Miracle-dz/UniFAR-FTUs huggingface dataset:
Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics

Pro-inflammatory signaling mediated by Toll-like receptor 4 (TLR4)/myeloid differentiation-2 (MD-2) complex plays a crucial role in the instantaneous protection against infectious challenge and largely contributes to recovery from Gram-negative infection. Activation of TLR4 also boosts the adaptive immunity which is implemented in the development of vaccine adjuvants by application of minimally toxic TLR4 activating ligands. The modulation of pro-inflammatory responses via the TLR4 signaling pathway was found beneficial for management of acute and chronic inflammatory disorders including asthma, allergy, arthritis, Alzheimer disease pathology, sepsis, and cancer. The TLR4/MD-2 complex can recognize the terminal motif of Gram-negative bacterial lipopolysaccharide (LPS)—a glycophospholipid lipid A. Although immense progress in understanding the molecular basis of LPS-induced TLR4-mediated signaling has been achieved, gradual, and predictable TLR4 activation by structurally defined ligands has not yet been attained. We report on controllable modulation of cellular pro-inflammatory responses by application of novel synthetic glycolipids—disaccharide-based lipid A mimetics (DLAMs) having picomolar affinity for TLR4/MD-2. Using crystal structure inspired design we have developed endotoxin mimetics where the inherently flexible β(1 → 6)-linked diglucosamine backbone of lipid A is replaced by a conformationally restricted α,α-(1↔1)-linked disaccharide scaffold. The tertiary structure of the disaccharide skeleton of DLAMs mirrors the 3-dimensional shape of TLR4/MD-2 bound E. coli lipid A. Due to exceptional conformational rigidity of the sugar scaffold, the specific 3D organization of DLAM must be preserved upon interaction with proteins. These structural factors along with specific acylation and phosphorylation pattern can ensure picomolar affinity for TLR4 and permit efficient dimerization of TLR4/MD-2/DLAM complexes. Since the binding pose of lipid A in the binding pocket of MD-2 (±180°) is crucial for the expression of biological activity, the chemical structure of DLAMs was designed to permit a predefined binding orientation in the binding groove of MD-2, which ensured tailored and species-independent (human and mice) TLR4 activation. Manipulating phosphorylation and acylation pattern at the sugar moiety facing the secondary dimerization interface allowed for adjustable modulation of the TLR4-mediated signaling. Tailored modulation of cellular pro-inflammatory responses by distinct modifications of the molecular structure of DLAMs was attained in primary human and mouse immune cells, lung epithelial cells and TLR4 transfected HEK293 cells.
PKCα Is Recruited to Staphylococcus aureus-Containing Phagosomes and Impairs Bacterial Replication by Inhibition of Autophagy

Hijacking the autophagic machinery is a key mechanism through which invasive pathogens such as Staphylococcus aureus replicate in their host cells. We have previously demonstrated that the bacteria replicate in phagosomes labeled with the autophagic protein LC3, before escaping to the cytoplasm. Here, we show that the Ca2+-dependent PKCα binds to S. aureus-containing phagosomes and that α-hemolysin, secreted by S. aureus, promotes this recruitment of PKCα to phagosomal membranes. Interestingly, the presence of PKCα prevents the association of the autophagic protein LC3. Live cell imaging experiments using the PKC activity reporter CKAR reveal that treatment of cells with S. aureus culture supernatants containing staphylococcal secreted factors transiently activates PKC. Functional studies reveal that overexpression of PKCα causes a marked inhibition of bacterial replication. Taken together, our data identify enhancing PKCα activity as a potential approach to inhibit S. aureus replication in mammalian cells.
Assessing the Regulatory Functions of LncRNA SNHG11 in Gastric Cancer Cell Proliferation and Migration

