Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulating Protein Stability to Switch Toxic Protein Function On and Off in Living Cells

Conditional toxicity can be switched on/off to arrest individual cells in vivo by a portable protein degradation cassette fused to a highly toxic protein. Toxic proteins are prime targets for molecular farming (the generation of pharmacologically active or biotechnologically usable compounds in plants) and are also efficient tools for targeted cell ablation in genetics, developmental biology, and biotechnology. However, achieving conditional activity of cytotoxins and maintaining the toxin-expressing plants as stably transformed lines remain challenging. Here, we produce a switchable version of the highly cytotoxic bacterial RNase barnase by fusing the protein to a portable protein degradation cassette, the low-temperature degron cassette. This method allows conditional genetics based on conditional protein degradation via the N-end rule or N-degron pathway and has been used to vice versa accumulate and/or deplete a diverse variety of highly active, unstable or stable target proteins in different living multicellular organisms and cell systems. Moreover, we expressed the barnase fusion under control of the trichome-specific TRIPTYCHON promoter. This enabled efficient temperature-dependent control of protein accumulation in Arabidopsis (Arabidopsis thaliana) leaf hairs (trichomes). By tuning the levels of the protein, we were able to control the fate of trichomes in vivo. The on-demand formation of trichomes through manipulating the balance between stabilization and destabilization of barnase provides proof of concept for a robust and powerful tool for conditional switchable cell arrest. We present this tool as a potential strategy for the manufacture and accumulation of cytotoxic proteins and toxic high-value products in plants or for conditional genetic cell ablation.
Vitamin D in the Prevention and Treatment of Osteoarthritis: From Clinical Interventions to Cellular Evidence

Older adults are recommended vitamin D to prevent fractures. Though this population is also at risk of osteoarthritis (OA), the effect of vitamin D on OA is unclear and may differ by disease state. The relationship between vitamin D and OA during OA initiation and progression were considered in this narrative review of in vivo and in vitro studies. Regarding OA initiation in humans, the small number of published observational studies suggest a lack of association between induction of OA and vitamin D status. Most randomized controlled trials were performed in White OA patients with relatively high vitamin D status (>50 nmol/L). These studies found no benefit of vitamin D supplementation on OA progression. However, subset analyses and one randomized controlled pilot trial indicated that vitamin D supplementation may alleviate joint pain in OA patients with low vitamin D status (<50 nmol/L). As the etiology of OA is recently being more fully uncovered, better animal and cell models are needed. According to currently available clinical results, evidence is lacking to set a vitamin D level to prevent OA, and increasing vitamin D status above 50 nmol/L does not seem to benefit OA patients.
Healthy-Sustainable Housing Index: A Pilot Study to Link Architecture and Public Health in a Semi-Urban Community in Mexico

The aim of this pilot study was to evaluate the link between housing and children´s respiratory symptoms, through the construction of an index (HSHI) based on the definition of healthy-sustainable housing criteria, in a semi-urban community from Morelos, Mexico. A general and household questionnaire, and respiratory symptoms diary were applied in 60 households to gather information about schoolchildren, respiratory health, housing and lifestyle characteristics. HSHI was constructed using principal component analysis. The association between HSHI and the presence and duration of respiratory symptoms was assessed using logistic and Poisson regression models. HSHI had five components, which accounted for 63% of variance, and were classified into poor and sufficient quality. It was observed that schoolchildren who inhabit a sufficient-quality house, showed a reduction in nose irritation duration and in the allergic symptoms probability regarding component 1 (ventilation, lighting and cloth washing) and presented three times less duration of common cold by component 2 (construction material, painted walls inside the house and type of bathroom) compared to poor-quality house inhabitants. Our results suggest that living in a sufficient-quality house, as described by the HSHI, reduced the prevalence of wheezing episodes and the probability of ear pain, providing evidence about the positive association of a healthy-sustainable housing on the respiratory health of schoolchildren.
[177Lu]Lu-PSMA-617 Salivary Gland Uptake Characterized by Quantitative In Vitro Autoradiography

