Miracle-dz/UniFAR-FTUs huggingface dataset:
A New Mechanism for β‐Lactamases: Class D Enzymes Degrade 1β‐Methyl Carbapenems through Lactone Formation

Abstract β‐Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl‐enzyme intermediate. We show that class D β‐lactamases also degrade clinically used 1β‐methyl‐substituted carbapenems through the unprecedented formation of a carbapenem‐derived β‐lactone. β‐Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl‐enzyme intermediate. The carbapenem‐derived lactone products inhibit both serine β‐lactamases (particularly class D) and metallo‐β‐lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required.
Impact of Type 1 Diabetes Technology on Family Members/Significant Others of People With Diabetes

Background: The aim was to explore the impact of diabetes-related technology to ensure that such devices are used in a way that returns maximum benefit from a medical and psychological perspective. Method: Spouses and caregivers of people with type 1 diabetes were invited to complete an online questionnaire about their experiences with diabetes technologies used by their family members. Participants were recruited via the Glu online community website. Questions explored impact on daily living, frequency and severity of hypoglycemia, and diabetes-related distress. Results: In all, 100 parents/caregivers and 74 partners participated in this survey. Average (mean) duration of living with a person with type 1 diabetes was 16 years (SD = 13) for partners, with duration of diabetes for children being 4.2 ± 3.2 years. Average duration of current therapy was 8.3 ± 7.3 years for adults and 3.4 ± 2.9 years for children. Of the participants, 86% partners and 82% parents/caregivers reported diabetes technology had made it easier for their family members to achieve blood glucose targets. Compared to partners, parents/caregivers reported more negative emotions (P < .001) and decreased well-being (P < .001) related to their family members type 1 diabetes. Diabetes-related distress was common, as was sleep disturbance associated with device alarms and fear of hypoglycemia. Reduced frequency and severity of hypoglycemia related to device use was reported by approximately half of participants. Conclusion: There is little doubt about the medical benefit of diabetes technologies and their uptake is increasing but some downsides were reported. Barriers to uptake of technologies lie beyond the mechanics of diabetes management. Supporting users in using diabetes technology to achieve the best possible glycemic control, in the context of their own life, is crucial. Furthermore, understanding these issues with input from the type 1 diabetes community including family members and caregivers will help innovation and design of new technology.
Synthesis of Samarium-Cobalt Sub-micron Fibers and Their Excellent Hard Magnetic Properties

High-throughput synthesis of Samarium-Cobalt sub-micron fibers with controlled composition and dimension was demonstrated by combining electrospinning and reduction-diffusion processes. The composition of fibers was readily varied (8 < Sm < 20 at.%) by adjusting precursor composition whereas the diameter of fibers was precisely controlled by varying electrospinning parameters (e.g., applied voltage, solution feed rate, temperature, and humidity) to reach single-domain size. X-ray diffraction patterns confirmed that single phase Sm2Co17 fibers were synthesized when the metal precursor ratio (Sm3+/(Sm3++Co2+)) was precisely controlled at 10.6%, whereas mixed phases (i.e., Co-Sm2Co17 or Sm2Co17-Sm2Co7) were observed when the ratio is deviated from the stoichiometric. Magnetic saturation (Ms) of the synthesized fibers monotonically decreased with an increased in Sm content. In contrast, coercivity (Hci) monotonically increased with an increase in Sm content.
FUNDAMENTAL MODE ESTIMATION FOR MODERN 1 CABLE-STAYED BRIDGES CONSIDERING THE TOWER 2 FLEXIBILITY 3

12 The design of cable-stayed bridges is typically governed by the dynamic response. This work 13 provides designers with essential information about the fundamental vibration modes proposing 14 analytical expressions based on the mechanical and geometrical properties of the structure. Differ15 ent bridge geometries are usually considered in the early design stages until the optimum solution 16 is defined. In these design stages the analytical formulation is advantageous as finite element mod17 els are not required and modifying the bridge characteristics is straightforward. The influence of 18 the tower flexibility is included in this study, unlike in previous attempts on mode estimation. The 19 dimensions and proportions of the canonical models proposed in the analytical study stem from 20 the previous compilation of the dimensions of a large number of constructed cable-stayed bridges. 21 Five tower shapes, central or lateral cable-system layouts and boxor ‘U’-shaped deck sections 22 have been considered. The vibration properties of more than one thousand cable-stayed bridges 23 with main spans ranging from 200 to 800 m long were extracted within an extensive parametric 24 1 Camara, July 16, 2013 analysis. The Vaschy-Buckingham theorem of dimensional analysis was applied to the numeri25 cal results in order to propose the formulation for period estimation. Finally, the formulae were 26 validated with the vibration properties of 17 real cable-stayed bridges constructed in different coun27 tries. The importance of the tower flexibility is verified and the errors observed are typically below 28 15 %, significantly improving the estimations obtained by previous research works. 29
Long-term functional outcome in patients with acquired infections after acute spinal cord injury

