Miracle-dz/UniFAR-FTUs huggingface dataset:
Enzymatic Cascades for Tailored 13C6 and 15N Enriched Human Milk Oligosaccharides

Several health benefits, associated with human milk oligosaccharides (HMOS), have been revealed in the last decades. Further progress, however, requires not only the establishment of a simple “routine” method for absolute quantification of complex HMOS mixtures but also the development of novel synthesis strategies to improve access to tailored HMOS. Here, we introduce a combination of salvage-like nucleotide sugar-producing enzyme cascades with Leloir-glycosyltransferases in a sequential pattern for the convenient tailoring of stable isotope-labeled HMOS. We demonstrate the assembly of [13C6]galactose into lacto-N- and lacto-N-neo-type HMOS structures up to octaoses. Further, we present the enzymatic production of UDP-[15N]GlcNAc and its application for the enzymatic synthesis of [13C6/15N]lacto-N-neo-tetraose for the first time. An exemplary application was selected—analysis of tetraose in complex biological mixtures—to show the potential of tailored stable isotope reference standards for the mass spectrometry-based quantification, using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) as a fast and straightforward method for absolute quantification of HMOS. Together with the newly available well-defined tailored isotopic HMOS, this can make a crucial contribution to prospective research aiming for a more profound understanding of HMOS structure-function relations.
The association between family members’ migration and cognitive function among people left behind in China

While internal migration is widely occurring in countries across the world and older people are more likely to be left behind by family members who out-migrated to other locations, little attention has been paid to the cognitive health of those people who have been left behind (PLB). Understanding how these demographic patterns relate to older persons’ cognitive health may inform efforts to reduce the disease burden due to cognitive decline. Data came from the China Health and Nutrition Survey in 1997, 2000 and 2004. Participants aged 55 to 93 who participated in a cognitive function screening test (score range: 0–31) in two or more waves and provided information on family members’ migration (n = 1,267) were included in the analysis. A mixed linear model was used to investigate the association between being left behind by any members who had not resided in the household for at least 6 months at baseline and cognitive function. Approximately 10% of the participants had been left behind by family members who migrated out of their communities. A significant interaction was observed in relation to cognitive function between being left behind and the number of years from the first test. Specifically, there was a less steep decline in cognitive function of PLB compared to people not left behind. This longitudinal study showed that PLB tended to have a higher cognitive function compared to those not left behind due to their relatively stable transition in cognitive function during the study period.
Diabetic Foot Infection Presenting Systemic Inflammatory Response Syndrome: A Unique Disorder of Systemic Reaction from Infection of the Most Distal Body

Diabetic foot infection (DFI) is a major complication of diabetic foot that lead to nontraumatic lower-extremity amputation (LEA). Such distal infection of the body having systemic inflammatory response syndrome (SIRS) is rarely reported. Consecutive patients treated for limb-threatening DFI in a major diabetic foot center in Taiwan were analyzed between the years 2014 to 2017. Clinical factors, laboratory data, perfusion, extent, depth, infection and sensation (PEDIS) wound score in 519 subjects with grade 3 DFI and 203 presenting SIRS (28.1%) were compared. Major LEA and in-hospital mortality were defined as poor prognosis. Patients presenting SIRS had poor prognosis compared with those with grade 3 DFI (14.3% versus 6.6% for major LEA and 6.4% versus 3.5% for in-hospital mortality). Age, wound size, and HbA1c were independent risk factors favoring SIRS presentation. Perfusion grade 3 (odds ratio 3.37, p = 0.044) and history of major adverse cardiac events (OR 2.41, p = 0.036) were the independent factors for poor prognosis in treating patients with DFI presenting SIRS. SIRS when presented in patients with DFI is not only limb- but life-threatening as well. Clinicians should be aware of the clinical factors that are prone to develop and those affecting the prognosis in treating patients with limb-threatening foot infections.
Fighting the flinch: Experimentally induced compassion makes a difference in health care providers.

