Miracle-dz/UniFAR-FTUs huggingface dataset:
Gibberellins Inhibit Flavonoid Biosynthesis and Promote Nitrogen Metabolism in Medicago truncatula

Bioactive gibberellic acids (GAs) are diterpenoid plant hormones that are biosynthesized through complex pathways and control various aspects of growth and development. Although GA biosynthesis has been intensively studied, the downstream metabolic pathways regulated by GAs have remained largely unexplored. We investigated Tnt1 retrotransposon insertion mutant lines of Medicago truncatula with a dwarf phenotype by forward and reverse genetics screening and phylogenetic, molecular, biochemical, proteomic and metabolomic analyses. Three Tnt1 retrotransposon insertion mutant lines of the gibberellin 3-beta-dioxygenase 1 gene (GA3ox1) with a dwarf phenotype were identified, in which the synthesis of GAs (GA3 and GA4) was inhibited. Phenotypic analysis revealed that plant height, root and petiole length of ga3ox1 mutants were shorter than those of the wild type (Medicago truncatula ecotype R108). Leaf size was also much smaller in ga3ox1 mutants than that in wild-type R108, which is probably due to cell-size diminution instead of a decrease in cell number. Proteomic and metabolomic analyses of ga3ox1/R108 leaves revealed that in the ga3ox1 mutant, flavonoid isoflavonoid biosynthesis was significantly up-regulated, while nitrogen metabolism was down-regulated. Additionally, we further demonstrated that flavonoid and isoflavonoid biosynthesis was induced by prohexadione calcium, an inhibitor of GA3ox enzyme, and inhibited by exogenous GA3. In contrast, nitrogen metabolism was promoted by exogenous GA3 but inhibited by prohexadione calcium. The results of this study further demonstrated that GAs play critical roles in positively regulating nitrogen metabolism and transport and negatively regulating flavonoid biosynthesis through GA-mediated signaling pathways in leaves.
Extracellular Heat Shock Proteins as Therapeutic Targets and Biomarkers in Fibrosing Interstitial Lung Diseases

Interstitial lung diseases (ILDs) include a large number of diseases and causes with variable outcomes often associated with progressive fibrosis. Although each of the individual fibrosing ILDs are rare, collectively, they affect a considerable number of patients, representing a significant burden of disease. Idiopathic pulmonary fibrosis (IPF) is the typical chronic fibrosing ILD associated with progressive decline in lung. Other fibrosing ILDs are often associated with connective tissues diseases, including rheumatoid arthritis-ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), or environmental/drug exposure. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, the course of these diseases is heterogeneous and cannot accurately be predicted for an individual patient. As a consequence, the discovery of novel biomarkers for these types of diseases is a major clinical challenge. Heat shock proteins (HSPs) are molecular chaperons that have been extensively described to be involved in fibrogenesis. Their extracellular forms (eHSPs) have been recently and successfully used as therapeutic targets or circulating biomarkers in cancer. The current review will describe the role of eHSPs in fibrosing ILDs, highlighting the importance of these particular stress proteins to develop new therapeutic strategies and discover potential biomarkers in these diseases.
A Systematic Review on Mobile Health Applications’ Education Program for Patients Taking Oral Anticoagulants

Warfarin is widely used as an oral anticoagulant. However, it is difficult to manage patients due to its narrow therapeutic range and individualized differences. Using controlled trials and real-world observational studies, this systematic review aimed to analyze health education’s impact among patients on warfarin therapy by mobile application. Smartphone and tablet applications have the potential to actively educate patients by providing them with timely information through push notifications. MEDLINE, EMBASE, CINAHL, Web of Science, and Cochrane electronic databases were searched using the keywords “anticoagulants,” “warfarin”, “mobile application”, and “smartphone” up to May 2020. Of the 414 articles obtained, 12 articles met the inclusion criteria for this review. The education and self-management programs using the mobile health application had diverse contents. A meta-analysis was not deemed appropriate because of the heterogeneity of populations, interventions, and outcomes. Thus, a narrative synthesis is presented instead. This review demonstrates that educating patients for anticoagulation management through their smartphones or tablets improves their knowledge levels, medication or treatment adherence, satisfaction, and clinical outcomes. Moreover, it has a positive effect on continuing health care. Future research concerning patients taking warfarin should include key self-management outcomes in larger, more rigorously designed studies, allowing for comparisons across studies. This study proposes a continuous application of timely education through smartphone applications to the current medical and nursing practice.
Disc Diffusion Testing of Azithromycin Against Clinical Isolates of Typhoidal Salmonellae: A Diagnostic Conundrum

