Miracle-dz/UniFAR-FTUs huggingface dataset:
Formulation and Evaluation of Novel Hybridized Nanovesicles for Enhancing Buccal Delivery of Ciclopirox Olamine

Ciclopirox olamine (CPO) is a topical wide-spectrum antimycotic agent that possesses antifungal, antibacterial and anti-inflammatory activities. Loading CPO into a hybridized vesicular system is expected to enhance its buccal permeation and hence, therapeutic activity, whereas the frequent administration and side effects are reduced. Vesicular systems with high penetration ability were prepared based on cholesterol, Lipoid S45 or Phospholipon 90H, with span 60 while incorporating a penetration enhancer (Labrafac or labrasol) followed by full assessment of their size, entrapment efficiency, and drug release profiles. The optimum formulation, composed of Lipoid S45 and Labrafac, possessed the smallest vesicle size (346.1 nm), highest entrapment efficiency (94.4%), and sustained CPO release pattern, and was characterized for its morphology and thermal properties. This powerful mixture of the penetration enhancers (Lipoid S45 and Labrafac) in the designed hybridized vesicles was thoroughly investigated for their characteristics after being incorporated in bioadhesive gel. Moreover, enhanced antifungal activity was demonstrated either upon testing the designed formulation on agar plates or in vivo upon treating infected rabbits with the proposed formulation. Results suggest that the presented bioadhesive gel incorporating the CPO-loaded vesicles can be a promising delivery system that can offer a prolonged localized antifungal treatment with enhanced therapeutic effect.
In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2

Janus kinase (JAK) inhibitors have been developed as novel immunomodulatory drugs and primarily used for treating rheumatoid arthritis and other inflammatory diseases. Recent studies have suggested that this category of anti-inflammatory drugs could be potentially useful for the control of inflammation “storms” in respiratory virus infections. In addition to their role in regulating immune cell functions, JAK1 and JAK2 have been recently identified as crucial cellular factors involved in influenza A virus (IAV) replication and could be potentially targeted for antiviral therapy. Gingerenone A (Gin A) is a compound derived from ginger roots and a dual inhibitor of JAK2 and p70 S6 kinase (S6K1). Our present study aimed to determine the antiviral activity of Gin A on influenza A virus (IAV) and to understand its mechanisms of action. Here, we reported that Gin A suppressed the replication of three IAV subtypes (H1N1, H5N1, H9N2) in four cell lines. IAV replication was also inhibited by Ruxolitinib (Rux), a JAK inhibitor, but not by PF-4708671, an S6K1 inhibitor. JAK2 overexpression enhanced H5N1 virus replication and attenuated Gin A-mediated antiviral activity. In vivo experiments revealed that Gin A treatment suppressed IAV replication in the lungs of H5N1 virus-infected mice, alleviated their body weight loss, and prolonged their survival. Our study suggests that Gin A restricts IAV replication by inhibiting JAK2 activity; Gin A could be potentially useful for the control of influenza virus infections.
Diversity of pink pigmented psychrophiles from Antarctica.

A group of 15 psychrophilic pink pigment producing bacteria investigated in the present study were retrieved from different inorganic samples collected in Antarctica (J. G. Mendel Station, James Ross Island) during the period of 2007 2010. The majority of isolates were Gram-negative, catalase positive rods, only one isolate represented Gram-positive coccus (Arthrobacter sp.). Phylogenetic position of all isolates was determined by partial 16S rDNA sequence analysis which assigned the Gram-negative isolates as members of sphingobacteria or oxalobacteria. Individual strains were phylogenetically placed within the genera Pedobacter (four strains), Massilia (four strains) and Hymenobacter (three strains). Remaining three Gram-negative isolates were classified as members of Massilia/Duganella/Janthinobacterium group. These cold-adapted bacteria represent probably novel species within the genera listed above and they might serve as sources of novel biochemical traits usable in biotechnological applications.
The Primary Cilium of Adipose Progenitors Is Necessary for Their Differentiation into Cancer-Associated Fibroblasts that Promote Migration of Breast Cancer Cells In Vitro

