Miracle-dz/UniFAR-FTUs huggingface dataset:
Acacia catechu (L.f.) Willd and Scutellaria baicalensis Georgi extracts suppress LPS‐induced pro‐inflammatory responses through NF‐кB, MAPK, and PI3K‐Akt signaling pathways in alveolar epithelial type II cells

Acacia catechu (L.f.) Willd (ACW) and Scutellaria baicalensis Georgi (SBG) are one of the most famous couplet Chinese medicines, widely used for treating infantile cough, phlegm, and fever caused by pulmonary infection. However, the underlying molecular mechanism of their anti‐inflammatory activity has not been determined. The aim of this study was to evaluate the protective effect of this couplet Chinese medicines (ACW‐SBG) on lipopolysaccharide (LPS)‐induced inflammatory responses in acute lung injury (ALI) model of rats and the potential molecular mechanisms responsible for anti‐inflammatory activities in alveolar epithelial type II cells (AEC‐II). Standardization of the 70% ethanol extract of ACW and SBG was performed by using a validated reversed‐phase high‐pressure liquid chromatography method. Rats were pretreated with ACW‐SBG for 7 days prior to LPS challenge. We assessed the effects of ACW‐SBG on the LPS‐induced production of tumor necrosis factor alpha (TNF‐α) and interleukin 1 beta (IL‐1β) in the bronchoalveolar lavage fluid (BALF). The wet‐to‐dry weight ratio was calculated, and hematoxylin and eosin staining of lung tissue was performed. Cell viability of AEC‐II was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. Real‐time quantitative reverse transcription polymerase chain reaction assay was carried out to quantify the relative gene expression of TNF‐α and IL‐1β in AEC‐II. The western blotting analysis was executed to elucidate the expression of mediators linked to nuclear factor‐kappa B (NF‐κB), mitogen‐activated protein kinase (MAPK), and phosphatidylinositol‐3 kinase‐protein kinase B (PI3K‐Akt) signaling pathways. ACW‐SBG significantly decreased lung wet‐to‐dry weight ratio, ameliorated LPS‐induced lung histopathological changes, and reduced the release of inflammatory mediators such as TNF‐α and IL‐1β in BALF. In AEC‐II, we found that the expression of TNF‐α mRNA was also inhibited by ACW‐SBG. ACW‐SBG blocked NF‐κB activation by preventing the phosphorylation of NF‐κB (p65) as well as the phosphorylation and degradation of the inhibitor of kappa B kinase. ACW‐SBG extracts also inhibited the phosphorylation of respective MAPKs (c‐Jun N‐terminal kinase, extracellular signal‐regulated kinase, and p38) as well as Akt. The present study demonstrated that ACW‐SBG played a potent anti‐inflammatory role in LPS‐induced ALI in rats. The potential molecular mechanism was involved in attenuating the NF‐κB, MAPKs, and PI3K‐Akt signaling pathways in LPS‐induced AEC‐II.
Homeobox B9 integrates bone morphogenic protein 4 with inflammation at atheroprone sites

Abstract Aims Atherosclerosis develops near branches and bends of arteries that are exposed to disturbed blood flow which exerts low wall shear stress (WSS). These mechanical conditions alter endothelial cells (EC) by priming them for inflammation and by inducing turnover. Homeobox (Hox) genes are developmental genes involved in the patterning of embryos along their anterior–posterior and proximal–distal axes. Here we identified Hox genes that are regulated by WSS and investigated their functions in adult arteries. Methods and results EC were isolated from inner (low WSS) and outer (high WSS) regions of the porcine aorta and the expression of Hox genes was analysed by quantitative real-time PCR. Several Hox genes (HoxA10, HoxB4, HoxB7, HoxB9, HoxD8, HoxD9) were significantly enriched at the low WSS compared to the high WSS region. Similarly, studies of cultured human umbilical vein EC (HUVEC) or porcine aortic EC revealed that the expression of multiple Hox genes (HoxA10, HoxB9, HoxD8, HoxD9) was enhanced under low (4 dyn/cm2) compared to high (13 dyn/cm2) WSS conditions. Gene silencing studies identified Hox genes (HoxB9, HoxD8, HoxD9) that are positive regulators of inflammatory molecule expression in EC exposed to low WSS, and others (HoxB9, HoxB7, HoxB4) that regulated EC turnover. We subsequently focused on HoxB9 because it was strongly up-regulated by low WSS and, uniquely, was a driver of both inflammation and proliferation. At a mechanistic level, we demonstrate using cultured EC and murine models that bone morphogenic protein 4 (BMP4) is an upstream regulator of HoxB9 which elicits inflammation via induction of numerous inflammatory mediators including TNF and downstream NF-κB activation. Moreover, the BMP4-HoxB9-TNF pathway was potentiated by hypercholesterolaemic conditions. Conclusions Low WSS induces multiple Hox genes that control the activation state and turnover of EC. Notably, low WSS activates a BMP4-HoxB9-TNF signalling pathway to initiate focal arterial inflammation, thereby demonstrating integration of the BMP and Hox systems in vascular pathophysiology.
Different dynamics of Usutu virus infections in Austria and Hungary, 2017–2018