Introduction: Typhoid remains a major healthcare problem in low and middle-income countries. The emergence of extremely drug-resistant (XDR) typhoid strains from the Indian subcontinent has led to very limited therapeutic options. Azithromycin being the only oral option for XDR typhoid faces a threat of rapid resistance due to its overuse after the COVID-19 pandemic. Objective: To evaluate the reliability of azithromycin disc diffusion testing against clinical isolates of typhoidal salmonellae in comparison with E-test minimum inhibitory concentrations (MICs). Study design: This is a cross-sectional validation study. Place and duration of the study: The Department of Microbiology, Pakistan Navy Ship Shifa hospital, Karachi from June 1 to December 31, 2020. Methodology: Antimicrobial susceptibility was performed by Kirby Bauer disc diffusion method for 60 isolates including Salmonella enterica ser. Typhi and Paratyphi A using Clinical Laboratory Standard Institute (CLSI) guidelines. MICs by the E-test method were determined for Azithromycin only. Results: A significant proportion of the isolates (55%) had high azithromycin MIC in the wild-type distribution range (8-16 µg/ml). Ten (16.6%) isolates showed false resistance, i.e., zone diameter <13 mm by disc diffusion method when compared to E-test MIC results. Isolates with MICs close to breakpoint, i.e., 16 µg/ml were more likely to show discordant results. The sensitivity, specificity, negative predictive value, positive predictive value, and diagnostic accuracy of the disc diffusion method versus E-test were 100%, 83%, 100%, 9%, and 83%, respectively. Conclusions: Disc diffusion method as recommended by CLSI is not reliable for azithromycin susceptibility testing particularly for isolates with high MICs in the susceptible range. The E-test method may be a better alternative to disc diffusion provided appropriate training is done prior to its application.
Antioxidative effect of dietary flavonoid isoquercitrin on human ovarian granulosa cells HGL5 in vitro.

This study aimed to examine the effect of dietary flavonoid isoquercitrin on ovarian granulosa cells using the immortalized human cell line HGL5. Cell viability, survival, apoptosis, release of steroid hormones 17beta-estradiol and progesterone, and human transforming growth factor-beta2 (TGF-beta2) and TGF-beta2 receptor as well as intracellular ROS generation were investigated after isoquercitrin treatment at the concentration range of 5-100 microg.ml-1. It did not cause any significant change (p>0.05) in cell viability as studied by AlamarBlue assay in comparison to control. No significant change was observed (p>0.05) in the proportion of live, dead and apoptotic cells as revealed by apoptotic assay using flow cytometry. Similarly, the release of 17beta-estradiol, progesterone, TGF-beta2 and its receptor were not affected significantly (p>0.05) by isoquercitrin as detected by ELISA, in comparison to control. Except for the highest concentration of 100 microg.ml-1, which led to oxidative stress, isoquercitrin exhibited antioxidative activity at lower concentration used in the study (5, 10, 25, and 50 microg.ml-1) by hampering the production of intracellular reactive oxygen species (ROS), in comparison to control, as detected by chemiluminescence assay (p<0.05). Findings of the present study indicate an existence of the antioxidative pathway that involves inhibition of intracellular ROS generation by isoquercitrin in human ovarian granulosa cells.
Short-Term and Long-Term Carcinogenic Effects of Food Contaminants (4-Hydroxynonenal and Pesticides) on Colorectal Human Cells: Involvement of Genotoxic and Non-Genomic Mechanisms