The aim of this study was to assess the regulatory functions of SNHG11 in gastric cancer (GC) cell proliferation and migration. Dual-luciferase reporter assay and bioinformatics prediction [starBase (http://starbase.sysu.edu.cn/) and TargetScan (http://www.targetscan.org)] indicated that SNHG11 functions as a miR-184 sponge that can directly act on CDC25A. Compared with normal healthy gastric tissue and mucosal epithelial cell GES-1, SNHG11 and CDC25A expressions were dramatically increased in GC samples and cell lines, whereas microRNA-184 (miR-184) levels were reduced. SNHG11 silencing led to increased miR-184 and reduced CDC25A, whereas miR-184 downregulation recovered the expression of CDC25A. Additionally, miR-184 upregulation also played a role in regulating CDC25A ablation. Then, SNHG11 was silenced or miR-184 was upregulated in two GC cells (SGC-7901 and MKN-28). SNHG11 silencing and miR-184 upregulation caused a notable decrease in GC cell growth and proliferation and increased the apoptotic level of GC cells. Furthermore, SNHG11 silencing and miR-184 upregulation contributed to a decreased migration capacity of GC cells. Downregulated miR-184 expression in SNHG11 silenced GC cells showed that miR-184 inhibition reversed the effect of SNHG11 silencing on the growth, proliferation, apoptosis, and migration of GC cells. Moreover, in vivo xenograft experiments demonstrated that SNHG11 knockdown can inhibit tumor growth. These observations confirmed that SNHG11 acts as an oncogene, whereas miR-194 served as a tumor suppressor in GC development. SNHG11 may provide a new biomarker for GC diagnosis, treatment, and prognosis.
Screening for Mycobacterium tuberculosis Infection Using Beijing/K Strain-Specific Peptides in a School Outbreak Cohort

Background The Beijing strain of Mycobacterium tuberculosis (M. tb) has been most frequently isolated from TB patients in South Korea, and the hyper-virulent Beijing/K genotype is associated with TB outbreaks. To examine the diagnostic potential of Beijing/K-specific peptides, we performed IFN-γ release assays (IGRA) using a MTBK antigen tube containing Beijing/K MTBK_24800, ESAT-6, and CFP-10 peptides in a cohort studied during a school TB outbreak. Methods A total of 758 contacts were investigated for M. tb infection, and 43 contacts with latent TB infection (LTBI) and 25 active TB patients were enrolled based on serial screening with QuantiFERON-TB Gold In-Tube tests followed by clinical examinations. Blood collected in MTBK antigen tubes was utilized for IGRA and multiplex cytokine bead arrays. Immune responses were retested in 24 patients after TB treatment, and disease progression was investigated in subjects with LTBI. Results Total proportions of active disease and LTBI during the outbreak were 3.7% (28/758) and 9.2% (70/758), respectively. All clinical isolates had a Beijing/K M. tb genotype. IFN-γ responses to the MTBK antigen identified M. tb infection and distinguished between active disease and LTBI. After anti-TB treatment, IFN-γ responses to the MTBK antigen were significantly reduced, and strong TNF-α responses at diagnosis were dramatically decreased. Conclusions MTBK antigen-specific IFN-γ has diagnostic potential for differentiating M. tb infection from healthy controls, and between active TB and LTBI as well. In addition, TNF-α is a promising marker for monitoring therapeutic responses. These data provide informative readouts for TB diagnostics and vaccine studies in regions where the Beijing/K strain is endemic.
Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies

Hepatocellular carcinoma (HCC) is the most common liver tumor and among the deadliest cancers worldwide. Advanced HCC overall survival is meager and has not improved over the last decade despite approval of several tyrosine kinase inhibitors (TKi) for first and second-line treatments. The recent approval of immune checkpoint inhibitors (ICI) has revolutionized HCC palliative care. Unfortunately, the majority of HCC patients fail to respond to these therapies. Here, we elaborate on the immune landscapes of the normal and cirrhotic livers and of the unique HCC tumor microenvironment. We describe the molecular and immunological classifications of HCC, discuss the role of specific immune cell subsets in this cancer, with a focus on myeloid cells and pathways in anti-tumor immunity, tumor promotion and immune evasion. We also describe the challenges and opportunities of immunotherapies in HCC and discuss new avenues based on harnessing the anti-tumor activity of myeloid, NK and γδ T cells, vaccines, chimeric antigen receptors (CAR)-T or -NK cells, oncolytic viruses, and combination therapies.
Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers

