Miracle-dz/UniFAR-FTUs huggingface dataset:
Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study

Introduction Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation. Materials and methods This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline. Results A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months. Discussion THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.
Seasonal growth and mortality of the pitchers of the Albany pitcher plant, Cephalotus follicularis labill

Growth, size and mortality of pitchers, and volume of their fluid contents were examined in the endemic Albany pitcher plant Cephalotus follicularis in relation to exposure, and age of the pitchers, and the time of year. C. follicularis had its growth season in spring and summer, between late October and February. Mortality was greatest in 'Year 2 or Older' pitchers, and greater in exposed pitchers in both age classes. The highest mortality was recorded between December and February. The pitchers opened when growth had finished, and their size was independent of age and year. There was no difference in size between sheltered localities, but one exposed locality had pitchers that were significantly larger than those of other localities. The pitchers contained fluid during development while the lid was closed which suggested that, initially, the fluid was a plant secretion. There was a significant difference in fluid volumes between shaded and exposed pitchers in late summer but these differences did not exist in spring following the winter rains.
Measurement of (1 → 3),(1 → 4)‐β‐D‐glucan in barley and oats: A streamlined enzymic procedure

A commercially available enzymic method for the quantitative measurement of (1 → 3),(1 → 4)-β-glucan has been simplified to allow analysis of up to 10 grain samples in 70 min or of 100–200 samples by a single operator in a day. These improvements have been achieved with no loss in accuracy or precision and with an increase in reliability. The glucose oxidase/peroxidase reagent has been significantly improved to ensure colour stability for periods of up to 1 h after development. Some problems experienced with the original method have been addressed and resolved, and further experiments to demonstrate the quantitative nature of the assay have been designed and performed.
THE GEOGRAPHICAL DISTRIBUTION OF ALLELIC DIVERSITY, A PRACTICAL MEANS OF PRESERVING AND USING MINOR ROOT CROP GENETIC RESOURCES

This paper addresses the preservation and use of minor root crop genetic resources, mostly aroids and yams. Conservation is fraught with difficulty: ex situ collections are expensive to maintain and methods for on-farm conservation have not been studied. Conventional breeding strategies present serious limitations when applied to these species. Furthermore, the evaluation and distribution of improved material are as problematical as its conservation. The similarities shared by these species regarding their domestication, breeding constraints and improvement strategies as well as farmers' needs, are briefly reviewed. Based on these biological constraints, we propose a practical alternative to current conservation and breeding strategies. This approach focuses on the geographical distribution of allelic diversity rather than localized ex situ and/or in situ preservation of genotypes. The practical steps are described and discussed. First, a core sample representing the useful diversity of the species is assembled from accessions selected for their diverse and distant geographic origins, wide genetic distances, quality, agronomic performances and functional sexuality. Second, the geographical distribution of this core sample, in vitro via a transit centre, allows the direct use of selected genotypes by farmers or for breeding purposes. Third, the distribution of genes is realized in the form of clones resulting from segregating progenies and, fourth, farmers select clones with local adaptation.
Loss of Chromosome Y and Its Potential Applications as Biomarker in Health and Forensic Sciences

Loss of chromosome Y (LOY) is a mosaic aneuploidy that can be detected mainly in blood samples of male individuals. Usually, LOY occurrence increases with chronological age in healthy men. Moreover, recently LOY has been reported in association with several diseases, such as cancer, where its frequency is even higher. The Y chromosome is one of the shortest chromosomes of the human karyotype, and it is crucial for correct male development. This chromosome has functions beyond the male reproductive system, and loss of its genes or even LOY can have consequences for the male body that are yet to be elucidated. Analyses of the Y chromosome are largely applied in forensic contexts such as paternity testing, ancestry studies, and sexual assault cases, among others. Thus, LOY can be a disadvantage, limiting laboratory methods and result interpretation. However, as an advantage, LOY detection could be used as a biological age biomarker due to its association with the aging process. The potential application of LOY as biomarker highlights the necessity to clarify the molecular mechanism behind its occurrence and its possible applications in both health and forensic studies.
Risk of psychiatric disorders among the surviving twins after a co-twin loss

Losing a co-twin by death is a severely stressful event yet with unknown impact on the surviving twin’s risk of psychiatric disorders. We identified all Swedish-born twins who lost a co-twin by death between 1973 and 2013 (n = 4,528), their 4939 non-twin full siblings, together with 22,640 age- and sex-matched non-bereaved twins. Compared to the non-bereaved twins, exposed twins were at increased risk of receiving a first diagnosis of psychiatric disorders (hazard ratio = 1.65, 95% confidence interval1.48–1.83), particularly during the first month after loss. Similarly, compared to non-twin full siblings, the relative risks were significantly increased after loss of monozygotic co-twin (2.45-fold), and loss of a dizygotic co-twin (1.29-fold), with higher HR observed with greater age gaps between twins and non-twin siblings. As dizygotic twins share equal genetic relatedness to the deceased twin as their full siblings, this pattern suggests that beyond the contribution of genetic factors, shared early life experiences and attachment contribute to the risk of psychiatric disorders among surviving twins after co-twin loss.
Components of fertilization success in the bluehead wrasse, Thalassoma bifasciatum

