‐min incubation significantly reduced the F‐actin artifacts without compromising signal brightness.
Substance and Substrate

Paragon derives from the old Italian word paragone, which means “touchstone,” a stone on which metal was rubbed to judge the purity of gold or silver. In modern English, paragon has come to signify a standard against which something should be judged. In the modern era of heart failure (HF), the use of left ventricular ejection fraction (LVEF) has almost become a paragon of phenotyping and may be misleading.
Control of Erigeron bonariensis with Thymbra capitata, Mentha piperita, Eucalyptus camaldulensis, and Santolina chamaecyparissus Essential Oils

In the search of sustainable and environmentally friendly methods for weed control, there is increasing interest in essential oils (EOs) as an approach to reduce synthetic herbicide use. The phytotoxicity of Thymbra capitata, Mentha piperita, Eucalyptus camaldulensis, and Santolina chamaecyparissus EOs against the noxious weed Erigeron bonariensis were evaluated in pre- and post-emergence assays in greenhouse conditions. The EOs were applied at 2, 4, and 8 µL/mL, with Fitoil used as emulsifier. In post-emergence, two ways of application were tested, irrigation and spraying. Several germination parameters (germination %, mean germination time, and synchrony of the germination process) were evaluated in pre-emergence tests, and the phytotoxicity level was assessed in post-emergence. In pre-emergence, all EOs significantly reduced seed germination as compared to the controls, ranking: T. capitata > E. camaldulensis > S. chamaecyparissus > M. piperita. The effectiveness of all EOs varied with the tested dose, always following the rank 2 μL < 4 μL < 8 μL, with T. capitata EO showing full effectiveness even at the lowest dose. In post-emergence, T. capitata was the most effective EO, inducing a rather complete inhibition of plantlet growth at the highest two doses. These EOs demonstrated to have good potential for the formulation of natural herbicides.
Association between tumor characteristics and second primary cancers with cutaneous melanoma survival: A nationwide cohort study

The increased survival in malignant cutaneous melanoma (melanoma) is probably due to early diagnosis combined with improved treatment most recently. National health campaigns and screening programs for melanoma detection were started in Sweden several decades ago. We want to assess the influence of tumor characteristics, based on the TNM classification, and of second primary cancers on overall survival in melanoma. We used the Swedish Cancer Registry to assess all‐cause survival in melanoma from 2003 to 2015. Hazard ratios (HRs) were estimated using multivariable Cox regression models. A total of 19,773 melanoma patients were diagnosed with TNM data. Survival showed a strong improving trend over time (p‐trend <.001). T1a was the most common classification (48.0% of all), while higher T class was associated systematically with worse survival (p‐trend <.001). For distant metastases, the HR was 3.17, accounting for 0.9% of the patients. Any types of second primary cancers, other than melanoma, were associated with an HR of 2.00, accounted for 6.7% of all cases. Even if melanoma survival in Sweden ranks among the best national rates, the large percentage of patients with advanced tumors (T3b, T4a, and T4b, 17%) and 21% of deaths with T1a call for improved preventive and follow‐up strategies.
The In Vitro Activity of Essential Oils against Helicobacter Pylori Growth and Urease Activity

The anti-H. pylori properties of 26 different commercial essential oils were examined in vitro by MIC (minimal inhibitory concentration) determination for the reference strain H. pylori ATCC 43504. We selected 9 essential oils with different anti-Helicobacter activities and established their phytochemical composition and urease inhibition activities. Phytochemical analysis of the selected essential oils by GC-MS method and antioxidant activity were performed. The phenol red method was used to screen the effect of essential oils on urease activity expressed as IC50 (the half of maximal inhibitory concentration). The most active essential oils, with MIC = 15.6 mg/L, were thyme, lemongrass, cedarwood and lemon balm oils; MIC = 31.3 mg/L—oregano oil; MIC = 62.5 mg/L—tea tree oil; MIC = 125 mg/L—pine needle, lemon and silver fir oils with bactericidal effect. Urease activity was inhibited by these oils with IC50 ranged from 5.3 to > 1049.9 mg/L. The most active was cedarwood oil (IC50 = 5.3 mg/L), inhibiting urease at sub-MIC concentrations (MIC = 15.6 mg/L). The statistical principal component analysis allowed for the division of the oils into three phytochemical groups differing in their anti-H. pylori activity. To summarize, the activity in vitro of the five essential oils silver fir, pine needle, tea tree, lemongrass, and cedarwood oils against H. pylori was found in this paper for the first time. The most active against clinical strains of H. pylori were cedar wood and oregano oils. Moreover, cedarwood oil inhibited the urease activity at subinhibitory concentrations. This essential oil can be regarded as a useful component of the plant preparations supporting the eradication H. pylori therapy.
The Neuroprotective and Biomarker Potential of PACAP in Human Traumatic Brain Injury

Traumatic brain injury remains a growing public health concern and represents the greatest contributor to death and disability globally among all trauma-related injuries. There are limited clinical data regarding biomarkers in the diagnosis and outcome prediction of TBI. The lack of real effective treatment for recovery calls for research of TBI to be shifted into the area of prevention, treatment of secondary brain injury and neurorehabilitation. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been reported to act as a hormone, a neuromodulator, a neurotransmitter and a trophic factor, and has been implicated in a variety of developmental and regenerative processes. The importance of PACAP in neuronal regeneration lies in the upregulation of endogenous PACAP and its receptors and the protective effect of exogenous PACAP after different central nervous system injury. The aim of this minireview is to summarize both the therapeutic and biomarker potential of the neuropeptide PACAP, as a novel possible target molecule presently being investigated in several human conditions including TBI, and with encouraging results in animal models of TBI.
Skin Barrier Impairment due to the Occlusive Effect of Firefighter Clothing