OBJECTIVES Although health care providers are required to sustain care in difficult circumstances, some patients challenge this principle. Evoking compassion seems likely to be helpful in such situations. This research aimed to evaluate whether inducing compassion in health care providers might mitigate disengagement with patients who have challenging presenting features such as those with disgusting symptoms and/or are to blame for their own health problems. DESIGN An online experimental study with clinical health care providers. METHODS Medical students (n = 219) and qualified health care professionals (n = 108) took part in an online experiment. Participants were randomized to view a slideshow of either neutral images (control) or compassion-inducing images (compassion condition) and were then presented with a series of patient vignettes where presenting problems systematically varied on patient responsibility and disgusting symptoms. Engagement was assessed by asking participants how caring they felt, how much they would want to help, how challenging it would be, and whether they would wear a mask. RESULTS Participants reported less engagement with patients who were responsible for their illness and who presented with disgusting symptoms. Induced compassion offset disengagement and qualified health professionals were more caring and willing to help patients than medical students. The compassion induction eliminated some differences between experienced and trainee clinicians. CONCLUSIONS This research demonstrates that disgust and patient responsibility impacts clinical engagement and that medical students are more impacted by such scenarios than qualified health providers. Inducing compassion may help to mitigate these differences, and further investigation into strategies that foster engagement with difficult patients is warranted. Statement of contribution What is already known on the subject? Health care providers are required to sustain care across all patients; however, some patients are more difficult to engage with than others. Clinical engagement appears to be impacted when patients present with disgusting symptoms and/or are to blame for their own health problems. What does this study add? This work reports on a vignette-based study that shows that disgusting symptoms and patient responsibility impact self-reported measures of clinical engagement in response to patient scenarios. Qualified health care providers are less likely to disengage in these situations than medical students. A very brief online induction of compassion has potential to mitigate differences between trained professionals and students.
A First-in-Human Phase I Study of INVAC-1, an Optimized Human Telomerase DNA Vaccine in Patients with Advanced Solid Tumors

Purpose: Human telomerase reverse transcriptase (hTERT) is highly expressed in >85% of human tumors and is thus considered as a good tumor-associated antigen candidate for vaccine development. We conducted a phase I study to investigate the safety, tolerability, clinical response, and immunogenicity of INVAC-1, a DNA plasmid encoding a modified hTERT protein in patients with relapsed or refractory solid tumors. Patients and Methods: INVAC-1 was either administered by intradermal route followed by electroporation or by Tropis, a needle-free injection system. Safety and tolerability were monitored by clinical and laboratory assessments. Progression-free survival and overall survival were reported using Kaplan–Meier survival analysis. Immunogenicity was studied by ELISpot, Luminex, and Flow Cytometry. Results: Twenty-six patients were treated with INVAC-1 administered at three dose levels (100, 400, and 800 μg). Vaccination was well tolerated and no dose-limiting toxicity was reported. One treatment-related grade 3 SAE was reported. Fifty-eight percent of patients experienced disease stabilization. PFS was 2.7 months, median OS was 15 months, and 1-year survival was reached for 65% of patients. INVAC-1 vaccination stimulated specific anti-hTERT CD4 T-cell response as well as cytotoxic CD8 T-cell response. No evidence of peripheral vaccine-induced immunosuppression was observed. Conclusions: INVAC-1 vaccination was safe, well tolerated, and immunogenic when administered intradermally at the three tested doses in patients with relapsed or refractory cancers. Disease stabilization was observed for the majority of patients (58%) during the treatment period and beyond. See related commentary by Slingluff Jr, p. 529
Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

Exosomes are served as substitutes for stem cell therapy, playing important roles in mediating heart repair during myocardial infarction injury. Evidence have indicated that lipopolysaccharide (LPS) pre‐conditioning bone marrow‐derived mesenchymal stem cells (BMSCs) and their secreted exosomes promote macrophage polarization and tissue repair in several inflammation diseases; however, it has not been fully elucidated in myocardial infarction (MI). This study aimed to investigate whether LPS‐primed BMSC‐derived exosomes could mediate inflammation and myocardial injury via macrophage polarization after MI. Here, we found that exosomes derived from BMSCs, in both Exo and L‐Exo groups, increased M2 macrophage polarization and decreased M1 macrophage polarization under LPS stimulation, which strongly depressed LPS‐dependent NF‐κB signalling pathway and partly activated the AKT1/AKT2 signalling pathway. Compared with Exo, L‐Exo had superior therapeutic effects on polarizing M2 macrophage in vitro and attenuated the post‐infarction inflammation and cardiomyocyte apoptosis by mediating macrophage polarization in mice MI model. Consequently, we have confidence in the perspective that low concentration of LPS pre‐conditioning BMSC‐derived exosomes may develop into a promising cell‐free treatment strategy for clinical treatment of MI.
Role of GOLPH3 and TPX2 in Neuroblastoma DNA Damage Response and Cell Resistance to Chemotherapy