To date, almost all solid malignancies have implicated insulin-like growth factor (IGF) signalling as a driver of tumour growth. However, the remarkable level of crosstalk between sex hormones, the IGF-1 receptor (IGF-1R) and its ligands IGF-1 and 2 in endocrine driven cancers is incompletely understood. Similar to the sex steroids, IGF signalling is essential in normal development as well as growth and tissue homoeostasis, and undergoes a steady decline with advancing age and increasing visceral adiposity. Interestingly, IGF-1 has been found to play a compensatory role for both estrogen receptor (ER) and androgen receptor (AR) by augmenting hormonal responses in the absence of, or where low levels of ligand are present. Furthermore, experimental, and epidemiological evidence supports a role for dysregulated IGF signalling in breast and prostate cancers. Insulin-like growth factor binding protein (IGFBP) molecules can regulate the bioavailability of IGF-1 and are frequently expressed in these hormonally regulated tissues. The link between age-related disease and the role of IGF-1 in the process of ageing and longevity has gained much attention over the last few decades, spurring the development of numerous IGF targeted therapies that have, to date, failed to deliver on their therapeutic potential. This review will provide an overview of the sexually dimorphic nature of IGF signalling in humans and how this is impacted by the reduction in sex steroids in mid-life. It will also explore the latest links with metabolic syndromes, hormonal imbalances associated with ageing and targeting of IGF signalling in endocrine-related tumour growth with an emphasis on post-menopausal breast cancer and the impact of the steroidal milieu.
A Balanced Act: The Effects of GH–GHR–IGF1 Axis on Mitochondrial Function

Mitochondrial function is multifaceted in response to cellular energy homeostasis and metabolism, with the generation of adenosine triphosphate (ATP) through the oxidative phosphorylation (OXPHOS) being one of their main functions. Selective elimination of mitochondria by mitophagy, in conjunction with mitochondrial biogenesis, regulates mitochondrial function that is required to meet metabolic demand or stress response. Growth hormone (GH) binds to the GH receptor (GHR) and induces the JAK2/STAT5 pathway to activate the synthesis of insulin-like growth factor 1 (IGF1). The GH–GHR–IGF1 axis has been recognized to play significant roles in somatic growth, including cell proliferation, differentiation, division, and survival. In this review, we describe recent discoveries providing evidence for the contribution of the GH–GHR–IGF1 axis on mitochondrial biogenesis, mitophagy (or autophagy), and mitochondrial function under multiple physiological conditions. This may further improve our understanding of the effects of the GH–GHR–IGF1 axis on mitochondrial function, which may be controlled by the delicate balance between mitochondrial biogenesis and mitophagy. Specifically, we also highlight the challenges that remain in this field.
Towards a Functional Cure of HIV-1: Insight Into the Chromatin Landscape of the Provirus

Despite potent combination antiretroviral therapy, HIV-1 infection persists due to irreversible integration of the virus in long-living cells of the immune system. The main focus of HIV-1 cure strategies has been on HIV-1 eradication, yet without great success so far. Therefore, HIV-1 remission or a functional cure, whereby the virus is silenced rather than eradicated, is considered as an alternative strategy. Elite controllers, individuals who spontaneously control HIV-1, may point us the way toward a functional HIV-1 cure. In order to achieve such a cure, a profound understanding of the mechanisms controlling HIV-1 expression and silencing is needed. In recent years, evidence has grown that the site of integration as well as the chromatin landscape surrounding the integration site affects the transcriptional state of the provirus. Still, at present, the impact of integration site selection on the establishment and maintenance of the HIV-1 reservoirs remains poorly understood. The discovery of LEDGF/p75 as a binding partner of HIV-1 integrase has led to a better understanding of integration site selection. LEDGF/p75 is one of the important determinants of integration site selection and targets integration toward active genes. In this review, we will provide an overview of the most important determinants of integration site selection. Secondly, we will discuss the chromatin landscape at the integration site and its implications on HIV-1 gene expression and silencing. Finally, we will discuss how interventions that affect integration site selection or modifications of the chromatin could yield a functional cure of HIV-1 infection.
ADOS-Eye-Tracking: The Archimedean Point of View and Its Absence in Autism Spectrum Conditions