In many species of marine organisms, males and females release gametes directly into the water column. Although free-spawning marine invertebrates appear to have highly variable fertilization success, in tropical reef fishes the average fertilization success is quite high, typically over 90%; nevertheless, substantial variation has been reported, and fertilization has a direct effect on fitness. We investigated the factors affecting fertilization success in natural spawnings of the bluehead wrasse, Thalassoma bifasciatum. During a two-year study at a site in St. Croix, we found extensive and predictable variation in fertilization success in pair spawns of this reef fish. Fertilization success averaged 95%, but was affected by the amount of sperm released, the water velocity at a site, the mating success of the male, and the size of the female. As sperm released in a spawn increases, and as water velocity at a site decreases, sperm concentrations should remain higher in the vicinity of eggs for a longer period of time, and both of these factors are correlated with increasing fertilization success. The recent history of individuals with partners or sites did not affect the fertilization success of their spawn. In an evolutionary context, the real and predictable variance in fertilization success in this species may influence the mating choices of males and females. However, there is currently no evidence that females use differences in fertilization success among males or sites in their reproductive decisions. Key words: bluehead wrasse; Coral reef fish; mate choice; fertilization; reproductive success; spawning; sperm limitation, Thalassoma bifasciatum. [Behav Ecol 12:237–245 (2001)]
Cognitive‐motivational, interpersonal, and behavioral functioning in relationship to treatment and research engagement in forensic patients with ADHD

Abstract Objectives To provide more insight into treatment and research responsivity in offenders with attention‐deficit hyperactivity disorder (ADHD). Method Via self‐reports and patients' scores on cognitive computer tasks, it was examined whether poorer cognitive‐motivational, interpersonal, and behavioral functioning were related to treatment no‐shows, longer treatment time duration intervals, and no‐show at the research appointment in 52 forensic outpatients with ADHD (M age = 35.3, SD = 9.38). Treatment adherence was tracked for 10 appointments after research participation. Results Regression analyses showed that higher self‐reported impulsivity was associated with research no‐show, and more alcohol use with longer treatment time intervals. Yet, self‐reported delay aversion was associated with fewer treatment no‐shows, and, uncontrolled for alcohol use, impulsivity was associated with shorter treatment time intervals in a subsample of patients. Conclusions These preliminary results indicate that externalizing behaviors increase the risk for nonadherence in forensic ADHD patients, but that cognitive‐motivational problems also motivate patients to be more engaged.
Zirconium(IV) Chloride Catalyzed Synthesis of 2,3‐Unsaturated C, N, O, S, and Heteroaromatic Glycosylation in the Ferrier Rearrangement

Abstract The reaction of tri‐O‐acetyl‐D‐glucal with nucleophiles to afford the corresponding 2,3‐unsaturated glycopyranosides in excellent yields by zirconium(IV) chloride in acetonitrile at ambient temperature has been demonstrated. #IICT Communication No 021011
DHA supplementation in infants born preterm and the effect on attention at 18 months’ corrected age: follow-up of a subset of the N3RO randomised controlled trial

Abstract Infants born preterm miss out on the peak period of in utero DHA accretion to the brain during the last trimester of pregnancy which is hypothesised to contribute to the increased prevalence of neurodevelopmental deficits in this population. This study aimed to determine whether DHA supplementation in infants born preterm improves attention at 18 months’ corrected age. This is a follow-up of a subset of infants who participated in the N3RO randomised controlled trial. Infants were randomised to receive an enteral emulsion of high-dose DHA (60 mg/kg per d) or no DHA (soya oil – control) from within the first days of birth until 36 weeks’ post-menstrual age. The assessment of attention involved three tasks requiring the child to maintain attention on toy/s in either the presence or absence of competition or a distractor. The primary outcome was the child’s latency of distractibility when attention was focused on a toy. The primary outcome was available for seventy-three of the 120 infants that were eligible to participate. There was no evidence of a difference between groups in the latency of distractibility (adjusted mean difference: 0·08 s, 95 % CI –0·81, 0·97; P = 0·86). Enteral DHA supplementation did not result in improved attention in infants born preterm at 18 months’ corrected age.
The use of genetic makers to reveal dynamic processes in a common toad (Bufo Bufo) population