Cancer associated fibroblasts (CAFs) are central elements of the microenvironment that control tumor development. In breast cancer, CAFs can originate from adipose progenitors (APs). We, and others, have shown that the primary cilium, an antenna-shaped organelle, controls several aspects of APs’ biology. We studied the conversion of human APs into CAFs by breast cancer cell lines (BCCs). Deletion of the cilium of APs by a pharmacological inhibitor, or by siRNA, allow us to demonstrate that the cilium is necessary for the differentiation of APs into CAFs. BCCs increase production of TGF-β1 by APs, which is a known inducer of CAFs. Pharmacological inhibition of TGF-β1 signaling in APs prevents their conversion into CAFs. Since we previously showed that deletion of the APs’ cilium inhibits TGF-β1 signaling, we propose that BCCs induce TGF-β1 production in Aps, which binds to the primary cilium of Aps and leads to their differentiation into CAFs. Inhibition of APs conversion into CAFs induces a loss in some of the biological effects of CAFs since deletion of the cilium of APs decreases their effect on the migration of BCCs. This is the first observation of a function of the cilium of APs in their conversion into CAFs, and its consequences on BCCs.
Pharmacokinetic and Pharmacodynamic Factors Contribute to Synergism between Let-7c-5p and 5-Fluorouracil in Inhibiting Hepatocellular Carcinoma Cell Viability

Pharmacological interventions for hepatocellular carcinoma (HCC) are hindered by complex factors, and rational combination therapy may be developed to improve therapeutic outcomes. Very recently, we have identified a bioengineered microRNA let-7c-5p (or let-7c) agent as an effective inhibitor against HCC in vitro and in vivo. In this study, we sought to identify small-molecule drugs that may synergistically act with let-7c against HCC. Interestingly, we found that let-7c exhibited a strong synergism with 5-fluorouracil (5-FU) in the inhibition of HCC cell viability as manifested by average combination indices of 0.3 and 0.5 in Hep3B and Huh7 cells, respectively. By contrast, coadministration of let-7c with doxorubicin or sorafenib inhibited HCC cell viability with, rather surprisingly, no or minimal synergy. Further studies showed that protein levels of multidrug resistance–associated protein (MRP) ATP-binding cassette subfamily C member 5 (MRP5/ABCC5), a 5-FU efflux transporter, were reduced around 50% by let-7c in HCC cells. This led to a greater degree of intracellular accumulation of 5-FU in Huh7 cells as well as the second messenger cyclic adenosine monophosphate, an endogenous substrate of MRP5. Since 5-FU is an irreversible inhibitor of thymidylate synthetase (TS), we investigated the interactions of let-7c with 5-FU at pharmacodynamic level. Interestingly, our data revealed that let-7c significantly reduced TS protein levels in Huh7 cells, which was associated with the suppression of upstream transcriptional factors as well as other regulatory factors. Collectively, these results indicate that let-7c interacts with 5-FU at both pharmacokinetic and pharmacodynamic levels, and these findings shall offer insight into molecular mechanisms of synergistic drug combinations. SIGNIFICANCE STATEMENT Combination therapy is a common strategy that generally involves pharmacodynamic interactions. After identifying a strong synergism between let-7c-5p and 5-fluorouracil (5-FU) against hepatocellular carcinoma cell viability, we reveal the involvement of both pharmacokinetic and pharmacodynamic mechanisms. In particular, let-7c enhances 5-FU exposure (via suppressing ABCC5/MRP5 expression) and cotargets thymidylate synthase with 5-FU (let-7c reduces protein expression, whereas 5-FU irreversibly inactivates enzyme). These findings provide insight into developing rational combination therapies based on pharmacological mechanisms.
Senescence-Associated Secretory Phenotype Determines Survival and Therapeutic Response in Cervical Cancer