Abstract Usutu virus (USUV), a mosquito‐borne flavivirus closely related to West Nile virus, emerged in Austria in 2001, when it caused a considerable mass‐mortality of Eurasian blackbirds. Cases in birds increased until 2003 and quickly declined thereafter, presumably due to developing herd immunity. Since 2006, no further cases were recorded, until two blackbirds were tested positive in 2016. In Hungary, USUV first appeared in 2005 and has caused only sporadic infections since then. Initially, the only genetic USUV lineage found across both countries was Europe 1. This changed in 2015/2016, when Europe 2 emerged, which has since then become the prevalent lineage. Due to dispersal of these strains and introduction of new genetic lineages, USUV infections are now widespread across Europe. In 2009, the first cases of USUV‐related encephalitis were described in humans, and the virus has been frequently detected in blood donations since 2016. To monitor USUV infections among the Austrian wild bird population in 2017/2018, 86 samples were investigated by RT‐PCR. In 67 of them, USUV nucleic acid was detected (17 in 2017, 50 in 2018). The majority of succumbed birds were blackbirds, found in Vienna and Lower Austria. However, the virus also spread westwards to Upper Austria and southwards to Styria and Carinthia. In Hungary, 253 wild birds were examined, but only six of them were infected with USUV (five in 2017, one in 2018). Thus, in contrast to the considerable increase in USUV‐associated bird mortality in Austria, the number of infections in Hungary declined after a peak in 2016. Except for one case of USUV lineage Africa 3 in Austria in 2017, Europe 2 remains the most prevalent genetic lineage in both countries. Since USUV transmission largely depends on temperature, which affects vector populations, climate change may cause more frequent USUV outbreaks in the future.
The counter-intuitive role of the neutrophil in the acute respiratory distress syndrome.

INTRODUCTION Neutrophils are the primary effectors of the innate immune system but are profoundly histotoxic cells. The acute respiratory distress syndrome (ARDS) is considered to be a prime example of neutrophil-mediated tissue injury. SOURCES OF DATA The information presented in this review is acquired from the published neutrophil cell biology literature and the longstanding interest of the senior authors in ARDS pathogenesis and clinical management. AREAS OF AGREEMENT Investigators in the field would agree that neutrophils accumulate in high abundance in the pulmonary microcirculation, lung interstitium and alveolar airspace of patients with ARDS. ARDS is also associated with systemic neutrophil priming and delayed neutrophil apoptosis and clearance of neutrophils from the lungs. In animal models, reducing circulating neutrophil numbers ameliorates lung injury. AREAS OF CONTROVERSY Areas of uncertainty include how neutrophils get stuck in the narrow pulmonary capillary network-whether this reflects changes in the mechanical properties of primed neutrophils alone or additional cell adhesion molecules, the role of neutrophil sub-sets or polarization states including pro-angiogenic and low-density neutrophils, whether neutrophil extracellular trap (NET) formation is beneficial (through bacterial capture) or harmful and the potential for neutrophils to participate in inflammatory resolution. The latter may involve the generation of specialized pro-resolving molecules (SPMs) and MMP-9, which is required for adequate matrix processing. GROWING POINTS Different and possibly stable endotypes of ARDS are increasingly being recognized, yet the relative contribution of the neutrophil to these endotypes is uncertain. There is renewed and intense interest in understanding the complex 'new biology' of the neutrophil, specifically whether this cell might be a valid therapeutic target in ARDS and other neutrophil-driven diseases and developing understanding of ways to enhance the beneficial role of the neutrophil in the resolution phase of ARDS. AREAS TIMELY FOR DEVELOPING RESEARCH Aside from treatment of the precipitating causes of ARDS, and scrupulous fluid, infection and ventilation management, there are no pharmacological interventions for ARDS; this represents an urgent and unmet need. Therapies aimed at reducing overall neutrophil numbers risk secondary infection; hence better ways are needed to reverse the processes of neutrophil priming activation, hyper-secretion and delayed apoptosis while enhancing the pro-resolution functions of the neutrophil.
Butterfly mimicry polymorphisms highlight phylogenetic limits of gene re-use in the evolution of diverse adaptations.