In contrast to birds and mammals for example, amphibian population studies only rarely capture information based on genealogical relationships among individuals. As a consequence, we only have very limited knowledge about individual fitness measures such as lifetime reproductive success and the consequences of such variation on the linkage between generations of amphibians in the wild. The present thesis makes use of an existing long-term study on the common toad (Bufo bufo) in southern England (Dorset) to genetically identify parent-offspring relationships among approximately 850 individual toads, representing two successive generations (2004/2005/2006 and 2008/2009). The dataset enabled the comparison of measures of effective population size as well as effective breeding size, revealing ratios between 0.07 and 0.26. These data also showed an increasing trend with time and were (by some estimators) confirmed by the cross-generational parentage analysis which revealed a high reproductive skew among individuals. Forty-five percent of offspring could be assigned to a least one parent; in total, 6% of male parents and 30% of female parents were inferred. The pedigree information was also used to identify a possible hereditary basis for an observed decrease in female body condition and fecundity correlated to increased environmental temperatures. There was no indication for heritability of body size, body weight and body condition, suggesting that the documented decrease is based on phenotypic plasticity rather than evolutionary adaptation. However, kinship data that shows the population is less inbred with time coupled with the effective breeding number estimates showing an increasing trend with time suggest that despite the absence of evolutionary change, this population may still be able to circumvent the adverse effects associated with decreased body condition.
Exercise and well-being during COVID 19 – time to boost your immunity

ABSTRACT Introduction The COVID-19 pandemic is causing devastating global morbidity and mortality. Worldwide measures are taken to prevent human to human transmission and improve general health. Public lifestyle and health are affected by social distancing and isolation. A strong host immune response to the novel coronavirus is a key factor, for protection against infection and avoiding reaching severe stages of the disease. Areas covered Pathophysiology and the human immune response of similar coronaviruses have been previously described. The novel coronavirus has distinct clinical stages related to the immune response. Exercise improves host innate immunity and affords protection to viral infections. Exercise also mitigates the negative effects of isolation including stress, anxiety, and sedentarism, all of which further reduces immunity and increases non-communicable disease risk. Expert opinion Improving host immunity and mitigating the negative effects of isolation via physical activity is strongly justified. Exercise should be done in moderate intensities and volumes during the current pandemic, which is a nutritionally, psychologically, socially challenging environment in the presence of a virulent viral organism. Proactively creating innovative health promotion models with technology and government involvement with the best available evidence should be encouraged to reduce physical inactivity during the current COVID-19 pandemic and after.
STUDIES ON BACTERIEMIA

Large numbers of E. coli were rapidly removed from the blood stream of rabbits at rates which initially paralleled the removal of similar numbers of staphylococci. Splanchnic tissues removed approximately two-thirds of the circulating bacilli in transit through the liver and spleen. In contrast to the cessation of splanchnic trapping noted 20 to 40 minutes following the injection of staphylococci, splanchnic trapping of E. coli continued unchanged for 3 to 5 hours unless the splanchnic tissues were dearly reseeding the blood stream. This resulted in the continued disappearance of E. coli over a 60 to 90 minute period, and differed from the constant bacteriemia maintained beyond 20 minutes after the injection of staphylococci. Some of the differences in the initial clearance of these two microorganisms appeared to relate to differences in host leukocyte-bacterium relationships. In vitro studies indicated that E. coli were rapidly killed following ingestion by rabbit polymorphonuclear leukocytes. Staphylococci survive such ingestion. The injection of E. coli was followed by a prolonged granulocytopenia with evidence of sequestration of granulocytes within the pulmonary vascular bed. The injection of staphylococci was followed by a transient leukopenia, with rapid return of granulocytes to the circulation (15). It appears probable that E. coli ingested by sequestered leukocytes are destroyed within the cell, and that leukocytes do not reenter the circulation containing living E. coli. Such intraleukocytic residence in the blood stream has been shown to be of possible importance in the maintenance of staphylococcal bacteriemia (14). An increasing E. coli bacteriemia occurred rapidly after the initial clearance period, indicating that many sequestered bacilli remained viable. Increasing bacteriemia also occurs 3 to 5 hours after the injection of staphylococci. The bacterial or host cell mechanisms which allow this secondary resurgence of bacterial populations are currently under investigation.
LATE CRETACEOUS AVIAN EGGS WITH EMBRYOS FROM ARGENTINA