Face perception and emotion categorization are widely investigated under laboratory conditions that are devoid of real social interaction. Using mobile eye-tracking glasses in a standardized diagnostic setting while applying the Autism Diagnostic Observation Schedule (ADOS-2), we had the opportunity to record gaze behavior of children and adolescents with and without Autism Spectrum Conditions (ASCs) during social interaction. The objective was to investigate differences in eye-gaze behavior between three groups of children and adolescents either (1) with ASC or (2) with unconfirmed diagnosis of ASC or (3) with neurotypical development (NTD) during social interaction with an adult interviewer in a diagnostic standard situation using the ADOS-2. In a case control study, we used mobile eye-tracking glasses in an ecologically valid and highly standardized diagnostic interview to investigate suspected cases of ASC. After completion of the ASC diagnostic gold standard including the ADOS-2, the participants were assigned to two groups based on their diagnosis (ASC vs. non-ASC) and compared with a matched group of neurotypically developed controls. The primary outcome measure is the percentage of total dwell times assessed for different areas of interest (AOI) with regard to the face and body of a diagnostic interviewer and the surrounding space. Overall, 65 children and adolescents within an age range of 8.3–17.9 years were included in the study. The data revealed significant group differences, especially in the central-face area. Previous investigations under laboratory conditions gave preferential attention to the eye region during face perception to describe differences between ASC and NTD. In this study – using an ecologically valid setting within a standard diagnostic procedure – the results indicate that neurotypically developed controls seem to process faces and facial expressions in a holistic manner originating from the central-face region. Conversely, participants on the Autism Spectrum (tAS) seem to avoid the central-face region and show unsystematic gaze behavior, not using the preferred landing position in the central-face region as the Archimedean point of face perception. This study uses a new approach, and it will be important to replicate these preliminary findings in future research.
Tooth-Bone-Borne Vs. Bone-Borne Palatal Expanders: A Systematic Review

The aim of this review was to evaluate the current evidence regarding post-treatment effects of tooth-bone-borne vs. bone-borne expanders. A search was conducted in MEDLINE via PubMed, Web of Science, Scopus, Cochrane Library, Google Scholar, and Open Gray; in addition to a hand search in reference lists of selected articles and creating a search alert in electronic databases. Selection criteria included randomized and prospective clinical trials comparing post-expansion skeletal and/or dento-alveolar effects of tooth-bone-borne expanders to those of bone-borne expanders. Following study retrieval and selection, relevant data was extracted, and risk of bias was assessed using the revised RoB 2 tool for randomized clinical trials. After examining 10 full text articles, one randomized clinical trial was finally included. The study compared the dento-alveolar effects of tooth-bone-borne and bone-borne expanders, following expansion and after 6 months, using digital dental casts. Using the RoB 2 tool, the study was judged overall to show some concerns. A definitive conclusion could not be drawn from this systematic review due to the scarcity of clinical trials tackling the research question. A need for future well-conducted research was highlighted in this review.
Impact of transatlantic transport episodes on summertime ozone in Europe

This paper reports on the transport of ozone (O 3 ) and related species over the North Atlantic ocean and its impact on Europe. Measurements of nitrogen dioxide (NO 2 ) and carbon monoxide (CO) columns from the GOME and MOPITT satellite instruments, respectively, are used in conjunction with the GEOS-CHEM global model of transport and tropospheric chemistry to identify the major events of long range transport that reach Europe over the course of summer 2000. Sensitivity model simulations are used to analyse observed O 3 distributions with respect to the impact of long range transport events. For that purpose, we used in-situ O 3 observations taken at the mountain site of Jungfraujoch as well as O 3 vertical profiles taken in the vicinity of central European cities. Over the course of summer 2000, we identified 9 major episodes of transatlantic pollution transport; 7 events are associated with transient cyclones while 2 events occur through zonal transport (e.g. by advection in the strong low-level westerly winds established in summer between the Azores anticyclone and transient cyclones). We find that on average three episodes occur per month with the strongest ones being in June. The number and frequency of long range transport events that reach Europe are driven by the position and strength of the Azores anticyclone. Model sensitivity simulations indicate that the summer mean North American O 3 contribution ranges from 3 to 5 ppb (7–11%) in the planetary boundary layer and 10 to 13 ppb (18–23%) in the middle and upper troposphere. During particular episodes, North American sources can result in O 3 enhancements up to 25–28 ppb in the layer between 800–600 hPa and 10–12 ppb in the boundary layer. The impact of the zonal transport events on O 3 distribution over Europe is more clearly seen below 700 hPa as they tend to transport pollution at lower levels while the events associated with transient cyclones are more likely to have an impact on the middle and upper troposphere (i.e. above 600 hPa). The air mass origins found in the GEOS-CHEM model are clearly confirmed by back trajectory analyses. During most of the 9 events, a strong contribution in North American O 3 is in general associated with only little European O 3 and vice-versa (in particular at the Jungfraujoch). A substantial North American contribution (e.g., 30% or higher) to O 3 over Europe does not always result in pronounced O 3 enhancements in the observations during our period of study.
Illness Severity Moderated Association Between Trait Anxiety and Amygdala-Based Functional Connectivity in Generalized Anxiety Disorder