Objective: To investigate whether prevalent hospital-acquired pneumonia and wound infection affect the clinical long-term outcome after acute traumatic spinal cord injury (SCI). Methods: This was a longitudinal cohort study within the prospective multicenter National Spinal Cord Injury Database (Birmingham, Alabama). We screened datasets of 3,834 patients enrolled in 20 trial centers from 1995 to 2005 followed up until 2016. Eligibility criteria were cervical SCI and American Spinal Cord Injury Association impairment scale A, B, and C. Pneumonia or postoperative wound infections (Pn/Wi) acquired during acute medical care/inpatient rehabilitation were analyzed for their association with changes in the motor items of the Functional Independence Measure (FIMmotor) using regression models (primary endpoint 5-year follow-up). Pn/Wi-related mortality was assessed as a secondary endpoint (10-year follow-up). Results: A total of 1,203 patients met the eligibility criteria. During hospitalization, 564 patients (47%) developed Pn/Wi (pneumonia n = 540; postoperative wound infection n = 11; pneumonia and postoperative wound infection n = 13). Adjusted linear mixed models after multiple imputation revealed that Pn/Wi are significantly associated with lower gain in FIMmotor up to 5 years after SCI (−7.4 points, 95% confidence interval [CI] −11.5 to −3.3). Adjusted Cox regression identified Pn/Wi as a highly significant risk factor for death up to 10 years after SCI (hazard ratio 1.65, 95% CI 1.26 to 2.16). Conclusion: Hospital-acquired Pn/Wi are predictive of propagated disability and mortality after SCI. Pn/Wi qualify as a potent and targetable outcome-modifying factor. Pn/Wi prevention constitutes a viable strategy to protect functional recovery and reduce mortality. Pn/Wi can be considered as rehabilitation confounders in clinical trials.
Dysfunctional BMPR2 signaling drives an abnormal endothelial requirement for glutamine in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is increasingly recognized as a systemic disease driven by alteration in the normal functioning of multiple metabolic pathways affecting all of the major carbon substrates, including amino acids. We found that human pulmonary hypertension patients (WHO Group I, PAH) exhibit systemic and pulmonary-specific alterations in glutamine metabolism, with the diseased pulmonary vasculature taking up significantly more glutamine than that of controls. Using cell culture models and transgenic mice expressing PAH-causing BMPR2 mutations, we found that the pulmonary endothelium in PAH shunts significantly more glutamine carbon into the tricarboxylic acid (TCA) cycle than wild-type endothelium. Increased glutamine metabolism through the TCA cycle is required by the endothelium in PAH to survive, to sustain normal energetics, and to manifest the hyperproliferative phenotype characteristic of disease. The strict requirement for glutamine is driven by loss of sirtuin-3 (SIRT3) activity through covalent modification by reactive products of lipid peroxidation. Using 2-hydroxybenzylamine, a scavenger of reactive lipid peroxidation products, we were able to preserve SIRT3 function, to normalize glutamine metabolism, and to prevent the development of PAH in BMPR2 mutant mice. In PAH, targeting glutamine metabolism and the mechanisms that underlie glutamine-driven metabolic reprogramming represent a viable novel avenue for the development of potentially disease-modifying therapeutics that could be rapidly translated to human studies.
Relationship between testosterone in serum, saliva and urine during treatment with intramuscular testosterone undecanoate in gender dysphoria and male hypogonadism

Long‐term testosterone replacement therapy is mainly monitored by trough levels of serum testosterone (S‐T), while urinary testosterone (U‐T) is used by forensic toxicology to evaluate testosterone doping. Testosterone in saliva (Sal‐T) may provide additional information and simplify the sample collection. We aimed to investigate the relationships between testosterone measured in saliva, serum and urine during standard treatment with 1,000 mg testosterone undecanoate (TU) every 12th week during 1 year. This was an observational study. Males with primary and secondary hypogonadism (HG; n = 23), subjects with gender dysphoria (GD FtM; n = 15) and a healthy control group of men (n = 32) were investigated. Sal‐T, S‐T and U‐T were measured before and after TU injections. Sal‐T was determined with Salimetrics® enzyme immunoassay, S‐T with Roche Elecsys® testosterone II assay and U‐T by gas chromatography‐mass spectrometry. Sal‐T correlated significantly with S‐T and calculated free testosterone in both controls and patients (HG men and GD FtM), while Sal‐T to U‐T showed weaker correlations. Trough values of Sal‐T after 12 months were significantly higher in the GD FtM group (0.77 ± 0.35 nmol/L) compared to HG men (0.53 ± 0.22 nmol/L) and controls (0.46 ± 0.15 nmol/L), while no differences between S‐T and U‐T trough values were found. Markedly elevated concentrations of salivary testosterone, 7–14 days after injection, were observed, especially in the GD FtM group. This study demonstrates that Sal‐T might be a useful clinical tool to monitor long‐term testosterone replacement therapy and might give additional information in forensic cases.
Etiologic effects and optimal intakes of foods and nutrients for risk of cardiovascular diseases and diabetes: Systematic reviews and meta-analyses from the Nutrition and Chronic Diseases Expert Group (NutriCoDE)