Simple Summary One’s environment, including diet, play a major role in the occurrence and the development of colorectal cancer (CRC). In this study, we are interested in two western diet associated food contaminants: 4-hydroxynonenal (HNE), a major lipid peroxidation product neoformed during digestion, and a mixture of pesticides to which we are commonly exposed to via fruit and vegetable consumption. The aim of this study was to analyse the impact of acute and long-term exposure to these contaminants, alone or in combination, on colorectal carcinogenesis. We used in vitro models of human colonic cells, either exhibiting or not different genetic susceptibilities to CRC. After acute exposure, we did not observe major alteration. However, long-term exposure to contaminants induce malignant transformation with different cellular mechanisms, depending on genetic susceptibility and contaminants alone or in mixtures. Abstract To investigate environmental impacts upon colorectal carcinogenesis (CRC) by diet, we assessed two western diet food contaminants: 4-hydroxynonenal (HNE), a major lipid peroxidation product neoformed during digestion, and a mixture of pesticides. We used human colonic cell lines ectopically eliciting varied genetic susceptibilities to CRC: the non-transformed human epithelial colonic cells (HCECs) and their five isogenic cell lines with the loss of APC (Adenomatous polyposis coli) and TP53 (Tumor protein 53) and/or ectopic expression of mutated KRAS (Kristen-ras). These cell lines have been exposed for either for a short time (2–24 h) or for a long period (3 weeks) to 1 µM HNE and/or 10 µM pesticides. After acute exposure, we did not observe any cytotoxicity or major DNA damage. However, long-term exposure to pesticides alone and in mixture with HNE induced clonogenic transformation in normal HCECs, as well as in cells representing later stages of carcinogenesis. It was associated with genotoxic and non-genomic mechanisms (cell growth, metabolic reprogramming, cell mobility and epithelial-mesenchymal transition) depending on genetic susceptibility. This study demonstrated a potential initiating and promoting effect of food contaminants on CRC after long-term exposure. It supports that these contaminants can accelerate carcinogenesis when mutations in oncogenes or tumor suppressor genes occur.
A Training Intervention through a 360° Multisource Feedback Model

Physicians and other health sciences professionals need continuous training, not only in technical aspects of their activity but also in nontechnical, transversal competencies with a cost-efficient impact on the proper functioning of healthcare. The objective of this paper is to analyze the behavioral change among health professionals at a large public hospital following a training intervention on a set of core nontechnical competencies: Teamwork, Adaptability-Flexibility, Commitment-Engagement, Results Orientation, and Leadership Skills for Supervisors. The 360° Multisource Feedback (MSF) model was applied using three sources of information: supervisors, co-workers, and the workers themselves (self-assessment). A quasi-experimental pretest–post-test single-group design with two points in time was utilized. The training intervention improved the scores of only one of the trained competencies—the “Results Orientation” competency—although the scores were slightly inflated. Moreover, significant discrepancies were detected between the three sources, with supervisors awarding the highest scores. The magnitude of behavioral change was related to certain sociodemographic and organizational variables. The study was not immune to the ceiling effect, despite control measures aimed at avoiding it. The empirical evidence suggests that the 360° MSF model must be maintained over time to enhance and reinforce an evaluation culture for better patient care.
Plasma Levels of Homocysteine is Associated with Liver Fibrosis in Health Check-Up Population

Object Studies have shown a link between homocysteine (Hcy) and heart diseases, kidney diseases, cerebrovascular diseases, liver diseases, and other pathological conditions. However, the relationship between Hcy and liver fibrosis (LF) is unclear. Here, we studied the link between plasma Hcy concentration and LF. Methods We determined and recorded the plasma Hcy concentration, general biochemical parameters, and liver stiffness measurement (LSM) in 1582 subjects, followed by statistical data analyses. Results During different stages of LF, we found a considerable difference (p <0.001 unless specified) in body mass index (BMI), sex, age, Hcy, the levels of alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT; P = 0.012), triglycerides (TG; P = 0.006), low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (FBS), and platelet count (PLT). There was a strong association between the plasma Hcy concentration and the serum biomarkers of LF (P <0.001) and the values of LSM (P <0.001). Conclusion The plasma Hcy concentration was substantially different among different stages of LF. The higher the plasma Hcy concentration, the more evident was the degree of LF.
Voice Prosthesis Coated with Sustained Release Varnish Containing Clotrimazole Shows Long-Term Protection against Candida albicans: An In Vitro Study

