Miracle-dz/UniFAR-FTUs huggingface dataset:
Interferon-gamma Induces Melanogenesis Via Post-Translational Modification of Tyrosinase

Melanogenesis (melanin pigment production) in melanocytes is canonically stimulated by the alpha-melanocyte stimulating hormone (αMSH), which activates the cyclic-AMP-mediated expression of the melanocyte inducing transcription factor (MITF) and its downstream melanogenic genes, including the principal rate-limiting melanogenic enzyme tyrosinase (Tyr). Here we report that interferon-gamma (IFNG; type II interferon), but not IFN-alpha (a type I interferon), induces a noncanonical melanogenic pathway. Inhibition of IFNG pathway by the JAK inhibitor ruxolitinib or knocking out Stat1 abrogated the IFNG-induced melanogenesis. Interestingly, IFNG-induced melanogenesis was independent of MITF. IFNG markedly increased the Tyr protein expression but did not affect the mRNA expression, suggesting a post-translational regulatory mechanism. In contrast, IFNG had no effect on the expression of other melanogenesis-related proteins, e.g. tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct). Glycosidase digestion assays revealed that IFNG treatment increased the mature glycosylated form of Tyr, but not its de novo synthesis. Moreover, cycloheximide chase assay showed that degradation of Tyr was decreased in IFNG-treated cells. These results suggest that the IFNG-STAT1 pathway regulates melanogenesis via modulation of the post-translational processing and protein stability of Tyr. SIGNIFICANCE The canonical pathway that controls melanogenesis in melanocytes is activated by the alpha melanocyte stimulating hormone (αMSH) via its receptor MC1R, which activates the cyclic-AMP-mediated expression of the melanocyte master regulator MITF and its downstream target genes involved in the melanogenic process. Here we report a novel non-canonical melanogenic pathway that is mediated via the Interferon-gamma cytokine signaling. We show that this non-canonical pathway is independent of MITF-mediated gene expression, but rather functions via post-translational modification of the principal melanogenic enzyme Tyrosinase.
Adaptive coding of pain prediction error in the anterior insula

Background Understanding the mechanisms behind the influence of expectation and context on pain perception is crucial for improving analgesic treatments. Prediction error (PE) signals how much a noxious stimulus deviates from expectation and is therefore crucial for our understanding of pain perception. It is thought that the brain engages in ‘adaptive coding’ of pain PE, such that sensitivity to unexpected outcomes is modulated by contextual information. While there is behavioural evidence that pain is coded adaptively, and evidence that reward PE signals are coded adaptively, controversy remains regarding the underlying neural mechanism of adaptively-coded pain PEs. Methods A cued-pain task was performed by 19 healthy adults while undergoing FMRI scanning. BOLD responses to the task were tested using an axiomatic approach to identify areas that may code pain PE adaptively. Results The left dorsal anterior insula demonstrated a pattern of response consistent with adaptively-coded pain PE. Signals from this area were sensitive to both predicted pain magnitudes on the instigation of expectation, and the unexpectedness of pain delivery. Crucially however, the response at pain delivery was consistent with the local context of the pain stimulation, rather than the absolute magnitude of delivered pain, a pattern suggestive of an adaptively-coded PE signal. Conclusions The study advances our understanding of the neural basis of pain prediction. Alongside existing evidence that the periaqueductal grey codes pain PE and the posterior insula codes pain magnitude, the results highlight a distinct contribution of the left dorsal anterior insula in the processing of pain. Significance statement Although there is behavioural evidence that pain is coded adaptively, the neural mechanisms serving this process are not well understood. This study used functional MRI to provide the first evidence that the left dorsal anterior insula, an area associated with aversive learning, responds to pain in a manner consistent with the adaptive coding of pain prediction error. This study aids our understanding of the neural basis of subjective pain representation, and thus can contribute to the advancement of analgesic treatments.
The nitrogen phosphotransferase regulator PtsN (EIIANtr) regulates inorganic polyphosphate production in Escherichia coli

