Novel skeletal effects of glucagon-like peptide-1 (GLP-1) receptor agonists

Type 2 diabetes mellitus (T2DM) leads to bone fragility and predisposes to increased risk of fracture, poor bone healing and other skeletal complications. In addition, some anti-diabetic therapies for T2DM can have notable detrimental skeletal effects. Thus, an appropriate therapeutic strategy for T2DM should not only be effective in re-establishing good glycaemic control but also in minimising skeletal complications. There is increasing evidence that glucagon-like peptide-1 receptor agonists (GLP-1RAs), now greatly prescribed for the treatment of T2DM, have beneficial skeletal effects although the underlying mechanisms are not completely understood. This review provides an overview of the direct and indirect effects of GLP-1RAs on bone physiology, focusing on bone quality and novel mechanisms of action on the vasculature and hormonal regulation. The overall experimental studies indicate significant positive skeletal effects of GLP-1RAs on bone quality and strength although their mechanisms of actions may differ according to various GLP-1RAs and clinical studies supporting their bone protective effects are still lacking. The possibility that GLP-1RAs could improve blood supply to bone, which is essential for skeletal health, is of major interest and suggests that GLP-1 anti-diabetic therapy could benefit the rising number of elderly T2DM patients with osteoporosis and high fracture risk

Long-Term Monitoring of Rare Gypsum Communities in the Eastern Mojave Desert: A Study in Science and Art

For land managers, reliable estimates of soil seed banks, and more specifically, change in seed banks over time, provide insight into the restoration and regeneration potential of the landscape, site history and disturbance mapping, and, invasive and rare plant management. To understand the intricacies of desert soil seed banks in relation to aboveground vegetation change, my research evaluated long-term change in soil seed banks, fertile islands, and plant communities of conservation-priority gypsum rare plant habitat of the eastern Mojave Desert. Research found significant spatial and temporal differences in seed bank composition and density over an 11-year period; however, the gypsum aboveground communities nevertheless maintain strong spatiotemporal patterns. This study also explored two related topics in order to support land managers in vulnerable desert landscapes from a conservation and restoration standpoint. The rare species Arctomecon californica occupies gypsum habitat and is considered critically endangered by the state of Nevada and is provided federal protection under the Clark County Multiple Species Habitat Conservation Plan. Results are the first to demonstrate the significant effect of cold stratification on A. californica seed germination in a laboratory setting providing a crucial step-forward in ecology of the species. The final component of this research involves the use of traditional and contemporary scientific illustration techniques to provide a novel identification tool for Mojave Desert seeds and young germinates. This guide will not only assist in future soil seed bank analysis and field surveys but could also be used as an important teaching and outreach tool for students

Biomanufacturing technology advances enable rapid response to disease outbreaks

Outbreaks can have devastating socio-economic and mental health impacts if the spread of disease is not stopped. Particularly in the case of COVID-19 which has claimed thousands of lives across the globe, the importance of rapid response to disease outbreaks is paramount. In the past, response to pandemics was following very long licensing and development timeframes, whereas in the case of COVID-19 the response was immediate while approval and manufacturing timeframes were much shorter. The global COVID-19 pandemic has highlighted the important role that scalable and flexible manufacturing solutions play in enabling rapid response to new disease outbreaks. In this unprecedent situation the industry joined forces and accelerated the development of new vaccine candidates to rapidly respond to the pandemic. Following this the next hurdle was to ensure that scaling up the production capacity to respond to the global immunization demand was feasible. Indeed, manufacturing capacity often acts as a bottleneck in rapid development programs. Traditional manufacturing processes are highly complex, require extensive process development efforts, and tend to suffer from a lack of scalability to rapidly reach commercial scale capacity. Considering the short timelines, vaccines are developed and scale-up at risk, with companies deploying manufacturing facilities at very early stage. Therefore, it is important that manufacturers can rapidly adapt their existing equipment and facilities for alternative drug candidates. This requires manufacturers to have facilities and equipment that are truly flexible and can be adapted for different drug candidates and processes. Please click Download on the upper right corner to see the full abstract

