Miracle-dz/UniFAR-FTUs huggingface dataset:
The AMPK-PP2A axis in insect fat body is activated by 20-hydroxyecdysone to antagonize insulin/IGF signaling and restrict growth rate

Significance Final body size determination in animals remains a long-standing puzzle in the field of developmental biology. In insects, insulin/insulin-like growth factor signaling (IIS) and the steroid hormone 20-hydroxyecdysone (20E) are mainly responsible for the growth rate and growth period, respectively, and consequently the final body size. Here, we report that 20E activates AMPK by up-regulating its gene expression and inducing sugar starvation. In turn, AMPK activates protein phosphatase 2A, which further dephosphorylates and inactivates key components in IIS in the fat body, and eventually suppresses the larval growth rate. These data answer the question of how 20E antagonizes IIS and modulates growth rate. In insects, 20-hydroxyecdysone (20E) limits the growth period by triggering developmental transitions; 20E also modulates the growth rate by antagonizing insulin/insulin-like growth factor signaling (IIS). Previous work has shown that 20E cross-talks with IIS, but the underlying molecular mechanisms are not fully understood. Here we found that, in both the silkworm Bombyx mori and the fruit fly Drosophila melanogaster, 20E antagonized IIS through the AMP-activated protein kinase (AMPK)-protein phosphatase 2A (PP2A) axis in the fat body and suppressed the growth rate. During Bombyx larval molt or Drosophila pupariation, high levels of 20E activate AMPK, a molecular sensor that maintains energy homeostasis in the insect fat body. In turn, AMPK activates PP2A, which further dephosphorylates insulin receptor and protein kinase B (AKT), thus inhibiting IIS. Activation of the AMPK-PP2A axis and inhibition of IIS in the Drosophila fat body reduced food consumption, resulting in the restriction of growth rate and body weight. Overall, our study revealed an important mechanism by which 20E antagonizes IIS in the insect fat body to restrict the larval growth rate, thereby expanding our understanding of the comprehensive regulatory mechanisms of final body size in animals.
High Variability in Erythrocyte, Plasma and Whole Blood EPA and DHA Levels in Response to Supplementation

(1) Aim: the aim of this secondary analysis was to report the variability in response to n-3 long chain polyunsaturated fatty acids (LCPUFA) supplementation in erythrocytes, plasma and whole blood of a previously published dose response study. (2) Methods: a randomized, double-blind, placebo-controlled trial of parallel design was conducted, whereby pre-menopausal women were randomly assigned to consume 0, 0.35, 0.7 or 1 g/day of supplemental eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA). Fasted blood samples were taken at baseline and after eight weeks intervention. Erythrocyte, plasma and whole blood fatty acids were extracted using the method of Lepage and Roy and analysed using gas chromatography. (3) Results: There were significant increases in EPA plus DHA levels in the 0.7 g and 1 g dose groups, with the highest increase with the 1 g dose notably: in erythrocytes (from 5.69% to 7.59%), plasma (from 2.94% to 5.48%) and in whole blood (from 3.81% to 6.03%). There was high variability in response to the supplement in erythrocytes, plasma and whole blood across the different doses. (4) Conclusion: there is high individual variability in n-3 LCPUFA levels in response to n-3 LCPUFA supplementation, which should be taken into account in clinical trials using n-3 LCPUFA supplements.
Investigating cognitive load modulation of distractor processing using pupillary luminance responses in the anti‐saccade paradigm