Inorganic polyphosphate (polyP) is synthesized by bacteria under stressful environmental conditions and acts by a variety of mechanisms to promote cell survival. While the kinase that synthesizes polyP (PPK, enocoded by the ppk gene) is well known, little is understood about how environmental stress signals lead to activation of this enzyme. Previous work has shown that the transcriptional regulators DksA, RpoN (σ54), and RpoE (σ24) positively regulate polyP production, but not ppk transcription, in Escherichia coli. In this work, we set out to examine the role of the alternative sigma factor RpoN and nitrogen starvation stress response pathways in controlling polyP synthesis in more detail. In the course of these experiments, we identified GlnG, GlrR, PhoP, PhoQ, RapZ, and GlmS as proteins that affect polyP production, and uncovered a central role for the nitrogen phosphotransferase regulator PtsN (EIIANtr) in a polyP regulatory pathway, acting upstream of DksA, downstream of RpoN, and apparently independently of RpoE. However, none of these regulators appears to act directly on PPK, and the mechanism(s) by which they modulate polyP production remain unclear. Unexpectedly, we also found that the pathways that regulate polyP production vary depending not only on the stress condition applied, but also on the composition of the media in which the cells were grown before exposure to polyP-inducing stress. These results constitute substantial progress towards deciphering the regulatory networks driving polyP production under stress, but highlight the remarkable complexity of this regulation and its connections to a broad range of stress-sensing pathways. IMPORTANCE Bacteria respond to changes in their environments with a complex regulatory network that controls the expression and activity of a wide range of effectors important for their survival. This stress response network is critical for the virulence of pathogenic bacteria and for the ability of all bacteria to grow in natural environments. Inorganic polyphosphate (polyP) is an evolutionarily ancient and almost universally conserved stress response effector that plays multiple roles in virulence, stress response, and survival in diverse organisms. This work provides new insights into the connections between well characterized nitrogen starvation and cell envelope stress response signaling pathways and the production of polyP in Escherichia coli.
Identification of electroporation sites in the complex lipid organization of the plasma membrane

The plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to a strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon, termed electroporation, is already utilized in many rapidly developing applications in medicine including gene therapy, cancer treatment, and treatment of cardiac arrythmias. However, the molecular mechanisms of electroporation are not yet sufficiently well understood; in particular, it is unclear where exactly pores form in the complex organization of the plasma membrane. In this study we combine coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis to identify how formation of pores depends on the local lipid organization. We show that pores do not form homogeneously across the membrane, but colocalize with domains that have specific features, the most important being high density of polyunsaturated lipids. We further show that knowing the lipid organization is sufficient to reliably predict poration sites with machine learning. However, by analysing poration kinetics with Bayesian survival analysis we then show that poration does not depend solely on local lipid arrangement, but also on membrane mechanical properties and the polarity of the electric field. Finally, we discuss how the combination of atomistic and coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis can guide the design of future experiments and help us to develop an accurate description of plasma membrane electroporation on the whole-cell level. Achieving this will allow us to shift the optimization of electroporation applications from blind trial-and-error approaches to mechanistic-driven design.
Validation of Death and Dying Distress Scale-Chinese Version and Prevalence of Death Anxiety Among Patients With Advanced Cancer