Neuroblastoma (NB) is an aggressive, relapse-prone infancy tumor of the sympathetic nervous system and is the leading cause of death among preschool age diseases, so the search for novel therapeutic targets is crucial. Golgi phosphoprotein 3 (GOLPH3) has been reported to be involved in the development, and in the DNA damage response, of various human cancers. Golgi dispersal is a common feature of DNA damage response in mammalian cells. Understanding how cells react to DNA damage is essential in order to recognize the systems used to escape from elimination. We induced DNA damage in two human neuroblastoma cell lines by curcumin. The exposure of neuroblastoma cells to curcumin induced: (a) up-regulation of GOLPH3+ cells; (b) augmentation of double-strand breaks; (c) Golgi fragmentation and dispersal throughout the cytoplasm; (d) increase of apoptosis and autophagy; (e) increased expression of TPX2 oncoprotein, able to repair DNA damage. Primary neuroblastoma samples analysis confirmed these observations. Our findings suggest that GOLPH3 expression levels may represent a clinical marker of neuroblastoma patients’ responsiveness to DNA damaging therapies—and of possible resistance to them. Novel molecules able to interfere with GOLPH3 and TPX2 pathways may have therapeutic benefits when used in combination with standard DNA damaging therapeutic agents in neuroblastoma
Impact of Multidomain Lifestyle Intervention on Frailty Through the Lens of Deficit Accumulation in Adults with Type 2 Diabetes Mellitus.

BACKGROUND Type 2 diabetes and obesity increase the accumulation of health deficits and may accelerate biological aging. Multidomain lifestyle interventions may mitigate against this. METHODS Within a large, randomized clinical trial of intensive lifestyle intervention including caloric restriction, increased physical activity, dietary counseling, and risk factor monitoring compared with diabetes support and education, we examined the accumulation of health deficits across 8 years. We used two complementary frailty indices (FIs) based on deficit accumulation, one modeled on work in the Systolic Blood Pressure Intervention Trial and the other including additional deficits related to obesity and type 2 diabetes mellitus. Differences between intervention groups and their consistency among subgroups were assessed with re-randomization tests. RESULTS Data from 4,859 adults (45-76 years at baseline, 59% female) were analyzed. Random assignment to intensive lifestyle intervention was associated with lower FI scores throughout follow-up as captured by areas under curves traced by longitudinal means (p ≤ .001), over which time mean (SE) differences between intervention groups averaged 5.8% (0.9%) and 5.4% (0.9%) for the two indices. At year 8, the percentage of participants classified as frail (FI > 0.21) was lower among intensive lifestyle intervention (39.8% and 54.5%) compared with diabetes support and education (42.7% and 60.9%) for both FIs (both p < .001). Intervention benefits were relatively greater for participants who were older, not obese, and without history of cardiovascular disease at baseline. CONCLUSIONS Eight years of multidomain lifestyle intervention create a buffer against the accumulation of age-related health deficits in overweight or obese adults with type 2 diabetes.ClinicalTrials. gov Identifier: NCT00017953.
Characterising HIV/AIDS knowledge and attitudes in the Middle East and North Africa: Systematic review and data synthesis

ABSTRACT This article reviews HIV/AIDS knowledge and attitudes in various population groups in the Middle East and North Africa (MENA), and highlights their relevance to HIV epidemiology and the design and implementation of preventions and treatment efforts. PubMed and the MENA HIV/AIDS Epidemiology Synthesis Project database of grey/unpublished literature were searched. Levels of knowledge were categorised based on presence of basic knowledge, comprehensive knowledge, and misconceptions and misinformation. Attitudes towards people living with HIV/AIDS (PLHIV) were classified into positive or negative. Basic knowledge was overall high among key populations at higher risk of infection (KPAR), and bridging and general population groups, but still a few population pockets had low basic knowledge. Level of comprehensive knowledge was overall low, and misinformation and misconceptions were prevalent. Some KPAR, including people who inject drugs, men who have sex with men, and female sex workers, were unaware of some modes of HIV transmission. Perception of risk of infection was low even among KPAR. We found differentials in knowledge putting women, rural populations, refugees, and other marginalised minorities at a disadvantage. Attitudes towards PLHIV tended to be negative. These findings are of concern, particularly for KPAR currently experiencing emerging HIV epidemics.
Lower extremity joints and muscle groups in the human locomotor system alter mechanical functions to meet task demand

ABSTRACT To facilitate movement through mechanically complex environments, terrestrial animals have evolved locomotor systems capable of flexibly altering internal mechanics to meet external demands. They do this by shifting imposed workloads between joints/muscle groups (central mechanical flexibility) and/or by altering the function of individual joints/muscle groups (local mechanical flexibility). In human locomotion research, central mechanical flexibility is well established and regularly reported. Local mechanical flexibility at major lower extremity joints and muscle groups, however, has received relatively less attention. We used an emerging biomechanical analysis known as functional indexing to test the hypothesis that lower extremity joints and muscle groups within the human locomotor system alter their mechanical function to meet altered locomotor demands. Thirteen healthy adults walked across a range of speeds (0.8, 1.2, 1.6, 2.0 m s−1) and slopes (0 deg, +5 deg, +10 deg) to determine whether hip, knee and ankle joints and their extensors and flexors altered their mechanical function in response to increased speed and slope. As walking speed increased, the knee and its extensors altered their function to behave more like mechanical springs while the ankle and its extensors altered their function to behave more like motors. As slope increased, all three joints and their extensors decreased spring- and damper-like behavior and increased motor-like behavior. Our results indicate that humans – similarly to many other terrestrial animals – utilize local mechanical flexibility to meet the demands of the locomotor task at hand. Summary: Joints and muscle groups in the human locomotor system alter their mechanical function to meet demands of the locomotor task being performed.
Exposure to organisational injustice and serious psychological distress: longitudinal analysis of details of exposure from a private Japanese company