Observers must select goal‐directed stimuli in lieu of distractors in the environment for preferential information processing. This selection, according to the load theory of attention, is modulated by cognitive load, involving the frontal cortices, with more significant distractor interference under high cognitive load, with strained executive control resources. Evidence in support of this theory exists; however, working memory tasks were predominately used in these investigations. The influence of other types of cognitive load on distractor processing is largely unknown. An interleaved pro‐ and anti‐saccade task has often been used to investigate executive control in which subjects are instructed in advance to either automatically look at the peripheral stimulus (pro‐saccade), or to suppress the automatic response and voluntarily look in the direction opposite of the stimulus (anti‐saccade). Distinct frontal preparatory activity has been clearly characterized during preparation for pro‐ and anti‐saccades, with higher inhibition‐related activity in preparation for anti‐saccades than pro‐saccades. Here, we used an interleaved pro‐ and anti‐saccade paradigm to investigate the modulation of distractor interference by cognitive load in a group of 24 healthy young adults. Luminant distractors were used to evoke automatic pupillary responses to evaluate distractor processing. Greater pupillary dilation following dark distractor presentation was observed in the anti‐saccade than the pro‐saccade preparation. These effects, however, were absent in pupillary constriction following bright distractors. Together, our results support the load theory of attention, importantly highlighting the potential of using involuntary changes in pupil size to objectively investigate attentional selection under load.
Prognostic factors affecting mortality in patients with esophageal GISTs.

PURPOSE Esophageal gastrointestinal stromal tumors (GISTs) compose a very rare clinical entity, representing 0.7% of all GISTs. Therefore, the clinicopathological factors that affect mortality are currently not adequately examined. We reviewed individual cases of esophageal GISTs found in the literature in order to identify the prognostic factors affecting mortality. METHODS MEDLINE, EMBASE, and the Cochrane Library were systematically searched to identify clinical studies and case reports referring to esophageal GISTs. The clinicopathological features were recorded and evaluated. RESULTS A total number of 105 patients were found. The median age of patients was 58 years (mean 52.4%). The majority of patients (71.6%) presented with tumor-associated symptoms. Tumors were mostly located at the lower esophagus (72.9%), and the median tumor size was 7 cm. Esophagectomy was the most common surgical approach (54.3%), followed by tumor enucleation (45.7%). The median follow-up period was 34 months; tumor recurrence occurred in 18 cases (18.9%) and 19 died of disease (19.2%). The overall survival rate was 75.8%. We found out that tumor size and high mitotic rate (>10 mitosis per hpf) were significant prognostic factors for survival. Presence of symptoms, ulceration, and tumor necrosis as well as tumor recurrence were also significant prognostic factors (p<0.01). CONCLUSIONS Esophageal GISTs' tumor size and mitotic rate are the most significant factors for survival. For dubious cases, a pre-operative biopsy can auspiciously establish the diagnosis of an esophageal GIST. Regarding surgical treatment, tumor enucleation can be safely and feasibly performed for relatively small, intact tumors, whereas large, aggressive tumors are resected with radical esophagectomy.
Identification of the most effective pharmaceutical products for smoking cessation: A literature review

ABSTRACT Introduction: The major causes of excess mortality among smokers are diseases related to smoking, including cancer as well as respiratory and vascular diseases. People who stop smoking greatly reduce their risk of disease and early death, so effective smoking-cessation interventions are extremely important management strategies. Aims: To undertake a major literature review to identify the most effective pharmaceutical products for smoking cessation and detail the latest research in smoking-cessation interventions. Methods: The Google Scholar, PubMed, Medline, and the Cochrane Library of Systematic Reviews databases were searched. The types of studies searched for were randomized controlled trials, systematic reviews, and meta-analyses. All studies were included except those involving patients with chronic obstructive pulmonary disease or infection by human immunodeficiency virus. Searched studies assessed nicotine replacement therapy (NRT), varenicline, combination therapy, bupropion, and antidepressants. Results: The literature search focused on the three first-line treatments for smoking cessation: NRT, bupropion, and varenicline. Current research in non-first-line treatments (electronic cigarettes, cytisine, “heat-not-burn” tobacco products) as well as smoking-cessation strategies in high-risk individuals (pregnant women, individuals with mental-health or addiction issues) was also detailed. Conclusions: Except for high-risk groups, use of NRT, bupropion, and varenicline can result in a higher prevalence of smoking cessation compared with placebos. Varenicline and combination NRT appear to be the most effective smoking-cessation strategies.
CXL146, a Novel 4H-Chromene Derivative, Targets GRP78 to Selectively Eliminate Multidrug-Resistant Cancer Cells