Background Dietary habits are major contributors to coronary heart disease, stroke, and diabetes. However, comprehensive evaluation of etiologic effects of dietary factors on cardiometabolic outcomes, their quantitative effects, and corresponding optimal intakes are not well-established. Objective To systematically review the evidence for effects of dietary factors on cardiometabolic diseases, including comprehensively assess evidence for causality; estimate magnitudes of etiologic effects; evaluate heterogeneity and potential for bias in these etiologic effects; and determine optimal population intake levels. Methods We utilized Bradford-Hill criteria to assess probable or convincing evidence for causal effects of multiple diet-cardiometabolic disease relationships. Etiologic effects were quantified from published or de novo meta-analyses of prospective studies or randomized clinical trials, incorporating standardized units, dose-response estimates, and heterogeneity by age and other characteristics. Potential for bias was assessed in validity analyses. Optimal intakes were determined by levels associated with lowest disease risk. Results We identified 10 foods and 7 nutrients with evidence for causal cardiometabolic effects, including protective effects of fruits, vegetables, beans/legumes, nuts/seeds, whole grains, fish, yogurt, fiber, seafood omega-3s, polyunsaturated fats, and potassium; and harms of unprocessed red meats, processed meats, sugar-sweetened beverages, glycemic load, trans-fats, and sodium. Proportional etiologic effects declined with age, but did not generally vary by sex. Established optimal population intakes were generally consistent with observed national intakes and major dietary guidelines. In validity analyses, the identified effects of individual dietary components were similar to quantified effects of dietary patterns on cardiovascular risk factors and hard endpoints. Conclusions These novel findings provide a comprehensive summary of causal evidence, quantitative etiologic effects, heterogeneity, and optimal intakes of major dietary factors for cardiometabolic diseases, informing disease impact estimation and policy planning and priorities.
Neither Cholinergic Nor Dopaminergic Enhancement Improve Spatial Working Memory Precision in Humans

Acetylcholine and dopamine are neurotransmitters that play multiple important roles in perception and cognition. Pharmacological cholinergic enhancement reduces excitatory receptive field size of neurons in marmoset primary visual cortex and sharpens the spatial tuning of visual perception and visual cortical fMRI responses in humans. Moreover, previous studies show that manipulation of cholinergic or dopaminergic signaling alters the spatial tuning of macaque prefrontal cortical neurons during the delay period of a spatial working memory (SWM) task and can improve SWM performance in macaque monkeys and human subjects. Here, we investigated the effects of systemic cholinergic and dopaminergic enhancement on the precision of SWM, as measured behaviorally in human subjects. Cholinergic transmission was increased by oral administration of 5 mg of the cholinesterase inhibitor donepezil, and dopaminergic signaling was enhanced with 100 mg levodopa/10 mg carbidopa. Each neurotransmitter system was separately investigated in double-blind placebo-controlled studies. On each trial of the SWM task, a square was presented for 150 ms at a random location along an invisible circle with a radius of 12 degrees of visual angle, followed by a 900 ms delay period with no stimulus shown on the screen. Then, the square was presented at new location, displaced in either a clockwise (CW) or counterclockwise (CCW) direction along the circle. Subjects used their memory of the location of the original square to report the direction of displacement. SWM precision was defined as the amount of displacement corresponding to 75% correct performance. We observed no significant effect on SWM precision for either donepezil or levodopa/carbidopa. There was also no significant effect on performance on the SWM task (percent correct across all trials) for either donepezil or levodopa/carbidopa. Thus, despite evidence that acetylcholine and dopamine regulate spatial tuning of individual neurons and can improve performance of SWM tasks, pharmacological enhancement of signaling of these neurotransmitters does not substantially affect a behavioral measure of the precision of SWM in humans.
Molecular adaptation in Rubisco: Discriminating between convergent evolution and positive selection using mechanistic and classical codon models