MARY H. SCHWEITZER1,2, FRANKIE D. JACKSON2, LUIS M. CHIAPPE3, JAMES G. SCHMITT2, JORGE O. CALVO4, and DAVID E. RUBILAR5 1Department of Microbiology, Montana State University, Bozeman, Montana 59717, schweitz@montana.edu; 2Department of Earth Sciences and Museum of the Rockies, Montana State University, Bozeman, Montana 59717; 3Natural History Museum of Los Angeles, Los Angeles, California 90007; 4Museo de Geologia y Paleontologia, Universidad Nacional del Comahue, Neuqu6n, Argentina; 5Instituto de Geociencias, Universidad Austral de Chile, Casilla 567, Valdivia, Chile, and Secci6n Paleontologia, Museo Nacional de Historia Natural, Casilla 787, Santiago, Chile
Step time asymmetry but not step length asymmetry is adapted to optimize energy cost of split‐belt treadmill walking

The relationship between spatiotemporal gait asymmetry and walking energetics is currently under debate. The split‐belt treadmill paradigm has been used to study adaptation of spatiotemporal gait parameters in relation to energetics, but it remains unclear why people reduce asymmetry in step lengths, but prefer asymmetry in step times. In this study we characterized the effects of step time asymmetry and step length asymmetry on energy cost during steady‐state walking on a split‐belt treadmill at increasing speed‐differences. Both the optimal and preferred step time asymmetry increased with greater speed differences, while preferred step lengths remained constant and nearly symmetric. Preferred asymmetric step times were energetically optimal across all speed‐difference conditions, while preferred step length asymmetry was not optimal. The findings show that humans will adopt an asymmetric gait that is associated with an energy reduction and suggest that step time asymmetry plays a dominant role in shaping the energetic cost of gait asymmetry.
Contrastive Divergence Constrained by Reconstruction Error

Deep learning is one of the most popular technology in machine learning at present. It brings a new breakthrough for intelligent information processing at Big Data era. The core algorithm of deep learning is Contrastive Divergence (CD) algorithm. The original training goal of CD is to maximize the likelihood of the probability distributions between the marginal distribution of the models visible nodes and the distribution of the training set. Aiming this training goal, the model is a one-way feature-extraction model, or encoding model. This is not suit for reconstructing information from features, or decoding model. In order to apply the model as a decoder, we need to consider the reconstruction performance additionally. A regularization constraint method based on cross entropy was designed, which adds reconstruction constraint to the visible layer of deep model. Experiments show that the new algorithm achieves reconstruction performance improvement while loses a certain likelihood degree.
Studies on the Biosynthesis of Tabtoxin (Wildfire Toxin). Origin of the Carbonyl C‐Atom of the β‐Lactam Moiety from the C1‐Pool

Re-isolation of Pseudomonas tabaci strain NCPPB 2730 from its host, the tobacco plant, led to an activation of the bacteria in order to produce the β-lactam dipeptide tabtoxin (Wildfire toxin, 1). Incorporation of several 14C-labelled amino acids as well as L-[methyl-13C]methionine, L-[1,2-13C2]- and L-[3,4-13C2]aspartate, rac -[1,2-13C2]glycerol, and [1,2-13C2]acetate into isotabtoxion (2) demonstrated that the building blocks of tabtoxin (1) are L-threonine, L-aspartate, the Me group of L-methionine and a C2-unit derived from the C3-pool (Fig. 3). The Me group of L-methionine provides the carbonyl C-atom of the β-lactam moiety. These findings represent a novel pathway in β-lactam biosynthesis. Mechanistic aspects with respect to the β-lactam ring formation are discussed. A biradical 16 is proposed as an intermediate during the cyclization of a N-formyl-α-amino ketone 15.
Rational optimization of a monoclonal antibody improves the aggregation propensity and enhances the CMC properties along the entire pharmaceutical process chain

ABSTRACT The discovery of therapeutic monoclonal antibodies (mAbs) primarily focuses on their biological activity favoring the selection of highly potent drug candidates. These candidates, however, may have physical or chemical attributes that lead to unfavorable chemistry, manufacturing, and control (CMC) properties, such as low product titers, conformational and colloidal instabilities, or poor solubility, which can hamper or even prevent development and manufacturing. Hence, there is an urgent need to consider the developability of mAb candidates during lead identification and optimization. This work provides a comprehensive proof of concept study for the significantly improved developability of a mAb variant that was optimized with the help of sophisticated in silico tools relative to its difficult-to-develop parental counterpart. Interestingly, a single amino acid substitution in the variable domain of the light chain resulted in a three-fold increased product titer after stable expression in Chinese hamster ovary cells. Microscopic investigations revealed that wild type mAb-producing cells displayed potential antibody inclusions, while the in silico optimized variant-producing cells showed a rescued phenotype. Notably, the drug substance of the in silico optimized variant contained substantially reduced levels of aggregates and fragments after downstream process purification. Finally, formulation studies unraveled a significantly enhanced colloidal stability of the in silico optimized variant while its folding stability and potency were maintained. This study emphasizes that implementation of bioinformatics early in lead generation and optimization of biotherapeutics reduces failures during subsequent development activities and supports the reduction of project timelines and resources.