A model describing the multiphasic dynamics of mixed meal glucose responses in healthy subjects

Modelling of the glucose metabolism for the purpose of improving the diagnosis and therapy of diabetes mellitus has been the subject of research for decades. Despite this effort, conventional models describing postprandial glucose profiles of healthy subjects fail to include the phenomenon of biphasic glucose responses. Continuous glucose monitoring data recorded from five healthy subjects show that mono- and biphasic glucose responses from regular meals are equally common. We therefore developed a suitable parametric model, capable of producing mono- as well as biphasic meal responses. It is expressed by linear second order differential equation with a dual Gaussian input function. Additionally, a simple method for classifying meal responses into mono- or biphasic profiles was developed. Model inversion was performed using a fully Bayesian method. R2 values of model output compared to CGM data was 91.6 ± 8.3%, indicating the models ability of accurately describing a wide range of mixed meal glucose responses. Parameters were found to be associated with characteristics of individual meals. We suggest that the model could be used to objectively assess postprandial hyperglycemia, one of the main measures for glycemic control

Tuning the Structure of Nylon 6,6 Electrospun Bundles to Mimic the Mechanical Performance of Tendon Fascicles

Tendon and ligament injuries are triggered by mechanical loading, but the specific mechanisms are not yet clearly identified. It is well established however, that the inflection and transition points in tendon stress-strain curves represent thresholds that may signal the onset of irreversible fibrillar sliding. This phenomenon often results in a progressive macroscopic failure of these tissues. With the aim to simulate and replace tendons, electrospinning has been demonstrated to be a suitable technology to produce nanofibers similar to the collagen fibrils in a mat form. These nanofibrous mats can be easily assembled in higher hierarchical levels to reproduce the whole tissue structure. Despite the fact that several groups have developed electrospun tendon-inspired structures, an investigation of the inflection and transition point mechanics is missing. Comparing their behavior with that of the natural counterpart is important to adequately replicate their behavior at physiological strain levels. To fill this gap, in this work fascicle-inspired electrospun nylon 6,6 bundles were produced with different collector peripheral speeds (i.e., 19.7 m s–1; 13.7 m s–1; 7.9 m s–1), obtaining different patterns of nanofibers alignment. The scanning electron microcopy revealed a fibril-inspired structure of the nanofibers with an orientation at the higher speed similar to those in tendons and ligaments (T/L). A tensile mechanical characterization was carried out showing an elastic-brittle biomimetic behavior for the higher speed bundles with a progressively more ductile behavior at slower speeds. Moreover, for each sample category the transition and the inflection points were defined to study how these points can shift with the nanofiber arrangement and to compare their values with those of tendons. The results of this study will be of extreme interest for the material scientists working in the field, to model and improve the design of their electrospun structures and scaffolds and enable building a new generation of artificial tendons and ligaments

First report of Brenneria goodwinii, Gibbsiella quercinecans and Rahnella victoriana in declining oaks in France

Acute Oak Decline, Quercus petraea, Quercus robur Acute Oak Decline (AOD) is mediated by abiotic factors (temperature and precipitation) and triggered by insects (mainly the bark-boring beetle Agrilus biguttatus) and a complex of bacterial species (mainly Bren-neria goodwinii, Gibbsiella quercinecans and Rahnella victoriana) (Denman et al., 2017; Doonan et al., 2020). Given the extent of oak dieback and the prevalence of A. biguttatus in France (Saintonge & Goudet, 2020; Sallé et al., 2022), a preliminary study was done in five French forests to assess the prevalence of AOD symptoms (bleeding cortical lesions on the trunk associated with insect emergence holes and dieback) and to determine the bacteria associated with those symptoms. The mean prevalence of AOD symptoms was estimated at 37% arround 20 trees assessed in each of the five forests. Bark samples and, when possible, exudates were taken from lesions associated with insect emergence holes and/or cracks (Fig. 1). Bacterial isolations were made from 43 bark samples and 11 exudate samples by plating on three agar media (Luria, Gifu Anaerobic and Eosin Methylene Blue) and incubated at 22 • C for one to five days. Bacterial strains were identified by high-resolution melting (Brady et al., 2016) or 16S rRNA sequencing (Denman et al., 2016). The sequenced strains had 100% identity with sequences of reference strains (GenBank Accession Nos. CP014137.1, CP014136.1 and NR_146847.1). The percentage of trees infected with G. quercinecans, B. goodwinii and R. victoriana was 21, 16 and 12, respectively. These AOD-associated bacteria were detected with a higher success rate in exudates (81%) than in bark (25%). Gibbsiella quercinecans and B. good-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