Fungal biofilm formation on voice prosthesis (VP) is a major health problem that requires repeated replacement of the prosthesis. Candida albicans is one of the pathogens that frequently inhabits the VP. We proposed that coating VPs with sustained-release varnish (SRV) containing clotrimazole (CTZ) might prevent fungal biofilm formation. The long-term antifungal activities of SRV-CTZ- versus SRV-placebo-coated VPs was tested daily by measuring the inhibition zone of C. albicans seeded on agar plates or by measuring the fungal viability of C. albicans in suspension. The extent of biofilm formation on coated VPs was analyzed by confocal microscopy and scanning electron microscopy. We observed that SRV-CTZ-coated VPs formed a significant bacterial inhibition zone around the VPs and prevented the growth of C. albicans in suspension during the entire testing period of 60 days. Fungal biofilms were formed on placebo-coated VPs, while no significant biofilms were observed on SRV-CTZ-coated VPs. HPLC analysis shows that CTZ is continuously released during the whole test period of 60 days at a concentration above the minimal fungistatic concentration. In conclusion, coating VPs with an SRV-CTZ film is a potential effective method for prevention of fungal infections and biofilm formation on VPs.
Key Enzymes Involved in the Synthesis of Hops Phytochemical Compounds: From Structure, Functions to Applications

Humulus lupulus L. is an essential source of aroma compounds, hop bitter acids, and xanthohumol derivatives mainly exploited as flavourings in beer brewing and with demonstrated potential for the treatment of certain diseases. To acquire a comprehensive understanding of the biosynthesis of these compounds, the primary enzymes involved in the three major pathways of hops’ phytochemical composition are herein critically summarized. Hops’ phytochemical components impart bitterness, aroma, and antioxidant activity to beers. The biosynthesis pathways have been extensively studied and enzymes play essential roles in the processes. Here, we introduced the enzymes involved in the biosynthesis of hop bitter acids, monoterpenes and xanthohumol derivatives, including the branched-chain aminotransferase (BCAT), branched-chain keto-acid dehydrogenase (BCKDH), carboxyl CoA ligase (CCL), valerophenone synthase (VPS), prenyltransferase (PT), 1-deoxyxylulose-5-phosphate synthase (DXS), 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR), Geranyl diphosphate synthase (GPPS), monoterpene synthase enzymes (MTS), cinnamate 4-hydroxylase (C4H), chalcone synthase (CHS_H1), chalcone isomerase (CHI)-like proteins (CHIL), and O-methyltransferase (OMT1). Furthermore, research advancements of each enzyme in terms of reaction conditions, substrate recognition, enzyme structures, and use in engineered microbes are described in depth. Hence, an extensive review of the key enzymes involved in the phytochemical compounds of hops will provide fundamentals for their applications in beer production.
Impact of Substantive Staging and Communicative Staging of Sustainable Servicescape on Behavioral Intentions of Hotel Customers through Overall Perceived Image: A Case of Boutique Hotels

Customers have become very sensitive regarding the innovative evaluation of services. Due to competition in the hospitality industry, it is a challenge for hotel marketers to understand customers’ behavior. There is scant research in the hotel industry of Pakistan and especially on boutique hotels. This research seeks to measure the relationship between substantive, communicative elements of the sustainable servicescape and behavioral intentions (word of mouth) in a boutique hotel setting. However, the mediating effect of the overall perceived image is examined between these constructs. Responses of boutique hotel visitors were collected from Lahore, Islamabad, Faisalabad, and Murree. Data were analyzed by using structural equation modeling (SEM). Results display that both substantive and communicative servicescape elements positively affect the perceived image of customers, which has a positive influence on behavioral intentions such as word of mouth (WOM). Theoretical and practical implications are also discussed.
Leveraging genetic data to investigate the effects of interleukin‐6 receptor signalling on levels of 40 circulating cytokines

Interleukin 6 (IL‐6) is a circulating cytokine implicated in inflammatory processes. However, the broad effects of IL‐6 receptor (IL‐6R) signalling on other circulating cytokines is not known. Using summary‐level data from genome‐wide association studies, we leveraged genetic variants that proxy IL‐6R signalling in two‐sample Mendelian randomization analyses to investigate effects on levels of 40 circulating cytokines. Increased genetically proxied IL‐6R signalling was associated with reduced levels of 10 circulating interleukins, chemokines and growth factors. The significant results include IL‐10 (Mendelian randomization estimate −0.306, standard error [SE] 0.093), IL‐4 (estimate −0.393, SE 0.1007), eotaxin (estimate −0.510, SE 0.1213) and Fibroblast growth factor (estimate −0.334, SE 0.1005). The findings from this study support the feedback effects of IL‐6R signalling on reducing levels of some circulating cytokines and identify compensatory mechanisms that maybe modulating its inflammatory effects. These results provide insight into the mechanisms by which IL‐6R signalling may be contributing to inflammatory and autoimmune diseases.
Clinical Risk Factors for Uterine Cervical Elongation among Women with Pelvic Organ Prolapse