Simple Summary Cervical cancer is the most common gynecological cancer caused by persistent infections with human papilloma viruses. Over time, this infection leads to secretion of inflammatory proteins in the cervix, which exacerbates the neoplastic and senescent changes to the cervical epithelial lining. We measured nineteen serum proteins in retrospectively collected samples from cervical cancer patients. We show here that 10 out of 19 proteins are associated with senescence phenotype in cervical cancer patients. This senescence associated protein signature influences how cervical cancer patients responds to therapy. Abstract Molecular biomarkers that can predict survival and therapeutic outcome are still lacking for cervical cancer. Here we measured a panel of 19 serum proteins in sera from 565 patients with stage II or III cervical cancer and identified 10 proteins that have an impact on disease specific survival (DSS) (Hazzard’s ratio; HR = 1.51–2.1). Surprisingly, all ten proteins are implicated in senescence-associated secreted phenotype (SASP), a hallmark of cellular senescence. Machine learning using Ridge regression of these SASP proteins can robustly stratify patients with high SASP, which is associated with poor survival, and patients with low SASP associated with good survival (HR = 3.09–4.52). Furthermore, brachytherapy, an effective therapy for cervical cancer, greatly improves survival in SASP-high patients (HR = 3.3, p < 5 × 10−5) but has little impact on survival of SASP-low patients (HR = 1.5, p = 0.31). These results demonstrate that cellular senescence is a major determining factor for survival and therapeutic response in cervical cancer and suggest that senescence reduction therapy may be an efficacious strategy to improve the therapeutic outcome of cervical cancer.
The Effect of Exercise on Nutritional Status and Body Composition in Hemodialysis: A Systematic Review

Chronic kidney disease (CKD) is associated with aggravating factors which can affect both body composition and nutritional status. The purpose of the present systematic review was to investigate the potential effects of any physical activity on body composition or nutritional status among patients with stage 5 CKD undergoing hemodialysis (HD). A literature search on PubMed, Scopus, Web of Science, Google Scholar, and Cochrane was conducted and 14 randomized clinical trials were included. Skeletal muscle index and mid-arm muscular circumference increased after resistance exercise, and the results on body mass index, % body fat, and lean body mass varied. Serum albumin and C-reactive protein, in most cases, showed a slight increase and decrease, respectively. An improvement was also observed in body strength and overall performance status. The results suggest that physical activity can be beneficial for both the body composition and nutritional status of patients undergoing HD and can help in the prevention of sarcopenia. However, further research is needed mainly in the field of nutritional status.
Effect of Branch Training of Asparagus ( Asparagus officinalis L.) on Yield and Harvesting Efficiency using Long-Shaft Scissors for Maintaining Mother Stem Cultivation

The use of long-shaft scissors allows laborers to harvest spears in a standing posture for maintaining mother stem cultivation of asparagus. Typically, it is time-consuming and fatiguing work for laborers to find and harvest spears that emerge near the mother stems, because asparagus spears are often hidden by lateral branches of mother stems. We studied the training of asparagus branches to improve the visibility of young spears that emerge from ridges; training allows a continuous standing posture during harvest with long-shaft scissors. Firstly, the effects of branch training using strings or nets on the yield and quality of asparagus spears were investigated. We found that the yield and quality were similar, irrespective of branch training methods. Secondly, the effect of branch training on harvest work efficiency and bending of the upper body of laborers who used long-shaft scissors was evaluated. No difference was found in harvest work efficiency among the branch training methods. It was, however, observed that the bending angle of the upper bodies was decreased in laborers in their 50s or 60s when branch training with strings or nets was applied as compared to the control. Visibility of the spears was improved by training with strings or nets for laborers in their 30s, 50s, and 60s. Additionally, we compared the working efficiency of training branches with strings and nets, and found that training with strings permits reduction of the working time (21% of the work time on training with nets).
Characterization of Novel Lytic Bacteriophages of Achromobacter marplantensis Isolated from a Pneumonia Patient

Achromobacter spp. are becoming increasingly associated with lung infections in patients suffering from cystic fibrosis (CF). A. marplatensis, which is closely related to A. xylosoxidans, has been isolated from the lungs of CF patients and other human infections. This article describes the isolation, morphology and characterization of two lytic bacteriophages specific for an A. marplatensis strain isolated from a pneumonia patient. This host strain was the causal agent of hospital acquired pneumonia–the first clinical report of such an occurrence. Full genome sequencing revealed bacteriophage genomes ranging in size from 45901 to 46,328 bp. Transmission electron microscopy revealed that the two bacteriophages AMA1 and AMA2 belonged to the Siphoviridae family. Host range analysis showed that their host range did not extend to A. xylosoxidans. The possibility exists for future testing of such bacteriophages in the control of Achromobacter infections such as those seen in CF and other infections of the lungs. The incidence of antibiotic resistance in this genus highlights the importance of seeking adjuncts and alternatives in CF and other lung infections.
Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery.
Printed Soft Sensor with Passivation Layers for the Detection of Object Slippage by a Robotic Gripper