A glucose-only model to extract physiological information from postprandial glucose profiles in subjects with normal glucose tolerance

Background: Current mathematical models of postprandial glucose metabolism in people with normal and impaired glucose tolerance rely on insulin measurements and are therefore not applicable in clinical practice. This research aims to develop a model that only requires glucose data for parameter estimation while also providing useful information on insulin sensitivity, insulin dynamics and the meal-related glucose appearance (GA). Methods: The proposed glucose-only model (GOM) is based on the oral minimal model (OMM) of glucose dynamics and substitutes the insulin dynamics with a novel function dependant on glucose levels and GA. A Bayesian method and glucose data from 22 subjects with normal glucose tolerance are utilised for parameter estimation. To validate the results of the GOM, a comparison to the results of the OMM, obtained by using glucose and insulin data from the same subjects is carried out. Results: The proposed GOM describes the glucose dynamics with comparable precision to the OMM with an RMSE of 5.1 ± 2.3 mg/dL and 5.3 ± 2.4 mg/dL, respectively and contains a parameter that is significantly correlated to the insulin sensitivity estimated by the OMM (r = 0.7) Furthermore, the dynamic properties of the time profiles of GA and insulin dynamics inferred by the GOM show high similarity to the corresponding results of the OMM. Conclusions: The proposed GOM can be used to extract useful physiological information on glucose metabolism in subjects with normal glucose tolerance. The model can be further developed for clinical applications to patients with impaired glucose tolerance under the use of continuous glucose monitoring data

Costs of Measuring Outcomes of Acute Hospital Care in a Longitudinal Outcomes Measurement System

It is widely acknowledged that the measurement of outcomes of care and the comparison of outcomes over time within health care providers and risk-adjusted comparisons among providers are important parts of improving quality and cost-effectiveness of care. However, few studies have assessed the costs of measuring outcomes of care. We sought to evaluate the personnel and financial resources spent for a prospective assessment of outcomes of acute hospital care by health professionals in internal medicine. The study included 15 primary care hospitals participating in a longitudinal outcomes measurement program and 2005 patients over an assessment period with an average duration of 6 months. Each hospital project manager participated in a previously-tested structured 30-minute telephone interview. Outcome measures include time spent by the individual job titles in implementing and running the outcomes measurement program. Job-title-specific times were used to calculate costs from the hospitals' perspective. One-time costs (C2132 + 1352) and administrative costs (95 97 per week) varied substantially. Costs per patient were fairly stable at around 20. We estimated that the total cost for each hospital to assess outcomes of care for accreditation (10 tracer diagnoses over 6 months) would be 9700 and that continuous monitoring of outcomes (5 tracer diagnoses) would cost 12,400 per year. This study suggests that outcomes of acute hospital care can be assessed with limited resources and that standardized training programs would reduce variability in overall costs. This study should help hospital decision makers to estimate the necessary funding for outcomes measurement initiatives

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother–child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germ-line mtDNA bottleneck at only ∼30–35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10−8 (interquartile range from 4.2 × 10−9 to 4.1 × 10−8) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification

The nature of delayed dream incorporation (‘dream-lag effect’): Personally significant events persist, but not major daily activities or concerns