Some genes have repeatedly been found to control diverse adaptations in a wide variety of organisms. Such gene re-use reveals the diversity of phenotypes these unique genes control, but also the composition of developmental gene networks and the genetic routes available to and taken by organisms during adaptation. However, the causes of gene re-use remain unclear. A small number of large-effect Mendelian loci control a huge diversity of mimetic butterfly wing color patterns, but reasons for their re-use are difficult to identify because the genetic basis of mimicry has been studied in two systems with correlated factors: female-limited Batesian mimicry in Papilio swallowtails (Papilionidae) and non-sex-limited Müllerian mimicry in Heliconius longwings (Nymphalidae). Here we break the correlation between phylogenetic relationship and sex-limited mimicry by identifying loci controlling female-limited mimicry polymorphism Hypolimnas misippus (Nymphalidae) and non-sex-limited mimicry polymorphism in Papilio clytia (Papilionidae). The P. clytia polymorphism is controlled by the genome region containing the gene cortex, the classic P supergene in Heliconius numata, and loci controlling color pattern variation across Lepidoptera. In contrast, female-limited mimicry polymorphism in Hypolimnas misippus is associated with a locus not previously implicated in color patterning. Thus, while many species repeatedly converged on cortex and its neighboring genes over 120 million years of evolution of diverse color patterns, female-limited mimicry polymorphisms each evolved using a different gene. Our results support conclusions that gene re-use occurs mainly within ∼10 million years and highlight the puzzling diversity of genes controlling seemingly complex female-limited mimicry polymorphisms.
IRES-mediated cap-independent translation, a path leading to hidden proteome

Abstract Most eukaryotic mRNAs are translated in a cap-dependent fashion; however, under stress conditions, the cap-independent translation driven by internal ribosomal entry sites (IRESs) can serve as an alternative mechanism for protein production. Many IRESs have been discovered from viral or cellular mRNAs to promote ribosome assembly and initiate translation by recruiting different trans-acting factors. Although the mechanisms of translation initiation driven by viral IRESs are relatively well understood, the existence of cellular IRESs is still under debate due to the limitations of translation reporter systems used to assay IRES activities. A recent screen identified > 1000 putative IRESs from viral and human mRNAs, expanding the scope and mechanism for cap-independent translation. Additionally, a large number of circular RNAs lacking free ends were identified in eukaryotic cells, many of which are found to be translated through IRESs. These findings suggest that IRESs may play a previously unappreciated role in driving translation of the new type of mRNA, implying a hidden proteome produced from cap-independent translation.
Myeloid loss of Beclin 1 promotes PD-L1hiprecursor B Cell lymphoma development.

Beclin 1 (Becn1) is a key molecule of the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of Becn1 homozygous deficient mice, the precise mechanisms and cell-type-specific role of Becn1 in the regulation of inflammation and tumor immunity remain elusive. Here, we report that myeloid-deficient Becn1 (Becn1ΔM) mice develop neutrophilia and hypersusceptible to LPS-induced septic shock, with a high risk of developing spontaneous precursor (pre)-B cell lymphoma with elevated expressions of immunosuppressive molecules PD-L1 and IL-10. Becn1 deficiency results in stabilization of neutrophil MEKK3, aberrant p38 activation, and neutrophil-B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil-B cell interplay leads to activations of IL-21/STAT3/IRF1 and CD40L/ERK signaling, together regulates the programmed death ligand 1 (PD-L1) expression, and suppresses CD8+ T cell function. Ablation of p38 in Becn1ΔM mice prevents neutrophil-inflammation and B cell tumorigenesis. Importantly, low Becn1 expression in human neutrophils correlates with PD-L1 levels in pre-B ALL patients. Our findings have identified myeloid Becn1 as a therapeutic target of cancer immunity and immunotherapy for pre-B lymphomas.
US Food and Drug Administration Approvals of Drugs and Devices Based on Nonrandomized Clinical Trials