Purpose: Death anxiety is commonly experienced by individuals with advanced cancer who have a limited life expectancy. The Death and Dying Distress Scale (DADDS) is a validated measure that was created to capture this experience; but no Chinese version is available to date. We conducted a cross-sectional study to explore the psychometric properties of a Chinese version DADDS (DADDS-C) and address prevalence of death anxiety among patients with advanced cancer. Methods: Patients with advanced cancer were recruited from Peking University Cancer Hospital. Measures administered included: DADDS-C, Patient Health Questionnaire (PHQ-9), General Anxiety Disorder-7(GAD-7), Quality of Life at End of Life in Cancer (QUAL-EC), Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-sp). McDonald's Omega, Cronbach's alpha, Exploratory Factor Analysis and Confirmatory Factor Analysis were used to test DADDS-C's reliability and validity. Logistic regression analysis was used to identify risk factors for death anxiety. Results: Of 300 patients approached, 256 (85%) provided informed consent and completed the questionnaires. Of these participants, 43 (16.8%) had moderate death anxiety based on scores of ≥45 on the DADDS-C. Three factors (feeling shortness of time, dying and death distress, being a burden to others) explained 71.643% of shared variation with factor loadings ranging from 0.629 to 0.822. Cronbach's alpha was 0.939; Omega total was 0.959. DADDS-C had acceptable convergent and discriminant validity. Logistic regression analysis indicated that two factors (better relationship with healthcare providers and preparation for end of life) protected patients from death anxiety. Conclusion: DADDS-C is a valid tool for measuring death anxiety in Chinese patients with advanced cancer. The presence of at least moderate death anxiety in a substantial minority of these patients calls for screening for this symptom and for more routine psychological interventions to alleviate and prevent such distress in this population.
Compatibility Evaluation and Anatomical Observation of Melon Grafted Onto Eight Cucurbitaceae Species

Melon (Cucumis melo) is one of the top 10 fruits in the world, and its production often suffers due to soil-borne diseases. Grafting is an effective way to solve this problem. However, graft incompatibility between scion and rootstock limits the application of melon grafting. In this study, the melon was grafted onto eight Cucurbitaceae species (cucumber, pumpkin, melon, luffa, wax gourd, bottle gourd, bitter gourd, and watermelon), and graft compatibility evaluation and anatomical observation were conducted. Taking melon homo-grafted plants as control, melon grafted onto cucumber and pumpkin rootstocks was compatible, while melon grafted onto luffa, wax gourd, bottle gourd, bitter gourd, and watermelon rootstocks was incompatible based on the scion dry weight on day 42 after grafting. Meanwhile, we found that starch–iodine staining of scion stem base is an index to predict graft compatibility earlier, on day 14 after grafting. Further, microsection observations showed that there was more cell proliferation at graft junction of melon hetero-grafted combinations; vascular reconnection occurred in all graft combinations. However, excess callose deposited at graft junction resulted in the blockage of photosynthate transport, thus, leading to starch accumulation in scion stem base, and finally graft incompatibility. In addition, undegraded necrotic layer fragments were observed at graft junctions of melon grafted onto incompatible bitter gourd and watermelon rootstocks. The above results provide clues for the selection and breeding of compatible Cucurbitaceae rootstocks of melon and demonstrate that starch accumulation in scion base and callose deposition at graft junction is associated with melon graft compatibility.
Inflammatory Bowel Disease and Risk of Colorectal Cancer: An Overview From Pathophysiology to Pharmacological Prevention

Increased risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients has been attributed to long-standing chronic inflammation, with the contribution of genetic alterations and environmental factors such as the microbiota. Moreover, accumulating data indicate that IBD-associated CRC (IBD-CRC) may initiate and develop through a pathway of tumorigenesis distinct from that of sporadic CRC. This mini-review summarizes the current knowledge of IBD-CRC, focusing on the main mechanisms underlying its pathogenesis, and on the important role of immunomodulators and biologics used to treat IBD patients in interfering with the inflammatory process involved in carcinogenesis.
Serum Aquaporin 4-Immunoglobulin G Titer and Neuromyelitis Optica Spectrum Disorder Activity and Severity: A Systematic Review and Meta-Analysis