Background: Cervical elongation is commonly associated with pelvic organ prolapse (POP). It was an identified risk for recurrent prolapse after hysteropexy, requiring additional surgeries. The aim of the study is to investigate the risk factors for uterine cervical elongation among women with POP. Methods: In this single-center retrospective cohort study, women who underwent vaginal total hysterectomy for POP between 2014 and 2016 were collected. The cervical and total uterine lengths were measured by pathologists, while the ratio of cervical length to total uterine length were calculated. The cervical elongation is defined as corpus/cervix ratio ≤ 1.5. Results: A total of 133 patients were enrolled in this study. Among these patients, 43 women had cervical elongation and 90 women had normal length of uterine cervix. We found that age > 65 years old (67.4% vs. 42.2%, p = 0.007), total vaginal length ≥ 9.5 cm (65.1% vs. 45.6%, p = 0.035), uterine weight < 51 gm (72.1% vs. 52.2%, p = 0.03), and Pelvic Organ Prolapse Distress Inventory 6 (POPDI-6) ≥ 12 (30.2% vs. 14.4%, p = 0.032) were associated with the risk of cervical elongation. There were no significant differences on preoperative urodynamic parameters in the two groups. Conclusion: The patient age > 65 years old, the total vaginal length of POP-Q system ≥ 9.5 cm, uterine weight < 51 g, and POPDI-6 ≥ 12 are independent risk factors of cervical elongation in women with POP. For women scheduled for pelvic reconstructive hysteropexy, concomitant cervical amputation should be considered.
Classification and Treatment of Diseases in the Age of Genome Medicine Based on Pathway Pathology

The focus of pathology as a biomedical discipline is the identification of the pathomechanisms of diseases and the integration of this knowledge into routine diagnosis and classification. Standard tools are macroscopic and microscopic analysis complemented by immunohistochemistry and molecular pathology. So far, classification has been based on the paradigm of cellular pathology established by Rudolf Virchow and others more than 150 years ago, stating that diseases originate from diseased cells. This dogma is meanwhile challenged by the fact that cells can be fully reprogrammed. Many diseases are nowadays considered to originate from undifferentiated stem cells, induced into a diseased state by genetic or epigenetic alterations. In addition, the completion of the Human Genome Project, with the identification of more than 20.000 genes and a much higher number of gene variants and mutations, led to the concept that diseases are dominated by genetics/epigenetics rather than cells of origin. The axiom of cellular pathology, however, still holds true, as cells are the smallest animate units from which diseases originate. Medical doctors and researchers nowadays have to deal with a tremendous amount of data. The International Classification of Diseases will expand from 14.400 entities/codes in ICD-10 to more than 55.000 in ICD-11. In addition, large datasets generated by “genomics“, e.g., whole-genome sequencing, expression profiling or methylome analysis, are meanwhile not only applied in research but also introduced into clinical settings. It constitutes a major task to incorporate all the data into routine medical work. Pathway pathology may help solve this problem. It is based on the realization that diseases are characterized by three essential components: (i) cells of origin/cellular context and (ii) the alteration of cellular as well as (iii) molecular/signal transduction pathways. The concept is illustrated by elaborating on two key cellular pathways, i.e., the cellular senescence of normal cells and the immortality of cancer cells, and by contrasting single cell/single pathway diseases, such as mycoplasma and coughing pneumonia, with complex diseases such as cancer, with multiple cell types as well as multiple affected cellular and signaling pathways. Importantly, the concept of pathway pathology is not just intended to classify disease, but also to conceive new treatment modalities. This article is dedicated to Dr. Leonard Hayflick, who made basic discoveries in pathway pathology not only by identifying cells causing disease (Mycoplasma pneumoniae) and establishing cell strains for treating disease (WI-38 for viral vaccines), but also by first describing cellular senescence and immortality.