Irradiation of salivary glands remains the main dose-limiting side effect of therapeutic PSMA-inhibitors, especially when using alpha emitters. Thus, further advances in radiopharmaceutical design and therapy strategies are needed to reduce salivary gland uptake, thereby allowing the administration of higher doses and potentially resulting in improved response rates and better tumor control. As the uptake mechanism remains unknown, this work investigates the salivary gland uptake of [177Lu]Lu-PSMA-617 by autoradiography studies on pig salivary gland tissue and on PSMA-overexpressing LNCaP cell membrane pellets. Displacement studies were performed with non-labeled PSMA-617 and 2-PMPA, respectively. The uptake of [177Lu]Lu-PSMA-617 in glandular areas was determined to be partly PSMA-specific, with a high non-specific uptake fraction. The study emphasizes that [177Lu]Lu-PSMA-617 accumulation in pig salivary glands can be attributed to a combination of both specific and non-specific uptake mechanisms. The observation is of high impact for future design of novel radiopharmaceuticals addressing the dose-limiting salivary gland irradiation of current alpha endoradiotherapy in prostate cancer.
Intravenous iron treatment reduces coagulability in patients with iron deficiency anaemia: a longitudinal study

Although many case reports and observational studies have reported a correlation between iron deficiency anaemia (IDA) and thrombotic events, the mechanism for this is poorly understood. To evaluate this, we examined the change in coagulability in patients receiving treatment for IDA. Adult patients with IDA were recruited for this study and treated with intravenous iron. The change in coagulability was assessed by thrombin generation using the calibrated automated thrombogram method. The change in factor VIII (FVIII) activity was later examined as a possible link. Forty‐eight participants received intravenous iron and were included in this study. After treatment with intravenous iron, endogenous thrombin potential and peak height decreased in IDA patients by a mean of 122·4 nmol/l/min (95% confidence interval [CI]: 17·9–227, P = 0·023) and 51·9 (95% CI: 26·6–77·2, P < 0·001) respectively. Time to peak (peak time) increased by a mean of 23·6 s (95% CI: 5·4–41·9, P = 0·012). FVIII activity was reduced by a mean of 9·6% (95% CI: 2·54–16·7, P = 0·009). In conclusion, treating IDA reduces the blood's coagulability, as evidenced by the change in thrombin generation and FVIII activity levels. No correlation was found between the degree of iron deficiency correction and thrombogram parameters.
Human coronaviruses OC43 and HKU1 bind to 9-O-acetylated sialic acids via a conserved receptor-binding site in spike protein domain A

Significance Human coronaviruses OC43 and HKU1 are related, yet distinct respiratory pathogens, associated with common colds, but also with severe disease in the frail. Both viruses employ sialoglycan-based receptors with 9-O-acetylated sialic acid (9-O-Ac-Sia) as key component. Here, we identify the 9-O-Ac-Sia–specific receptor-binding site of OC43 S and demonstrate it to be conserved and functional in HKU1. The considerable difference in receptor-binding affinity between OC43 and HKU1 S, attributable to differences in local architecture and receptor-binding site accessibility, is suggestive of differences between OC43 and HKU1 in their adaptation to the human sialome. The data will enable studies into the evolution and pathobiology of OC43 and HKU1 and open new avenues toward prophylactic and therapeutic intervention. Human betacoronaviruses OC43 and HKU1 are endemic respiratory pathogens and, while related, originated from independent zoonotic introductions. OC43 is in fact a host-range variant of the species Betacoronavirus-1, and more closely related to bovine coronavirus (BCoV)—its presumptive ancestor—and porcine hemagglutinating encephalomyelitis virus (PHEV). The β1-coronaviruses (β1CoVs) and HKU1 employ glycan-based receptors carrying 9-O-acetylated sialic acid (9-O-Ac-Sia). Receptor binding is mediated by spike protein S, the main determinant of coronavirus host specificity. For BCoV, a crystal structure for the receptor-binding domain S1A is available and for HKU1 a cryoelectron microscopy structure of the complete S ectodomain. However, the location of the receptor-binding site (RBS), arguably the single-most important piece of information, is unknown. Here we solved the 3.0-Å crystal structure of PHEV S1A. We then took a comparative structural analysis approach to map the β1CoV S RBS, using the general design of 9-O-Ac-Sia-binding sites as blueprint, backed-up by automated ligand docking, structure-guided mutagenesis of OC43, BCoV, and PHEV S1A, and infectivity assays with BCoV-S–pseudotyped vesicular stomatitis viruses. The RBS is not exclusive to OC43 and related animal viruses, but is apparently conserved and functional also in HKU1 S1A. The binding affinity of the HKU1 S RBS toward short sialoglycans is significantly lower than that of OC43, which we attribute to differences in local architecture and accessibility, and which may be indicative for differences between the two viruses in receptor fine-specificity. Our findings challenge reports that would map the OC43 RBS elsewhere in S1A and that of HKU1 in domain S1B.
A novel combinatorial technique for simultaneous quantification of oxygen radicals and aggregation reveals unexpected redox patterns in the activation of platelets by different physiopathological stimuli