Rubisco (Ribulose-1, 5-biphosphate carboxylase/oxygenase) is the most important enzyme on earth, catalyzing the first step of CO2 fixation in photosynthesis. Its molecular adaptation to C4 photosynthetic pathway has attracted a lot of attention. C4 plants, which comprise less than 5% of land plants, have evolved more efficient photosynthesis compared to C3 plants. Interestingly, a large number of independent transitions from C3 to C4 phenotype have occurred. Each time, the Rubisco enzyme has been subject to similar changes in selective pressure, thus providing an excellent model for convergent evolution at the molecular level. Molecular adaptation is often identified with positive selection and is typically characterized by an elevated ratio of non-synonymous over synonymous substitution rates (dN/dS). However, convergent adaptation is expected to leave a different molecular signature, taking the form of repeated transitions toward identical or similar amino acids. Here, we use a previously introduced codon-based differential selection model to detect and quantify consistent patterns of convergent adaptation in Rubisco in Amaranthaceae. We further contrast the results thus obtained with those obtained under classical codon models based on the estimation of dN/dS. We find that the two classes of models tend to select distinct, although overlapping, sets of positions. This discrepancy in the results illustrates the conceptual difference between these models, while emphasizing the need to better discriminate between qualitatively different selective regimes, by using a broader class of codon models than those currently considered in molecular evolutionary studies.
Promoting Holistic Well-Being in Chronic Stroke Patients Through Leisure Art-Based Creative Engagement

Purpose: To examine the potential value of a creative art-based activity as a caring modality for promoting holistic well-being among chronic stroke patients, and to explore the feelings and meanings that stroke patients derived from their experience in leisure art-based creative engagement (LACE). Design: Qualitative design. Method: Participants were recruited through purposive and snowball sampling. Individual semi-structured interviews were conducted. Qualitative content analysis was performed. The design and implementation of LACE was guided by Watson’s theory of caring. Findings: Twenty-four participants completed the study. Four themes emerged from participants’ account of experiences with the LACE: (1) appreciation of opportunities, (2) appreciation of self, (3) appreciation of others, and (4) appreciation of life. Conclusion: From the perspective of the participants, engaging in LACE enhances their sense of enjoyment and self-expression. Furthermore, they perceived LACE as an affirmation of life and an empowering process strengthening their connection and appreciation with the self and others. Clinical Relevance: This study adds evidence to existing literature on Watson’s theory-guided design and implementation of caring initiatives for community rehabilitation and has laid the groundwork for developing further evidencebased research in leisure art-based caring occasions for promoting holistic well-being in stroke rehabilitation.
Direct Quantification of Cytochromes P450 and Drug Transporters—A Rapid, Targeted Mass Spectrometry-Based Immunoassay Panel for Tissues and Cell Culture Lysates

The quantification of drug metabolizing enzymes and transporters has recently been revolutionized on the basis of targeted proteomic approaches. Isotope-labeled peptides are used as standards for the quantification of the corresponding proteins in enzymatically fragmented samples. However, hurdles in these approaches are low throughput and tedious sample prefractionation steps prior to mass spectrometry (MS) readout. We have developed an assay platform using sensitive and selective immunoprecipitation coupled with mass spectrometric readout allowing the quantification of proteins directly from whole cell lysates using less than 20,000 cells per analysis. Peptide group-specific antibodies (triple X proteomics antibodies) enable the enrichment of proteotypic peptides sharing a common terminus. These antibodies were employed to establish a MS-based immunoassay panel for the quantification of 14 cytochrome P450 (P450) enzymes and nine transporters. We analyzed the P450 enzyme and transporter levels in genotyped liver tissue homogenates and microsomes, and in samples from a time course induction experiment in human hepatocytes addressing different induction pathways. For the analysis of P450 enzymes and transporters only a minute amount of sample is required and no prefractionation is necessary, thus the assay platform bears the potential to bridge cell culture model experiments and results from whole organ tissue studies.
RESPONSE OF GROWTH PATTERNS IN SWEET PEPPER TO DIFFERENT NPK LEVELS

ABDELAZIZ, M. E. , HANNFY AHMED, A. H. , BEKHIT, R. S. , POKLUDA, R. : Response of growth patterns in sweet pepper to diff erent NPK levels. Acta univ. agric. et silvic. Mendel. Brun. , 2008, LVI, No. 1, pp. 241–244 This work was conducted to study the eff ect of fi ve NPK fertigation levels on the growth rate of sweet pepper (Capsicum annuum L. cv. Bruyo) grown under the plastic greenhouse using diff erent growth analysis formulas. Leaf area ratio (LAR), specifi c leaf area (SLA), relative growth rate (RGR) and net