The 78-kDa glucose-regulated protein (GRP78), an endoplasmic reticulum (ER) chaperone, is a master regulator of the ER stress. A number of studies revealed that high levels of GRP78 protein in cancer cells confer multidrug resistance (MDR) to therapeutic treatment. Therefore, drug candidate that reduces GRP78 may represent a novel approach to eliminate MDR cancer cells. Our earlier studies showed that a set of 4H-chromene derivatives induced selective cytotoxicity in MDR cancer cells. In the present study, we elucidated its selective mechanism in four MDR cancer cell lines with one lead candidate (CXL146). Cytotoxicity results confirmed the selective cytotoxicity of CXL146 toward the MDR cancer cell lines. We noted significant overexpression of GRP78 in all four MDR cell lines compared with the parental cell lines. Unexpectedly, CXL146 treatment rapidly and dose-dependently reduced GRP78 protein in MDR cancer cell lines. Using human leukemia (HL) 60/mitoxantrone (MX) 2 cell line as the model, we demonstrated that CXL146 treatment activated the unfolded protein response (UPR); as evidenced by the activation of inositol-requiring enzyme 1α, protein kinase R–like ER kinase, and activating transcription factor 6. CXL146-induced UPR activation led to a series of downstream events, including extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase activation, which contributed to CXL146-induced apoptosis. Targeted reduction in GRP78 resulted in reduced sensitivity of HL60/MX2 toward CXL146. Long-term sublethal CXL146 exposure also led to reduction in GRP78 in HL60/MX2. These data collectively support GRP78 as the target of CXL146 in MDR treatment. Interestingly, HL60/MX2 upon long-term sublethal CXL146 exposure regained sensitivity to mitoxantrone treatment. Therefore, further exploration of CXL146 as a novel therapy in treating MDR cancer cells is warranted. SIGNIFICANCE STATEMENT Multidrug resistance is one major challenge to cancer treatment. This study provides evidence that cancer cells overexpress 78-kDa glucose-regulated protein (GRP78) as a mechanism to acquire resistance to standard cancer therapies. A chromene-based small molecule, CXL146, selectively eliminates cancer cells with GRP78 overexpression via activating unfolded protein response–mediated apoptosis. Further characterization indicates that CXL146 and standard therapies complementarily target different populations of cancer cells, supporting the potential of CXL146 to overcome multidrug resistance in cancer treatment.
Copy Number and Prevalence of Porcine Endogenous Retroviruses (PERVs) in German Wild Boars

Porcine endogenous retroviruses (PERVs) are integrated in the genome of pigs and are transmitted like cellular genes from parents to the offspring. Whereas PERV-A and PERV-B are present in all pigs, PERV-C was found to be in many, but not all pigs. When PERV-C is present, recombination with PERV-A may happen and the PERV-A/C recombinants are characterized by a high replication rate. Until now, nothing has been known about the copy number of PERVs in wild boars and little is known about the prevalence of the phylogenetically youngest PERV-C in ancient wild boars. Here we investigated for the first time the copy number of PERVs in different populations of wild boars in and around Berlin using droplet digital PCR. Copy numbers between 3 and 69 per genome have been measured. A lower number but a higher variability was found compared to domestic pigs, including minipigs reported earlier (Fiebig et al., Xenotransplantation, 2018). The wild boar populations differed genetically and had been isolated during the existence of the Berlin wall. Despite this, the variations in copy number were larger in a single population compared to the differences between the populations. PERV-C was found in all 92 analyzed animals. Differences in the copy number of PERV in different organs of a single wild boar indicate that PERVs are also active in wild boars, replicating and infecting new cells as has been shown in domestic pigs.
Ocular complications of lamellar ichthyosis

Ichthyosis is a rare heterogeneous cutaneous disorder characterized by hyperkeratinization of the skin. They may be inherited or acquired following malnutrition, malignancy, or autoimmune disorders. Common forms of ichthyosis include lamellar ichthyosis (LI), X-linked ichthyosis, bullous ichthyosiform erythroderma, and ichthyosis vulgaris. LI may be associated with ectropion and eclabion and if poorly managed could result in vision loss. The case of a 7-month-old girl who presented with bilateral keratitis, panophthalmitis, and perforated right cornea is reported in this communication.
Methionine Dependence of Cancer