The regulation of platelets by oxidants is critical for vascular health and may explain thrombotic complications in diseases such as diabetes and dementia, but remains poorly understood. Here, we describe a novel technique combining electron paramagnetic resonance spectroscopy and turbidimetry, which has been utilized to monitor simultaneously platelet activation and oxygen radical generation. This technique has been used to investigate the redox-dependence of human and mouse platelets. Using selective peptide inhibitors of NADPH oxidases (NOXs) on human platelets and genetically modified mouse platelets (NOX1−/− or NOX2−/−), we discovered that: 1) intracellular but not extracellular superoxide anion generated by NOX is critical for platelet activation by collagen; 2) superoxide dismutation to hydrogen peroxide is required for thrombin-dependent activation; 3) NOX1 is the main source of oxygen radicals in response to collagen, while NOX2 is critical for activation by thrombin; 4) two platelet modulators, namely oxidized low density lipoproteins (oxLDL) and amyloid peptide β (Aβ), require activation of both NOX1 and NOX2 to pre-activate platelets. This study provides new insights into the redox dependence of platelet activation. It suggests the possibility of selectively inhibiting platelet agonists by targeting either NOX1 (for collagen) or NOX2 (for thrombin). Selective inhibition of either NOX1 or NOX2 impairs the potentiatory effect of tested platelet modulators (oxLDL and Aβ), but does not completely abolish platelet hemostatic function. This information offers new opportunities for the development of disease-specific antiplatelet drugs with limited bleeding side effects by selectively targeting one NOX isoenzyme.
Nitrogen Supply Drives Senescence-Related Seed Storage Protein Expression in Rapeseed Leaves

In general, yield and fruit quality strongly rely on efficient nutrient remobilization during plant development and senescence. Transcriptome changes associated with senescence in spring oilseed rape grown under optimal nitrogen supply or mild nitrogen deficiency revealed differences in senescence and nutrient mobilization in old lower canopy leaves and younger higher canopy leaves. Having a closer look at this transcriptome analyses, we identified the major classes of seed storage proteins (SSP) to be expressed in vegetative tissue, namely leaf and stem tissue. Expression of SSPs was not only dependent on the nitrogen supply but transcripts appeared to correlate with intracellular H2O2 contents, which functions as well-known signaling molecule in developmental senescence. The abundance of SSPs in leaf material transiently progressed from the oldest leaves to the youngest. Moreover, stems also exhibited short-term production of SSPs, which hints at an interim storage function. In order to decipher whether hydrogen peroxide also functions as a signaling molecule in nitrogen deficiency-induced senescence, we analyzed hydrogen peroxide contents after complete nitrogen depletion in oilseed rape and Arabidopsis plants. In both cases, hydrogen peroxide contents were lower in nitrogen deficient plants, indicating that at least parts of the developmental senescence program appear to be suppressed under nitrogen deficiency.
The Association of Joint Pain and Dipeptidyl Peptidase-4 Inhibitor Use Among U.S. Adults With Type-2 Diabetes Mellitus