Trait anxiety is considered a vulnerability factor for the development of generalized anxiety disorder (GAD). The amygdala is related to both trait anxiety and GAD. Thus, we investigated amygdala-based functional connectivity (FC) in drug-naive non-comorbid GAD patients and explored its associations with personality, symptoms, and illness severity. FC analyses using the bilateral amygdala as seeds were performed with resting-state functional MRI data from 38 GAD patients and 20 matched healthy controls (HCs). Clinical characteristics were correlated with FC Z-scores from regions showing significant group differences. Furthermore, moderation analyses were used to explore the conditional effect of illness severity measured by the Clinical Global Impression–Severity (CGI-S) scale on the relationship between FC and trait anxiety. Relative to HCs, GAD patients showed hypoconnectivity between the amygdala and the rostral anterior cingulate cortex (rACC), inferior frontal gyrus (IFG), parahippocampal gyrus, and cerebellum and hyperconnectivity between the amygdala and the superior temporal gyrus (STG), insula, and postcentral gyrus. In GAD patients, amygdala–rACC connectivity was negatively associated with symptom severity and trait anxiety, and amygdala–IFG connectivity was positively associated with symptom severity. Moreover, CGI-S scores moderated the negative correlation between trait anxiety and amygdala–rACC FC. We demonstrate that there is extensive amygdala-based network dysfunction in patients with GAD. More importantly, amygdala–rACC connectivity plays a key role in the neural pathology of trait anxiety. Finally, the more severe the illness, the stronger the negative association between trait anxiety and amygdala–rACC FC. Our results emphasize the importance of personalized intervention in GAD.
Determination of Methoxypyrazines in Red Wines by Stable Isotope Dilution Gas Chromatography-Mass Spectrometry

Quantitative analysis of methoxypyrazines in a range of red wines is reported for the first time. By stable isotope dilution gas chromatography-mass spectrometry, 2-methoxy-3-(2-methylpropyl)pyrazine was determined in 12 Australian and New Zealand Cabernet Sauvignon wines (mean concentration, 19.4 ngL) and in 6 Bordeaux wines that are blends, to varying degrees, of Cabernet Sauvignon, Merlot, and Cabernet Franc (mean concentration, 9.8 ngL). These findings suggest that the concentration of the methoxypyrazine in wines of these varieties is ca. 30 times lower than that indicated in a previous study. In these 18 wines, the concentration of the methoxypyrazine exceeded its sensory detection threshold in water, consistent with its contributing to wine flavor. The concentration in two French Pinot noir wines was below the sensory detection threshold. In all wines, the level of 2-methoxy-3-(l-methylpropyl)pyrazine was less than 2 ngL.
Representativeness of Apple Aroma Extract Obtained by Vacuum Hydrodistillation: Comparison of Two Concentration Techniques

ARSTRACT: Vacuum hydrodistillation, which is a very gentle work-up procedure, has never been used for the extraction of apple aroma. During the concentration of aroma that follows vacuurn hydrodistillation, some very volatile components can be lost. The aim of this study was to compace 2 different concentration techniques, liquid-liquid exudation and solid phase extraction, to obtain an apple aroma extract as close as possible to fresh apple. After the elimination of solvent from the extract by gas chromatography, the study of the odor characteristics of solvent-free extracts was made possible. Vacuum hydrodistillation was conventent for fresh applex.