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed.
Temporary Relocation during Rest Periods: Relocation Stress and Other Factors Influence Hair Cortisol Concentrations in Horses

Simple Summary Horses are frequently transported and exposed to a new environment for sport competition or working tasks and must readapt to their original conditions after a temporary relocation. The objective of this study was to determine if a temporary relocation, and multiple factors associated with a rest period, affect the adrenal response through the analysis of hair cortisol concentrations (HCCs) in horses. Cortisol is a glucocorticoid released after the activation of the hypothalamic–pituitary–adrenal axis and its assessment is being increasingly used as a bioindicator of stress response. Results showed that changes in the daily routine of the animals, including a supposed rest period, increased the HCCs. However, the risk of using low statistical power due to the small sample size cannot be completely ruled out. The elevation in HCCs could be a consequence of the change in the horses’ environmental and routine conditions, which could, in turn, have an impact on their welfare. Abstract Horse transportation for temporary relocation during rest periods is a common and widespread practice among horse owners, either from sport competition or working tasks. This study aimed to determine the effect of a relocation period and the multiple factors associated with a rest period on hair cortisol concentrations (HCCs) in horses. Additionally, this study reports the seasonal effect on HCCs and hair growth over a year. Thirteen police horses, Pure Spanish stallions of various ages (5–13 y), were selected to participate in this study. Hair sample collection was carried out approximately every 30 d for seven months (Study 1) and a year (Study 2). Cortisol determinations were performed by enzyme immunoassay. Interestingly, Study 1 revealed that relocated horses (n = 4) exhibited elevated HCCs compared with control horses (n = 4) after the relocation period (p < 0.05). Study 2 (n = 5) showed higher HCCs during summer compared with autumn and winter, and higher hair growth rates in winter compared with the other seasons (p < 0.05). Relocated horses had higher HCCs, suggesting a change in their welfare status, probably related to the sudden change in their surrounding conditions. However, these results should be interpreted cautiously due to the low sample size used. The nature of the relationship between HCCs and horse welfare needs to be further examined.
The Prevalence of Burnout Syndrome among Nursing Staff Working at King Abdulaziz University Hospital, Jeddah, Saudi Arabia, 2017

Objective: Burnout syndrome is a state of decreased physical and psychological efficiency due to on-going exposure to occupational stressors. In addition, it is usually represented by three elements; emotional exhaustion, depersonalization, and reduced personal accomplishment. Whereas nurses play an integral part in the healthcare system and they are always liable to occupational burnout. We aimed this study to determine the prevalence of burnout syndrome among nursing staff working at King Abdulaziz University Hospital in Jeddah, Saudi Arabia. Methodology: This is a cross-sectional study survey which was conducted among 182 nurses (n=182) working at King Abdulaziz University Hospital in Jeddah, Saudi Arabia in 2017. Our data was collected using a self-demonstrated survey comprised of two parts; part one was sociodemographic and work-related questions, and part two was Maslach Burnout Inventory-Human Services Survey for Medical Personnel. Description of data findings was shown in this study. In addition, we used the definition of burnout syndrome to calculate the prevalence as; the composition of high emotional exhaustion (EE), high depersonalization (DP), and low personal accomplishment (PA). Findings: Regarding the socio-demographic data, 90.7% of the nurses were female, 92.3% were non- Saudi, and 68.7% were not satisfied with their income. Moreover and out of expectations, the prevalence of burnout syndrome in this study was 9.34%. However, emotional exhaustion alone was 59.89%. Conclusions: Nurses nowadays have a significant role in the healthcare system, and research like this will help to improve their individual-work relationship, resulting in a better evidence-based work environment. As we mentioned, the prevalence of burnout syndrome in our study was low, (out of what we expected compared to previous literature). However, the high level of emotional exhaustion gives us more opportunity to do more studies in this area.
Premenopausal Plasma Osteoprotegerin and Breast Cancer Risk: A Case–Control Analysis Nested within the Nurses' Health Study II