Abstract The purpose of this study was to examine the association of dipeptidyl peptidase-4 inhibitors (DPP4Is) with joint pain in adults with type 2 diabetes mellitus (T2DM). This was a retrospective cross-sectional study design, pooling data from the 2012 and 2014 Medical Expenditure Panel Survey. The sample consisted of 4,559 T2DM patients older than 40 years with (n = 3,224) or without joint pain (n = 1,335). Chi-square test and logistic regression were used to describe association of DPP4I use with joint pain. Among adults with T2DM, 70.7% reported physician-diagnosed joint pain. There were no significant differences in DPP4I use among those with and without joint pain (7.8% vs 6.3%). Even after adjusting for other factors that may affect DPP4I use, there was not a statistically significant difference in DPP4I use among adults with T2DM with and without joint pain (AOR = 1.04; 95% CI, 0.74–1.48). Adults with public health insurance (AOR = 1.76; 95% CI, 1.01–3.04), with prescription insurance (AOR = 1.76; 95% CI, 1.02–3.03), and with a heart disease (AOR = 1.59; 95% CI, 1.18–2.15). DPP4I use was not affected by the presence of joint pain.
Spontaneous eye movements during focused-attention mindfulness meditation

Oculometric measures have been proven to be useful markers of mind-wandering during visual tasks such as reading. However, little is known about ocular activity during mindfulness meditation, a mental practice naturally involving mind-wandering episodes. In order to explore this issue, we extracted closed-eyes ocular movement measurements via a covert technique (EEG recordings) from expert meditators during two repetitions of a 7-minute mindfulness meditation session, focusing on the breath, and two repetitions of a 7-minute instructed mind-wandering task. Power spectral density was estimated on both the vertical and horizontal components of eye movements. The results show a significantly smaller average amplitude of eye movements in the delta band (1–4 Hz) during mindfulness meditation than instructed mind-wandering. Moreover, participants’ meditation expertise correlated significantly with this average amplitude during both tasks, with more experienced meditators generally moving their eyes less than less experienced meditators. These findings suggest the potential use of this measure to detect mind-wandering episodes during mindfulness meditation and to assess meditation performance.
Buspirone for the treatment of anxiety-related symptoms in Angelman syndrome: a case series

Objectives Angelman syndrome (AS) is a neurogenetic disorder associated with impaired expression of the ubiquitin-protein ligase E3A gene on chromosome 15. AS results in intellectual disability with limited expressive language, epilepsy, ataxia, sleep impairment, and problematic behavior which may include anxiety. Buspirone is a serotonin (5-HT)1A receptor partial agonist used in the treatment of anxiety disorders and may, therefore, have a treatment role for patients with AS. Methods We describe three patients who were given open-label buspirone for the treatment of behaviors thought to be related to anxiety. Results We found significant improvement in symptoms of anxiety with buspirone. Patients tolerated long-term usage of the medication. Conclusion The findings of this study suggest that buspirone may be effective for the amelioration of behaviors related to anxiety in patients with AS, and well tolerated. Limitations include the open-label nature of these treatments, the small sample size and the absence of a control group.
Content of n-3 LC-PUFA in Breast Milk Four Months Postpartum is Associated with Infancy Blood Pressure in Boys and Infancy Blood Lipid Profile in Girls

Blood pressure (BP) and blood lipid profile (BLP) have been shown to track from childhood into adulthood, and n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) in breast milk have been suggested as mediators of the beneficial long-term effect of breastfeeding on BP and BLP. We aimed to investigate associations between n-3 LC-PUFA content in breast milk at 4 months postpartum and offspring BP and BLP in early life. BP and BLP were measured at 4, 18, and 36 months. Statistical analyses were sex-stratified and adjusted for gestational age, maternal pre-pregnancy body mass index (BMI), and maternal educational level. Based on 336 mother-child dyads, high n-3 LC-PUFA in breast milk was inversely associated with systolic and diastolic BP in boys at 4 months (β = −20.0 (95% CI = −33.4, −6.7), p = 0.004 and β = −10.2 (95% CI = −19.8, −0.5), p = 0.039, respectively); inversely associated with HDL cholesterol, and directly associated with triglyceride in girls at 4 months (β = −0.7 (95% CI = −1.1, −0.3), p = 0.001 and β = 3.1 (95% CI = 1.0, 5.2), p = 0.005, respectively). Associations observed at the later time points were non-significant. Furthermore, we observed sex-specific changes over time in both size and direction of the associations. Our results indicate that early intake of n-3 LC-PUFA can affect early development in cardiometabolic factors such as BP and BLP in a sex-specific manner. Follow-up and further investigation in later childhood is planned.
The Relationship Between Grit, Burnout, and Well‐being in Emergency Medicine Residents