Continuous and Segmented-Flow Microfluidics for Biomolecular Analysis

Segmented flows in microfluidics have attracted much recent attention. Of particular interest is the use of nanolitre droplets as interface tools in microfluidics. A droplet interface connects techniques while leaving them sufficiently independent of each other; a task that difficult to perform within a continuous flow system. The first part of this thesis is dedicated to sample preparation and analysis in continuous flow microfluidic systems. The polymerase chain reaction (PCR) is investigated, using electroosmotic flow to transport the sample across various temperature zones. Additionally, a novel sieving matrix for electrophoretic separation of dsDNA fragments and PCR amplicons on microchip and capillary is demonstrated. The second part of this thesis focuses on interfacing segmented and continuous flows. Two novel interfaces are described and demonstrated. The first interface connects droplet flows and a chip-based electrophoresis device. Using this interface, samples or reactions performed in droplets can be directly transferred to a separation channel without suspending the separation. This allows multiple samples to be analysed in a single separation channel, without cross contamination between droplets. Consequently, PCR reactions and dsDNA calibration ladders can be prepared in droplet format and analysed in high throughput. The second interface links nano-liquid chromatography and MALDI mass spectrometry. Droplet fractionation post nano-LC separation is used to preserve resolution between separated bands. The droplets are subsequently delivered to a MALDI plate for mass spectrometric analysis by removing the continuous oil phase using a hydrophobic oleophilic membrane. The tools developed here reduce manual intervention and provide a link between multiple analytical techniques involved in biomolecule analysis. These innovations will improve reproducibility and reduce cross-contamination between samples

Teaching Excellence Programs – Lessons Learned At Two Universities

Universities are seeking novel ways to strengthen the collective educational competence of their faculty and promote educational merits. In this paper we describe and compare the experiences of two recently started initiatives for teaching excellence, the Program for Future Leaders for Strategic Educational Development at KTH Royal Institute of Technology (henceforth KTH) and the Teaching Fellowship Programme at the University of Twente. Both programs have recently completed one complete round of implementation. The programmes are similar in that the participants work on a project of their own for an extended time, while also being part of a community with regular meetings and supported by coaches. The main differences are the programme duration, number of participants, and whether the projects are in a specific theme or wholly formulated by the participants. In this study, both programs are evaluated using similar themes. We analyse this data, and reflect on the context, conditions and design of the programs and our lessons learned from these first experiences.</p