Tactile sensing, particularly the detection of object slippage, is required for skillful object handling by robotic grippers. The real-time measurement and identification of the dynamic shear forces that result from slippage events are crucial for slip detection and effective object interaction. In this study, a ferroelectric polymer-based printed soft sensor for object slippage detection was developed and fabricated by screen printing. The proposed sensor demonstrated a sensitivity of 8.2 μC·cm−2 and was responsive to shear forces applied in both the parallel and perpendicular directions. An amplifier circuit, based on a printed organic thin-film transistor, was applied and achieved a high sensitivity of 0.1 cm2/V·s. Therefore, this study experimentally demonstrates the effectiveness of the proposed printable high-sensitivity tactile sensor, which could serve as part of a wearable robotic e-skin. The sensor could facilitate the production of a system to detect and prevent the slippage of objects from robotic grippers.
Low Serum Magnesium is Associated with Incident Dementia in the ARIC-NCS Cohort

Higher serum magnesium is associated with lower risk of multiple morbidities, including diabetes, stroke, and atrial fibrillation, but its potential neuroprotective properties have also been gaining traction in cognitive function and decline research. We studied 12,040 participants presumed free of dementia in the Atherosclerosis Risk in Communities (ARIC) study. Serum magnesium was measured in fasting blood samples collected in 1990–1992. Dementia status was ascertained through cognitive examinations in 2011–2013, 2016–2017, and 2018–2019, along with informant interviews and indicators of dementia-related hospitalization events and death. Participants’ cognitive functioning capabilities were assessed up to five times between 1990–1992 and 2018–2019. The cognitive function of participants who did not attend follow-up study visits was imputed to account for attrition. We identified 2519 cases of dementia over a median follow-up period of 24.2 years. The lowest quintile of serum magnesium was associated with a 24% higher rate of incident dementia compared to those in the highest quintile of magnesium (HR, 1.24; 95% CI, 1.07, 1.44). No relationship was found between serum magnesium and cognitive decline in any cognitive domain. Low midlife serum magnesium is associated with increased risk of incident dementia, but does not appear to impact rates of cognitive decline.
The Utility of Grimace Scales for Practical Pain Assessment in Laboratory Animals

Simple Summary Grimace scales for laboratory animals were first reported ten years ago. Yet, despite their promise as pain assessment tools it appears that they have not been implemented widely in animal research establishments for clinical pain assessment. We discuss potential reasons for this based on the knowledge gained to date on their use and suggest avenues for further research, which might improve uptake of their use in laboratory animal medicine. Abstract Animals’ facial expressions are widely used as a readout for emotion. Scientific interest in the facial expressions of laboratory animals has centered primarily on negative experiences, such as pain, experienced as a result of scientific research procedures. Recent attempts to standardize evaluation of facial expressions associated with pain in laboratory animals has culminated in the development of “grimace scales”. The prevention or relief of pain in laboratory animals is a fundamental requirement for in vivo research to satisfy community expectations. However, to date it appears that the grimace scales have not seen widespread implementation as clinical pain assessment techniques in biomedical research. In this review, we discuss some of the barriers to implementation of the scales in clinical laboratory animal medicine, progress made in automation of collection, and suggest avenues for future research.
Pupillary response to representations of light in paintings

It is known that, although the level of light is the primary determinant of pupil size, cognitive factors can also affect pupil diameter. It has been demonstrated that photographs of the sun produce pupil constriction independently of their luminance and other low-level features, suggesting that high-level visual processing may also modulate pupil response. Here, we measure pupil response to artistic paintings of the sun, moon, or containing a uniform lighting, that, being mediated by the artist's interpretation of reality and his technical rendering, require an even higher level of interpretation compared with photographs. We also study how chromatic content and spatial layout affect the results by presenting grey-scale and inverted versions of each painting. Finally, we assess directly with a categorization test how subjective image interpretation affects pupil response. We find that paintings with the sun elicit a smaller pupil size than paintings with the moon, or paintings containing no visible light source. The effect produced by sun paintings is reduced by disrupting contextual information, such as by removing color or manipulating the relations between paintings features that make more difficult to identify the source of light. Finally, and more importantly, pupil diameter changes according to observers’ interpretation of the scene represented in the same stimulus. In conclusion, results show that the subcortical pupillary response to light is modulated by subjective interpretation of luminous objects, suggesting the involvement of cortical systems in charge of cognitive processes, such as attention, object recognition, familiarity, memory, and imagination.