Key Points Question Are US Food and Drug Administration (FDA) decisions to approve new therapies based on nonrandomized clinical trials (non-RCTs) associated with the sizes of treatment effects? Findings In this systematic review and meta-analysis, the magnitude of treatment effects was approximately 2.5-fold higher among treatments that were approved based on non-RCTs than among treatments that required further testing in RCTs, but only approximately 1% to 2% of the drugs approved by the FDA based on non-RCTs displayed so-called dramatic effects. No clear threshold of magnitude of treatment effect above which the FDA would not request further RCTs was found. Meaning Based on this study’s findings, the size of therapeutic effects was important to FDA approval of treatments based on non-RCTs.
Quantifying the nativeness of antibody sequences using long short-term memory networks

Abstract Antibodies often undergo substantial engineering en route to the generation of a therapeutic candidate with good developability properties. Characterization of antibody libraries has shown that retaining native-like sequence improves the overall quality of the library. Motivated by recent advances in deep learning, we developed a bi-directional long short-term memory (LSTM) network model to make use of the large amount of available antibody sequence information, and use this model to quantify the nativeness of antibody sequences. The model scores sequences for their similarity to naturally occurring antibodies, which can be used as a consideration during design and engineering of libraries. We demonstrate the performance of this approach by training a model on human antibody sequences and show that our method outperforms other approaches at distinguishing human antibodies from those of other species. We show the applicability of this method for the evaluation of synthesized antibody libraries and humanization of mouse antibodies.
Histopathological evaluation of minor salivary gland papillary–cystic tumours: focus on genetic alterations in sialadenoma papilliferum and intraductal papillary mucinous neoplasm

Minor salivary gland tumours showing a predominant papillary–cystic structure are rare, and constitute a mixture of various types of neoplasm; thus, the histopathological assessment of these tumours poses a significant diagnostic challenge. We aimed to delineate the histological characteristics of these tumours and further mutational aspects with a particular focus on sialadenoma papilliferum (SP) and intraductal papillary mucinous neoplasm (IPMN).
High Risk of Influenza Virus Infection Among Swine Workers: Examining a Dynamic Cohort in China

Abstract Background China is thought to be a hotspot for zoonotic influenza virus emergence, yet there have been few prospective studies examining the occupational risks of such infections. Methods We present the first 2 years of data collected from a 5-year, prospective, cohort study of swine-exposed and -unexposed participants at 6 swine farms in China. We conducted serological and virological surveillance to examine evidence for swine influenza A virus infection in humans. Results Of the 658 participants (521 swine-exposed and 137 swine-unexposed), 207 (31.5%) seroconverted against at least 1 swine influenza virus subtype (swine H1N1 or H3N2). Swine-exposed participants’ microneutralization titers, especially those enrolled at confined animal feeding operations (CAFOs), were higher against the swine H1N1 virus than were other participants at 12 and 24 months. Despite elevated titers, among the 187 study subjects for whom we had complete follow-up, participants working at swine CAFOs had significantly greater odds of seroconverting against both the swine H1N1 (odds ratio [OR] 19.16, 95% confidence interval [CI] 3.55–358.65) and swine H3N2 (OR 2.97, 95% CI 1.16–8.01) viruses, compared to unexposed and non-CAFO swine workers with less intense swine exposure. Conclusions While some of the observed increased risk against swine viruses may have been explained by exposure to human influenza strains, study data suggest that even with elevated preexisting antibodies, swine-exposed workers were at high risk of infection with enzootic swine influenza A viruses.
Epigenetic variation for agronomic improvement: an opportunity for vegetatively propagated crops