Burnout has become endemic in medicine, across all specialties and levels of training. Grit, defined as “perseverance and passion for long‐term goals,” attempts to quantify the ability to maintain sustained effort throughout an extended length of time. Our objective is to assess burnout and well‐being and examine their relationship with the character trait, grit, in emergency medicine residents.
Clinical indices and mortality of hospitalized avian influenza A (H7N9) patients in Guangdong, China

Background: Six epidemic waves of human infection with avian influenza A (H7N9) virus have emerged in China with high mortality. However, study on quantitative relationship between clinical indices in ill persons and H7N9 outcome (fatal and non-fatal) is still unclear. A retrospective cohort study was conducted to collect laboratory-confirmed cases with H7N9 viral infection from 2013 to 2015 in 23 hospitals across 13 cities in Guangdong Province, China. Methods: Multivariable logistic regression model and classification tree model analyses were used to detect the threshold of selected clinical indices and risk factors for H7N9 death. The receiver operating characteristic curve (ROC) and analyses were used to compare survival and death distributions and differences between indices. A total of 143 cases with 90 survivors and 53 deaths were investigated. Results: Average age (Odds Ratio (OR) = 1.036, 95% Confidence Interval (CI) = 1.016–1.057), interval days between dates of onset and confirmation (OR = 1.078, 95% CI = 1.004–1.157), interval days between onset and oseltamivir treatment (OR = 5.923, 95% CI = 1.877–18.687), body temperature (BT) (OR = 3.612, 95% CI = 1.914–6.815), white blood cell count (WBC) (OR = 1.212, 95% CI = 1.092–1.346) were significantly associated with H7N9 death after adjusting for confounders. The chance of death from H7N9 infection was 80.0% if BT was over 38.1 °C, and chance of death is 67.4% if WBC count was higher than 9.5 (109/L). Only 27.1% of patients who began oseltamivir treatment less than 9.5 days after disease onset died, compared to 68.8% of those who started treatment more than 15.5 days after onset. Conclusions: The intervals between date of onset and confirmation of diagnosis, between date of onset to oseltamivir treatment, age, BT and WBC are found to be the best predictors of H7N9 mortality.
Comparison of the Medtronic SelectSecure and conventional pacing leads: Long‐term follow‐up in a multicenter pediatric and congenital cohort

The Medtronic SelectSecure™ (Minneapolis, MN, USA) pacing lead (SS) has theoretical advantages compared to conventional (C) transvenous pacing leads (PLs). The study purpose was to determine whether differences in electrical function and lead survival exist between these PLs in a large data set of pediatric and congenital patients.
Molecular and Functional Characterization of Elicitor PeBC1 Extracted from Botrytis cinerea Involved in the Induction of Resistance against Green Peach Aphid (Myzus persicae) in Common Beans (Phaseolus vulgaris L.)

Elicitors are biofactors that induce resistance in plants against different insect pests. This in vitro study evaluated the impact of a novel elicitor protein PeBC1, extracted from a necrotrophic fungus Botrytis cinerea, on the development and fecundity parameters of green peach aphid (Myzus persicae) on common beans (Phaseolus vulgaris L.). Three different concentrations of PeBC1 elicitor (i.e., 33.56, 25.43, 19.33 µg mL−1) were applied at three different temperature regimes (i.e., 18, 21, and 25 °C). Elicitor treatments were applied topically on the bean plants at 3-leaf stage and newly emerged (0–6 h old) apterous adult aphids were exposed to these treated leaves. In addition to the biological parameters of aphids, the relative expression levels of key genes associated with jasmonic acid (JA) and salicylic acid (SA) plant defense pathways were also determined through RT-qPCR. Results of bioassays revealed that the application of PeBC1 elicitor protein exhibited pronounced and significant (p < 0.05) sub-lethal effects on green peach aphids. The fecundity was reduced and the nymphal development time was prolonged by different concentrations of PeBC1 elicitor and temperature regimes. Gene expression studies showed that the exogenous application of PeBC1 induced a significant upregulation of the expression levels of JA and SA pathway-associated genes in bean plants. As compared to control, elicitor-treated plants exhibited an induced resistance against aphids. Our findings suggest the potential use of PeBC1 elicitor protein in future bio-intensive management strategies against sap-sucking insect pests such as green peach aphids.