Background: Emerging evidence supports a role of the receptor activator of NF-κB (RANK) pathway in normal mammary gland development and breast carcinogenesis. Osteoprotegerin (OPG) is the endogenous decoy receptor for RANK-ligand (RANKL), which inhibits RANK-signaling. Whether OPG may be a biomarker of breast cancer risk remains unclear. Methods: We evaluated the association between plasma OPG and breast cancer risk in a case (n = 297)–control (n = 297) study nested within the Nurses' Health Study II. Cases were women who were cancer-free and premenopausal at blood collection who developed invasive breast cancer. OPG was quantified using an ELISA. Conditional logistic regression was used to estimate multivariable odds ratios (OR) and 95% confidence intervals (CI) for the association between OPG levels and breast cancer risk, adjusting for potential confounders. Unconditional logistic regression, additionally adjusting for matching factors, was used for stratified analyses. Results: Overall, there was no substantial evidence for an association between plasma OPG levels and breast cancer risk, although the point estimate for the highest (vs. lowest) quartile was below 1 (OR = 0.78; 95% CI, 0.46–1.33; Ptrend = 0.30). There was no evidence of heterogeneity by various reproductive, hormonal, or tumor characteristics, including hormone receptor status and grade (all Pheterogeneity ≥ 0.17). Conclusions: Findings from this prospective study do not provide substantial evidence for an association between circulating OPG and breast cancer risk among premenopausal women; however, we were underpowered in stratified analyses. Impact: Results do not provide strong evidence for OPG as a potential biomarker of breast cancer risk among premenopausal women.
Interferon Response in Hepatitis C Virus-Infected Hepatocytes: Issues to Consider in the Era of Direct-Acting Antivirals

When interferons (IFNs) bind to their receptors, they upregulate numerous IFN-stimulated genes (ISGs) with antiviral and immune regulatory activities. Hepatitis C virus (HCV) is a single-stranded, positive-sense RNA virus that affects over 71 million people in the global population. Hepatocytes infected with HCV produce types I and III IFNs. These endogenous IFNs upregulate a set of ISGs that negatively impact the outcome of pegylated IFN-α and ribavirin treatments, which were previously used to treat HCV. In addition, the IFNL4 genotype was the primary polymorphism responsible for a suboptimal treatment response to pegylated IFN-α and ribavirin. However, recently developed direct-acting antivirals have demonstrated a high rate of sustained virological response without pegylated IFN-α. Herein, we review recent studies on types I and III IFN responses in HCV-infected hepatocytes. In particular, we focused on open issues related to IFN responses in the direct-acting antiviral era.
Induced Systemic Resistance by a Plant Growth-Promoting Rhizobacterium Impacts Development and Feeding Behavior of Aphids

The effects of microorganisms on plant-insect interactions have usually been underestimated. While plant growth-promoting rhizobacteria (PGPR) are known to induce plant defenses, endosymbiotic bacteria hosted by herbivorous insects are often beneficial to the host. Here, we aimed to assess whether PGPR-induced defenses in broad bean plants impact the pea aphid, depending on its genotype and the presence of endosymbionts. We estimated aphid reproduction, quantified defense- and growth-related phytohormones by GC-MS, and measured different plant growth and physiology parameters, after PGPR treatment. In addition, we recorded the feeding behavior of aphids by electropenetrography. We found that the PGPR treatment of broad bean plants reduced the reproduction of one of the pea aphid clones. We highlighted a phenomenon of PGPR-induced plant defense priming, but no noticeable plant growth promotion. The main changes in aphid probing behavior were related to salivation events into phloem sieve elements. We suggest that the endosymbiont Hamiltonella defensa played a key role in plant-insect interactions, possibly helping aphids to counteract plant-induced resistance and allowing them to develop normally on PGPR-treated plants. Our results imply that plant- and aphid-associated microorganisms add greater complexity to the outcomes of aphid-plant interactions.