Background: Aquaporin 4-immunoglobulin G (AQP4-IgG) plays a major role in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). Seropositive status for this antibody has become one of the required indicators for NMOSD diagnosis. Objective: Our goal was to systematically review and perform a meta-analysis of the current works of literature evaluating the clinical relevance of serum AQP4-IgG titer in patients with NMOSD. We sought to determine whether AQP4-IgG could indicate disease activity or severity, in addition to its diagnostic value in NMOSD. Methods: Electronic databases were searched for published literature, yielding 4,402 hits. Of the 124 full articles screened, 17 were included in the qualitative analysis and 14 in the meta-analysis. Results: There were no significant differences in serum AQP4-IgG titers between the relapse and remission phases in patients with NMOSD [standard mean difference (SMD): 0.32, 95% CI (−0.10, 0.74), p = 0.14]. Subgroup meta-analysis of AQP4-IgG detected by cell-based assays (CBA), an AQP4-IgG testing method recommended by the 2015 international consensus diagnostic criteria for NMOSD, confirmed the aforementioned result [SMD: 0.27, 95% CI (−0.01, 0.55), p = 0.06]. Moreover, the serum AQP4-IgG titer was positively correlated with the number of involved spinal cord segments [correlation coefficient (COR): 0.70, 95% CI (0.28–0.89), p = 0.003] and the Expanded Disability Status Scale (EDSS) score [COR: 0.54, 95% CI (0.06-0.82), p = 0.03] in the attack phase in patients with NMOSD. Conclusions: The present study systematically assessed the association between serum AQP4-IgG titer and NMOSD activity and severity. The results demonstrated that the serum AQP4-IgG titer was not associated with disease activity but indicated the disease severity in the attack phase in patients with NMOSD. A further meta-analysis with a larger number of studies that employed standardized AQP4-IgG assays and detected attack–remission paired samples from the same patients with detailed medication information will be required to confirm our findings and shed more light on optimizing clinical AQP4-IgG monitoring. Systematic Review Registration: [www.crd. york.ac. uk/PROSPERO/display_record. php? RecordID=208209], PROSPERO, identifier [CRD42020208209].
Diagnostic Efficacy and Decision-Making Role of Preoperative Endoscopic Ultrasonography in Early Gastric Cancer

Objectives: Endoscopic ultrasonography (EUS) is the most commonly used method for T staging of early gastric cancer (EGC). However, the studies pertaining to EUS for staging EGC reported widely varied sensitivities and specificities. This study aimed to estimate the overall diagnostic accuracy of EUS for staging the depth of EGCs and to explore the influential factors. Methods: We retrospectively reviewed data from 208 consecutive patients with EGC, and all patients underwent EUS for estimating tumor invasion depth, followed by either curative surgery or endoscopic submucosal dissection (ESD). The diagnostic accuracy of EUS was evaluated by comparing the final histologic results of resected specimens. The correlation between accuracy of EUS and characteristics of EGC lesion was analyzed. Results: A total of 211 EGC lesions in 208 patients were included. The overall diagnostic accuracy of EUS in assessing the tumor invasion depth of EGC was 55.9%. Multivariate analysis showed that submucosal invasion (OR 2.615; 95% CI 1.203–5.684, P = 0.015) was independently associated with misdiagnosis of the depth of EGC and 0-III type lesions (OR 31.495; 95% CI 2.083–476.256, P = 0.013) were an independent risk factor for over-diagnosis of invasion depth by EUS. However, EUS was only suitable for lesions within absolute indications for endoscopic resection. Conclusions: The overall accuracy of EUS in diagnosing invasion depth of EGC was relatively low. Thus, EUS is not necessary routinely for determining the therapeutic strategy for EGC.
The Efficacy and Tolerability of Selective Serotonin Reuptake Inhibitors for Motor Recovery in Non-depressed Patients After Acute Stroke: A Meta-Analysis