Abstract At fire scenes, firefighters are exposed to potentially harmful substances. Besides inhalation of these products, also skin contamination and the risk of dermal absorption is getting more attention. In this perspective, skin barrier impairment due to the occlusive effect of firefighter clothes could enhance the risk of penetration of hazardous substances. The effect of a firefighter jacket and cellophane on the skin was studied in a paired comparison involving 16 volunteers. Biophysical parameters were measured before, immediately after and 30 min after ending the occlusion. Reflectance confocal microscopy was used to study the skin morphology. Immediately after wearing a firefighter jacket, Transepidermal Water Loss values were significantly increased. This is an indication of an occlusive effect of the firefighter jacket. The skin barrier was fully restored after 30 min after occlusion with cellophane or wearing a firefighter jacket.
Defining a Healthy Diet: Evidence for the Role of Contemporary Dietary Patterns in Health and Disease

The definition of what constitutes a healthy diet is continually shifting to reflect the evolving understanding of the roles that different foods, essential nutrients, and other food components play in health and disease. A large and growing body of evidence supports that intake of certain types of nutrients, specific food groups, or overarching dietary patterns positively influences health and promotes the prevention of common non-communicable diseases (NCDs). Greater consumption of health-promoting foods and limited intake of unhealthier options are intrinsic to the eating habits of certain regional diets such as the Mediterranean diet or have been constructed as part of dietary patterns designed to reduce disease risk, such as the Dietary Approaches to Stop Hypertension (DASH) or Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. In comparison with a more traditional Western diet, these healthier alternatives are higher in plant-based foods, including fresh fruits and vegetables, whole grains, legumes, seeds, and nuts and lower in animal-based foods, particularly fatty and processed meats. To better understand the current concept of a “healthy diet,” this review describes the features and supporting clinical and epidemiologic data for diets that have been shown to prevent disease and/or positively influence health. In total, evidence from epidemiological studies and clinical trials indicates that these types of dietary patterns reduce risks of NCDs including cardiovascular disease and cancer.
Oral antibiotic therapy in diabetic foot osteomyelitis: one small step or a giant leap of faith?

One in 3 subjects with diabetes may experience foot ulcers during their lifetime. Over half of such ulcerations are complicated by infection (1), often involving bones as well. It is estimated that a degree of diabetic foot osteomyelitis (DFO) may affect 20–60% of all infected diabetic foot ulcers (2). The presence of DFO is associated with significantly poor clinical outcomes, including slower time to healing, longer duration of hospitalisation and a higher likelihood of amputation (3). The presentation of DFO can often be insidious. Indeed, the typical features of axial bone and joint infections, such as pain and localised erythema, can often be absent or subtle. Thus, detection and management of DFO remains one of the most challenging and debated facets of diabetic foot care (2,3).
Reduction of the Multipath Propagation Effect in a Hydroacoustic Channel Using Filtration in Cepstrum

During data transmission in a hydroacoustic channel, one of the problems is the multipath propagation effect, which leads to a decrease in the transmission parameters and sometimes completely prevents it. Therefore, we have attempted to develop a method, which is based on a recorded hydroacoustic signal, that allows us to recreate the original (generated) signal by eliminating the multipath effect. In our method, we use cepstral analysis to eliminate replicas of the generated signal. The method has been tested in simulation and during measurements in a real environment. Additionally, the influence of the method on data transmission in the hydroacoustic channel was tested. The obtained results confirmed the usefulness of the application of the developed method and improved the quality of data transmission by reducing the multipath propagation effect.
A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101+bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101+bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS Patients with mRCC and 2-3 prior lines of therapy were randomized 1:1 to CRLX101+bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS In total, 111 patients were randomized and received≥1 dose of drug (CRLX101+bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101+bevacizumab and SOC arms was 3.7months (95% confidence interval, 2.0-4.3) and 3.9months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P=0.831). The objective response rate by IRR was 5% with CRLX101+bevacizumab versus 14% with SOC (Mantel-Haenszel test, P=0.836). Consistent with previous studies, the CRLX101+bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101+bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION NCT02187302 (NIH).
Evaluation of Silica Nanofluids in Static and Dynamic Conditions by an Optical Fiber Sensor

This work presents an optical fiber dynamic light scattering sensor capable of simultaneously assessing concentration and flow speed of nanofluids. Silica nanoparticles (189 nm) in water were tested, yielding a sensitivity of 0.78288 × 10³ s−1 for static conditions. Then, the sensor was submitted to situations that simulate spatial concentration changes, offering better results than those obtained by traditional mathematical models. Finally, in flow tests, the light backscattered by the nanoparticles were collected by a fiber probe placed parallel to the streamline, whereas intensity values were processed by artificial neural networks. The sensor provides average errors of 0.09 wt% and 0.26 cm/s for concentration and speed measurements, respectively, and can be further applied to assess different types of nanofluids and inline processes.