Objectives Studies have shown that organisational injustice (OIJ) is associated with mental disorders. However, there is little research regarding details on OIJ exposure. We examined the effect of OIJ on serious psychological distress (SPD) by considering the exposure frequency, the exposure duration and the OIJ-free period after the disappearance of exposure. Methods We used a prospective cohort design. OIJ exposure was assessed three times with 1-year intervals between assessments, and the subjects were grouped according to the exposure histories. The outcome assessment for SPD by scores of 13 or higher on the K6 questionnaire was carried out 3 years after the baseline scores were obtained. Participants were all full-time regular employees of one office of a manufacturing company in Japan. Participants who were being treated for mental disorders, those with SPD and those with missing data on the K6 questionnaire in the baseline survey were excluded from the prospective cohort. Self-reported questionnaire data from 1087 employees who participated in all surveys and answered all questions were analysed. Logistic regression analysis was used to explore the effect of OIJ on SPD. Results SPD developed in 35 participants. Frequent OIJ exposure was associated with a higher risk for SPD (p for trend=0.002). Of the 1087 participants, 319 (29.3%) experienced a change in OIJ exposure at least once, and 8.6% of subjects experienced such a change twice. These changes in OIJ exposure were more strongly related to SPD than was the frequency of OIJ exposure. Conclusions OIJ was associated with SPD onset particularly when the workers were more frequently exposed to it. Moreover, frequent changes in the OIJ exposure were associated with a higher risk for SPD. Because OIJ exposure can change in a relatively short time, considering exposure histories may provide useful information for preventing mental disorders.
Modulation of the Lipid Profile of Reconstructed Skin Substitutes after Essential Fatty Acid Supplementation Affects Testosterone Permeability

Skin models with efficient skin barrier function are required for percutaneous absorption studies. The contribution of media supplementation with n-3 and n-6 polyunsaturated fatty acids (PUFAs) to the development of the skin barrier function of in vitro skin models remains incompletely understood. To investigate whether PUFAs, alpha-linolenic acid (ALA, n-3 PUFA) and linoleic acid (LA, n-6 PUFA), could enhance the impermeability of a three-dimensional reconstructed human skin model, skin substitutes were produced according to the self-assembly method using culture media supplemented with either 10 μM ALA or 10 μM LA. The impact of PUFAs on skin permeability was studied by using a Franz cell diffusion system to assess the percutaneous absorption of testosterone and benzoic acid. Our findings showed that ALA supplementation induced a decrease in the absorption of testosterone, while LA supplementation did not significantly influence the penetration of testosterone and benzoic acid under present experimental conditions. Both ALA and LA were incorporated into phospholipids of the skin substitutes, resulting in an increase in n-3 total PUFAs or n-6 total PUFAs. Collectively, these results revealed the under-estimated impact of n-3 PUFA supplementation as well as the importance of the n-6 to n-3 ratio on the formation of the skin barrier of in vitro reconstructed human skin models.
A Design of Experiments Strategy to Enhance the Recovery of Polyphenolic Compounds from Vitis vinifera By-Products through Heat Reflux Extraction

The aim of the present study was to establish the best experimental conditions that lead to the extracts richest in polyphenolic compounds obtained from pomace and canes of Vitis vinifera. In this regard, a D-Optimal design of experiments (DoE) method was applied to investigate the extraction process parameters from each of three materials: red pomace (RP), white pomace (WP) and canes (C). The input variables were the extraction temperature and the ethanol ratio and as response, the total polyphenols content (TPC) was determined. A design space was generated for each of the plant materials and the most concentrated polyphenol extracts were obtained using 50% ethanol at a temperature of 80 °C. Further, the phenolic profiles of the concentrated extracts were detected by LC/MS/MS and the results showed that WP extract was richer in polyphenolic compounds, both flavonoid and phenolic acids, followed by the RP and C extracts. The antioxidant assays revealed that WP and RP extracts exhibited a higher antioxidant activity which correlated to the high content of polyphenols. These findings revealed that RP, WP and C, currently considered agricultural wastes from winery, may be valorized as an important source of natural antioxidants.