Objective: To explore the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) for motor recovery in non-depressed patients after acute stroke. Methods: According to the predefined retrieval strategy, multiple electronic databases were searched for randomized controlled trials (RCTs) that met the inclusion criteria. The primary efficacy outcome was measured by Fugl-Meyer Motor Scale (FMMS) score and the indicators of tolerability included withdrawal rate and the incidence of adverse events (AEs). Results: 10RCTs were included, the pooled analyses showed patients who received fluoxetine (endpoint: MD = 21.17, 95% CI 14.13–28.21, P < 0.00001; mean change: MD = 16.27, 95% CI 10.05–22.50, P < 0.00001) and citalopram (endpoint: MD = 22.93, 95% CI 11.13–34.73, P = 0.0001; mean change: MD = 24.06, 95% CI 10.47–37.65, P = 0.0005) experienced greater improvement in FMMS score. There was no evident difference in total withdrawal rate (fluoxetine: OR = 1.11, 95% CI 0.90–1.27, P = 1.38; citalopram: OR = 0.94, 95% CI 0.69–1.28, P = 0.71; escitalopram: OR = 0.87, 95% CI 0.58–1.28, P = 0.47) between two groups. Besides, the incidence of hyponatremia (OR = 2.01, 95% CI 1.16–3.50, P = 0.01), seizure (OR = 1.46, 95% CI 1.03–2.08, P = 0.04) and fracture (OR = 2.34, 95% CI 1.61–3.40, P < 0.00001) in the fluoxetine group was higher than in the placebo group. Conclusions: Fluoxetine and citalopram can promote motor recovery in non-depressed patients with acute stroke, but it is necessary to pay attention to the possible AEs of fluoxetine, such as hyponatremia, seizure and fracture. Systematic Review Registration: PROSPERO, identifier [CRD42021227452].
Iron Isotopic Composition of Biological Standards Relevant to Medical and Biological Applications

Iron isotopes are fractionated by multiple biological processes, which offers a novel opportunity to study iron homeostasis. The determination of Fe isotope composition in biological samples necessitates certified biological reference materials with known Fe isotopic signature in order to properly assess external reproducibility and data quality between laboratories. We report the most comprehensive study on the Fe isotopic composition for widely available international biological reference materials. They consist of different terrestrial and marine animal organs (bovine, porcine, tuna, and mussel) as well as apple leaves and human hair (ERC-CE464, NIST1515, ERM-DB001, ERM-BB186, ERM-BB184, ERM-CE196, BCR668, ERM-BB185, ERM-BB124). Previously measured Fe isotopic compositions were available for only two of these reference materials (ERC-CE464 tuna fish and ERM-BB186 pig kidney) and these literature data are in excellent agreement with our data. The Fe isotopic ratios are reported as the permil deviation of the 56Fe/54Fe ratio from the IRMM-014 standard. All reference materials present δ56Fe ranging from −2.27 to −0.35%0. Combined with existing data, our results suggest that animal models could provide useful analogues of the human body regarding the metabolic pathways affecting Fe isotopes, with many potential applications to medicine.
Thermal Performance Curves Are Shaped by Prior Thermal Environment in Early Life

Understanding links between thermal performance and environmental variation is necessary to predict organismal responses to climate change, and remains an ongoing challenge for ectotherms with complex life cycles. Distinct life stages can differ in thermal sensitivity, experience different environmental conditions as development unfolds, and, because stages are by nature interdependent, environmental effects can carry over from one stage to affect performance at others. Thermal performance may therefore respond to carryover effects of prior thermal environments, yet detailed insights into the nature, strength, and direction of those responses are still lacking. Here, in an aquatic ectotherm whose early planktonic stages (gametes, embryos, and larvae) govern adult abundances and dynamics, we explore the effects of prior thermal environments at fertilization and embryogenesis on thermal performance curves at the end of planktonic development. We factorially manipulate temperatures at fertilization and embryogenesis, then, for each combination of prior temperatures, measure thermal performance curves for survival of planktonic development (end of the larval stage) throughout the performance range. By combining generalized linear mixed modeling with parametric bootstrapping, we formally estimate and compare curve descriptors (thermal optima, limits, and breadth) among prior environments, and reveal carryover effects of temperature at embryogenesis, but not fertilization, on thermal optima at completion of development. Specifically, thermal optima shifted to track temperature during embryogenesis, while thermal limits and breadth remained unchanged. Our results argue that key aspects of thermal performance are shaped by prior thermal environment in early life, warranting further investigation of the possible mechanisms underpinning that response, and closer consideration of thermal carryover effects when predicting organismal responses to climate change.