Crop breeding has been historically associated with genetic variation because genetic variants harboring traits with agronomic value can be artificially generated (e.g., hybrid crosses) and selected at the population (e.g., mass selection) or individual level (e.g., single seed descent) through classical crop breeding methods. Crop genetic improvement, however, has become increasingly difficult, and crop genetic diversity has been declining at an alarming rate, threatening world food security and sustainable development (Esquinas‐Alcázar, 2005). The stakes are high to find solutions. Cross breeding with closely related wild species, genomic selection informed by molecular markers and creation of genetically modified organisms are examples of ongoing research developments for crop improvement. Another potential research approach that is currently arising is epigenetics (Kenchanmane Raju and Niederhuth, 2018). Epigenetic variants in crops might represent an additional and timely resource for crop breeding. In this essay, we do not aim to comprehensively review the potential interest of epigenetics in agriculture but to outline the nature of some possible drawbacks, such as the instability of epigenetic marks, and opportunities, for example, clonal multiplication, associated with this potential. EPIGENETIC VARIANTS OF INTEREST FOR CROP BREEDING: WHERE ARE WE NOW?
Suppression of Blue Light at Night Ameliorates Metabolic Abnormalities by Controlling Circadian Rhythms.

Purpose Light-emitting diodes that emit high-intensity blue light are associated with blue-light hazard. Here, we report that blue light disturbs circadian rhythms by interfering with the clock gene in the suprachiasmatic nucleus (SCN) and that suppression of blue light at night ameliorates metabolic abnormalities by controlling circadian rhythms. Methods C57BL/6J mice were exposed to 10-lux light for 30 minutes at Zeitgeber time 14 for light pulse with blue light or blue-light cut light to induce phase shift of circadian rhythms. Phase shift, clock gene expression in SCN, and metabolic parameters were analyzed. In the clinical study, healthy participants wore blue-light shield eyewear for 2 to 3 hours before bed. Anthropometric data analyses, laboratory tests, and sleep quality questionnaires were performed before and after the study. Results In mice, phase shift induced with a blue-light cut light pulse was significantly shorter than that induced with a white light pulse. The phase of Per2 expression in the SCN was also delayed after a white light pulse. Moreover, blood glucose levels 48 hours after the white light pulse were higher than those after the blue-cut light pulse. Irs2 expression in the liver was decreased with white light but significantly recovered with the blue-cut light pulse. In a clinical study, after 1 month of wearing blue-light shield eyeglasses, there were improvements in fasting plasma glucose levels, insulin resistance, and sleep quality. Conclusions Our results suggest that suppression of blue light at night effectively maintains circadian rhythms and metabolism.
Hemodynamic Stability and Contrast Nephropathy Development in Patients With Acute Myocardial Infarction

We read the article entitled “Contrast-Induced Nephropathy and Long-Term Mortality After Percutaneous Coronary Intervention in Patients with Acute Myocardial Infarction” by Sun et al with interest. They found that contrast-induced nephropathy (CIN) was an independent predictor for long-term mortality, even in patients with a stable hemodynamic status and preserved left ventricular ejection fraction (LVEF). Meanwhile, renal insufficiency played an important role in the prognosis of CIN, and the use of b-blockers was a protective factor. They also proposed that the adverse outcome of CIN did not depend on cardiac function. The LVEF parameter used by the authors in the definition of hemodynamic stability is not sufficient according to current heart failure guidelines. New York Heart Association functional status, volume status, diastolic heart failure, or combined (systolic and diastolic heart failure) heart failure was not mentioned in the text. All of these abovementioned parameters are closely related to the patients’ cardiovascular status. In addition, the development of heart failure is more common in patients with anterior myocardial infarction (MI), but there is no information about MI typing in the text. ORCID iDs
Maternal Envelope gp41 Ectodomain-Specific Antibodies Are Associated With Increased Mother-to-Child Transmission of Human Immunodeficiency Virus-1

Abstract Mother-to-child transmission of human immunodeficiency virus (HIV) occurs in the setting of maternal and passively acquired antibodies, providing a unique window into immune correlates of HIV risk. We compared plasma antibody binding to HIV antigens between 51 nontransmitting mother-infant pairs and 21 transmitting mother-infant pairs. Plasma antibody binding to a variety of gp41 ectodomain-containing antigens was associated with increased odds of transmission. Understanding the reasons why gp41 ectodomain-targeting antibodies are associated with transmission risk will be important in determining whether they can directly enhance infection or whether their presence reflects a redirecting of the humoral response away from targeting more protective epitopes.