A synthesis of knowledge on the large Pleistocene mammalian fauna from Corsica

Durant els darrers deu anys, el coneixement sobre la fauna de grans mamífers del Pleistocè de Còrsega s'ha incrementat significativament gràcies a l'estudi de vuit conjunts fossilifers provinents de 6 jaciments fossilifers : Castiglione 1 et 3 (Oletta/ Haute-Corse), La Coscia abri sud, abri nord-oeust (Rogliano, Cap Corse, Corte (Haute-Corse), Punta di Calcina (Corse du Sud). Divuit espècies extingides (6 micromamífers i 12 macromamífers) es troben distribuïdes en un interval de temps que abasta des del Pleistocè Mitjà fins a la fi del Pleistocè Superior. Aquests taxa, o bé són endèmics de Còrsega i Sardenya, o bé només de Còrsega i fins a la data no es coneixen de nivells sards d'edat similar o més primerenca. Els estudis revelen una fauna disharmònica, i no il·lustren cap cas de nanisme o gegantisme insular durant aquest interval temporal. Durant el Pleistocè Mitjà, els membres d'aquesta fauna ja havien adquirit les característiques de les espècies evolucionades sota condicions d'insularitat. D'ençà del Pleistocè Mitjà, la fauna no va sofrir cap renovació d'espècies, si bé va perdre alguns dels seus elements durant el Pleistocè Mitjà o a la fi d'aquest període, o allimit Tardiglacial/Holocè. En comparació i contrastant amb el que esdevé a altres illes mediterrànies, la diversitat de la macrofauna de mamífers de Còrsega és notable i cal emfatitzar que els carnivors es troben relativament ben representats al Pleistocè Mitjà, amb dues famílies (Canidae, Mustelidae) i cinc taxa reconeguts (Canissp., Cuoninae indeterminat, Cyrnolutra castiglionis, dos Mustelidae indeterminats). Respecte els artiodàctils, hi ha dues famílies (Cervidae, Suidae) i tres gèneres (Megaloceros, Cervus, Sus). Aquesta contribució tracta de representar algunes dades sobre la morfologia i la distribució estratigràfica dels macromamífers de Còrsega i tracta d'indicar els problemes relacionats amb les migracions i extincions d'espècies al Pleistocè.During the past ten years, the knowledge about the Corsican Pleistocene large mammalian fauna has significantly increased owing the study of eight assemblages extracted from six fossiliferous deposits: Castiglione 1 et 3 (Oletta/HauteCorse), La Coscia abri sud, abri nord-oeust (Rogliano, Cap Corse, Corte (Haute-Corse), Punta di Calcina (Corse du Sud). Eighteen extinct species (6 small mammals and 121arge ones) are distributed in a time interval extending from the Middle Pleistocene up to the end of Upper Pleistocene. These taxa are either endemic to Corsica and Sardinia or only known in Corsica and up to now unknown from Sardinia levels of similar age or earlier. Studies indicate an unbalanced fauna, without any illustration of island dwarfism or gigantism during the involved time interval. At the time of the Middle Pleistocene, the members of this fauna already acquired characteristics of species having evolved under conditions of isolation. Since the Middle Pleistocene, the fauna underwent no species renewal but lost some of its members during the Middle Pleistocene or at the end of this period, or at the Tardiglacial/Holocene boundary. In comparison with and by contrast to some oilier Mediterranean islands, the diversity of the Corsican large mammal fauna is worth to be emphasised even if carnivores are rather well represented in the Middle Pleistocene with two families (Canidae, Mustelidae) and five recognised taxa (Canis sp., Cuoninae indet., Cyrnolutra castiglionis, two Mustelidae indet.). With respect to artiodactyls, there are two famílies (Cervidae, Suidae) and three genera (Megaloceros, Cervus, Sus). This contribution intends to present some data on the morphology and ilie stratigraphical distribution of the members of the Corsican large mammal fauna and to point out the problems connected with Pleistocene migration and extinction of species

Sex Differences in Arm Muscle Fatigability With Cognitive Demand in Older Adults

Background Muscle fatigability can increase when a stressful, cognitively demanding task is imposed during a low-force fatiguing contraction with the arm muscles, especially in women. Whether this occurs among older adults (\u3e 60 years) is currently unknown. Questions/purposes We aimed to determine if higher cognitive demands, stratified by sex, increased fatigability in older adults (\u3e 60 years). Secondarily, we assessed if varying cognitive demand resulted in decreased steadiness and was explained by anxiety or cortisol levels. Methods Seventeen older women (70 ± 6 years) and 13 older men (71 ± 5 years) performed a sustained, isometric, fatiguing contraction at 20% of maximal voluntary contraction until task failure during three sessions: high cognitive demand (high CD = mental subtraction by 13); low cognitive demand (low CD = mental subtraction by 1); and control (no subtraction). Results Fatigability was greater when high and low CD were performed during the fatiguing contraction for the women but not for the men. In women, time to failure with high CD was 16 ± 8 minutes and with low CD was 17 ± 4 minutes, both of which were shorter than time to failure in control contractions (21 ± 7 minutes; high CD mean difference: 5 minutes [95% confidence interval {CI}, 0.78–9.89], p = 0.02; low CD mean difference: 4 minutes [95% CI, 0.57–7.31], p = 0.03). However, in men, no differences were detected in time to failure with cognitive demand (control: 13 ± 5 minutes; high CD mean difference: −0.09 minutes [95% CI, −2.8 to 2.7], p = 1.00; low CD mean difference: 0.75 minutes [95% CI, −1.1 to 2.6], p = 0.85). Steadiness decreased (force fluctuations increased) more during high CD than control. Elevated anxiety, mean arterial pressure, and salivary cortisol levels in both men and women did not explain the greater fatigability during high CD. Conclusions Older women but not men showed marked increases in fatigability when low or high CD was imposed during sustained static contractions with the elbow flexor muscles and contrasts with previous findings for the lower limb. Steadiness decreased in both sexes when high CD was imposed. Clinical Relevance Older women are susceptible to greater fatigability of the upper limb with heightened mental activity during sustained postural contractions, which are the foundation of many work-related tasks