Incorporation of details from waking life events into rapid eye movement (REM) sleep dreams has been found to be highest on the 2 nights after, and then 5–7 nights after, the event. These are termed, respectively, the day‐residue and dream‐lag effects. This study is the first to categorize types of waking life experiences and compare their incorporation into dreams across multiple successive nights. Thirty‐eight participants completed a daily diary each evening and a dream diary each morning for 14 days. In the daily diary, three categories of experiences were reported: major daily activities (MDAs), personally significant events (PSEs) and major concerns (MCs). After the 14‐day period each participant identified the correspondence between items in their daily diaries and subsequent dream reports. The day‐residue and dream‐lag effects were found for the incorporation of PSEs into dreams (effect sizes of .33 and .27, respectively), but only for participants (n = 19) who had a below‐median total number of correspondences between daily diary items and dream reports (termed “low‐incorporators” as opposed to “high‐incorporators”). Neither the day‐residue or dream‐lag effects were found for MDAs or MCs. This U‐shaped timescale of incorporation of events from daily life into dreams has been proposed to reflect REM sleep‐dependent memory consolidation, possibly related to emotional memory processing. This study had a larger sample size of dreams than any dream‐lag study hitherto with trained participants. Coupled with previous successful replications, there is thus substantial evidence supporting the dream‐lag effect and further explorations of its mechanism, including its neural underpinnings, are warranted

Comparative maturation of cynomolgus monkey oocytes in vivo and in vitro

BACKGROUND: In vitro maturation (IVM) of oocytes followed by fertilization in vitro (IVF) and embryo transfer offers an alternative to conventional IVF treatment that minimises drug administration and avoids ovarian hyperstimulation. However, the technique is less efficient than maturation in vivo. In the present study, a non-human primate model was used to address the hypothesis that the number of oocytes is increased and their nuclear and cytoplasmic maturity after IVM are improved when maturation is initiated in vivo by priming with hCG. METHODS: Young, adult cynomolgus monkeys were given recombinant human (rh) gonadotropins to stimulate the development of multiple follicles, and oocytes were aspirated 0, 12, 24, or 36 h after injection of an ovulatory dose of rhCG. The nuclear status of oocytes was determined at the time of recovery and after culture for a total elapsed time of 40–44 hours after hCG. RESULTS: Priming with hCG significantly increased the number of oocytes harvested, especially after delaying aspiration for 24 h or longer. Nuclear maturation after the full period in culture was also enhanced by priming: 71.5, 83.6, and 94.6% of oocytes collected at 0, 12, and 24 h hCG had progressed to MII by the end of the culture period, compared to 87.8% of oocytes that were retrieved at 36 h. A large proportion of oocytes reaching the MII stage had either or both abnormal spindles (>40%) and misaligned chromosomes (>60%), judging by immunofluorescence microscopy, but these abnormalities were independent of culture time. The mitochondria were evenly distributed throughout the cytoplasm at all stages of maturation. Importantly, there was no microscopic evidence that the duration of culture had any injurious effects on the cells. CONCLUSION: In conclusion, the evidence supports this non-human primate as a model for human IVM and the practice of priming with hCG to promote developmental potential

Incorporation of recent waking-life experiences in dreams correlates with frontal theta activity in REM sleep

Rapid eye movement (REM) sleep and its main oscillatory feature, frontal theta, have been related to the processing of recent emotional memories. As memories constitute much of the source material for our dreams, we explored the link between REM frontal theta and the memory sources of dreaming, so as to elucidate the brain activities behind the formation of dream content. Twenty participants were woken for dream reports in REM and slow wave sleep (SWS) while monitored using electroencephalography. Eighteen participants reported at least one REM dream and 14 at least one SWS dream, and they, and independent judges, subsequently compared their dream reports with log records of their previous daily experiences. The number of references to recent waking-life experiences in REM dreams was positively correlated with frontal theta activity in the REM sleep period. No such correlation was observed for older memories, nor for SWS dreams. The emotional intensity of recent waking-life experiences incorporated into dreams was higher than the emotional intensity of experiences that were not incorporated. These results suggest that the formation of wakefulness-related dream content is associated with REM theta activity, and accords with theories that dreaming reflects emotional memory processing taking place in REM sleep