Report of the first Brazilian infantile Pompe disease patient to be treated with recombinant human acid alpha-glucosidase

Objetivo: Relatar o primeiro caso de forma infantil da doença de Pompe tratado no Brasil. Descrição: Trata-se de doença de depósito lisossomal que se caracteriza por defeitos da enzima alfa-glicosidase ácida, com acúmulo intracelular de glicogênio, principalmente nos músculos. São descritas a forma infantil e tardia. Desde 2006, está disponível tratamento com enzima recombinante humana. Descreve-se o primeiro caso de forma infantil da doença tratado no Brasil. Trata-se de menina com 2,5 meses de idade e progressão rápida da doença, com perda dos movimentos dos membros, miocardiopatia hipertrófica e insuficiência respiratória aos 7 meses de idade. Após 10 meses de tratamento, apresentou boa resposta clínica, com remissão da insuficiência respiratória, recuperação parcial dos movimentos dos membros e melhora importante do quadro cardiológico. Comentários: Apesar de pouco freqüente, a forma infantil da doença de Pompe é letal. A disponibilidade de tratamento eficaz aumenta a necessidade de conhecimento e diagnóstico precoce da doença.Objective: To describe the first case of infantile Pompe disease to be treated in Brazil. Description: Pompe disease is a glycogen storage disease related to defects in the acid alpha-glucosidase enzyme, leading to an intracellular accumulation of glycogen, mainly in muscles. Two forms are described: infantile and juvenile. Since 2006, treatment with recombinant human acid alpha-glucosidase has been available. This article describes the first case of infantile Pompe disease treated in Brazil. A girl presented at 2.5 months of age with rapid disease progression, exhibiting severe hypotonia, loss of movements in both upper and lower limbs and hypertrophic cardiomyopathy, progressing to respiratory failure by the age of 7 months. After 10 months of treatment, she exhibited a good clinical response, with remission of the respiratory failure, partial recovery of arm and leg movements and improvement of cardiologic condition. Comments: Despite its low incidence, infantile Pompe disease is lethal. The availability of an effective treatment has created an urgent need to improve knowledge and early diagnosis of this disease

Optimizing access to drinking water in remote areas. Application to Nepal

This study is motivated by the need to restore part of the Nepal water distribution network that was destroyed by the Gorkha and Dolakha earthquakes in April and May 2015. The problem consists of two hierarchical subproblems: locating water taps to ensure a good coverage of the population, and connecting these water taps to water sources by means of a pipe distribution network. Both subproblems are subject to a variety of accessibility and technical constraints that make the problem unique and highly complex. Namely, because Nepal is highly mountainous, elevations must be taken into account in the distance calculations, and the distribution network is gravity-fed, meaning that pumps are not used. The problem is solved by means of a two-phase matheuristic: the first subproblem is a constrained location–allocation problem which is solved exactly by integer linear programming, while the second subproblem is tackled by means of a cluster-first, tree-second heuristic. Several variants of the heuristic are developed and compared. The network design problem is of very large scale, being solved on a graph with as many as 29,900 vertices and 75,200 arcs. Tests are performed on real-world data, obtained by satellite imagery, from the Suspa Kshemawati and Lapilang communities in the Dolakha district. Extensive computational results confirm the effectiveness of the proposed methodology and enable an identification of the best parameter settings and algorithmic tactical choices.</p