There is a need for anti-diabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was 1) to evaluate safety and tolerability; 2) to evaluate pharmacokinetics and 3) to assess indications of receptor engagement of single ascending doses of KBP-042, a Dual Amylin and Calcitonin Receptor Agonists (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 evening and 40µg) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after four hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20µg and above. Doses of 5 to 40 μg KBP-042 were behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 μg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Objectives: Severe disease characterized by interstitial pneumonia may develop in some cases of coronavirus disease (COVID-19). Periostin has been associated with many respiratory diseases. In this study, we aimed to investigate whether periostin could be a useful new biomarker in the follow-up and severity assessment of the disease in patients with COVID-19 pneumonia. Methods: In the study, 32 patients followed up during May–July 2020 due to COVID-19 and 24 healthy controls were included. The patients were divided into two groups, namely, mild/moderate and severe, according to the severity of the disease. Serum periostin and transforming growth factor beta (TGF-β) levels were tested using an enzyme-linked immunosorbent assay (ELISA) method using commercially available ELISA kits. Results: It was observed that the periostin level was significantly higher in both mild/moderate cases and severe cases compared to the control group at first presentation. However, TGF-β levels at first presentation were similar between the groups. Conclusions: Our study is the first study to investigate periostin levels in patients with COVID-19, and we believe that periostin can be used as a new biomarker. Keywords: COVID-19, Periostin, TGF-β, Pneumonia, New Biomarker Coronaviruses are among the main pathogens that mainly target the human respiratory system. Severe disease characterized by interstitial pneumonia develops in 10-20% of patients. Periostin has recently been shown to be an indicator of disease progression in idiopathic pulmonary fibrosis and asthma. In this study, we aimed to investigate whether periostin could be a useful new biomarker in the follow-up and severity assessment of the disease in patients with COVID-19 pneumonia. This article demonstrated that periostin is a useful new biomarker for disease follow-up and severity in patients with COVID-19 pneumonia. It is also the first study on periostin levels in patients with COVID-19

Spirometry, a gold standard technique for measuring lung functions, has been restricted to a select cohort of patients in current COVID-19 pandemic due to the enhanced risk of disease dissemination. To monitor pulmonary functions in various obstructive (e.g., asthma) and restrictive diseases (e.g., COVID-19 pneumonia) on in- and out-patients serially, there is an urgent requirement of an alternate reliable test. Impulse Oscillometry (IOS) measures lung functions by working at tidal volumes and thus reduces the risk of potential aerosol generation. Feasibility of IOS in smaller children and its ability to detect parenchymal and peripheral airway involvement are other advantages over conventional spirometry. IOS could be a potential solution to periodically monitor lung functions in current pandemic situation to keep a check on diseases affecting lung functionality.

If an initial frame of vectors $\{e_i\}$ is related to a final frame of vectors $\{f_i\}$ by, in geometric algebra (GA) terms, a {\it rotor}, or in linear algebra terms, an {\it orthogonal transformation}, we often want to find this rotor given the initial and final sets of vectors. One very common example is finding a rotor or $4\times 4$ orthogonal matrix representing rotation and translation, given knowledge of initial and transformed points. In this paper we discuss methods in the literature for recovering such rotors and then outline a GA method which generalises to cases of any signature and any dimension, and which is not restricted to orthonormal sets of vectors. The proof of this technique is both concise and elegant and uses the concept of {\it characteristic multivectors} as discussed in the book by Hestenes \& Sobczyk, which contains a treatment of linear algebra using geometric algebra. Expressing orthogonal transformations as rotors, enables us to create {\it fractional transformations} and we discuss this for some classic transforms. In real applications, our initial and/or final sets of vectors will be noisy. We show how to use the characteristic multivector method to find a ‘best fit’ rotor between these sets and compare our results with other methods.

Since coronavirus disease 2019 (COVID-19) was reported globally pandemic, dentistry is known as one of the most critical disciplines. Teledentistry as a sub branch of telemedicine which can be a useful modality is defined by using any telecommunication technology facility, including digital photo and video to deliver oral care to isolated patients in distant places by low cost(1). Although teledentistry has been introduced as a valid tool to prevent unnecessary referrals, policy makers have not shown much interest on it yet (2,3).Diagnosis, treatment, and monitoring could be performed, meanwhile research and continuing education or public education could be done via teledentistry. In COVID-19 pandemic, teledentistry can prevent human and non-human resources burden. Oral chronic diseases like vesiculobullous and painful conditions are so dreadful and exhausting needing more care. Pediatric patients and those who are suffering from cancer are no more exceptions to this point. Tablets, smart phones, and all types of electronic gadgets can facilitate virtual communication which is helpful in telehealth.Traditional visual examination is a gold standard, in order to reach a better diagnosis and treatment plan. In teledentistry, intra oral or other high quality cameras can provide essential documents. There are so many investigations to compare visual and virtual examination, which showed only some problems in diagnosing interproximal carious lesions which is solved by digital radiography (3).Teledentistry examinations are valid, feasible, and comparable to visual examination for oral screening. Data storage is another crucial part in teledentistry due to privacy policies (2,3).Pediatric dentistry, oral medicine, orthodontics, and periodontics are the most common disciplines that have studied the efficacy of teledentistry rather than effectiveness. In developing countries, where emergency care is more important than preventive care, conservatism of decision makers, lack of resources and ICT infrastructure are the most common problems in providing teledentistry (4).Meanwhile there is a hidden advantage for teledentistry and telemedicine that it can avoid feelings of isolation and stress for patients; so, it can be more useful during COVID-19 quarantine (5).Teledentistry performs in two ways; asynchronous by transmission intraoral or extraoral images that are not used in real time; also, known as the store and forward method, synchronous by use of real-time interactive technologies, such as video or photoconferencing, and mobile health care services via smartphone apps and text messages.All the process should be recorded in patients file for further information. Accurate triage is another prominent advantage of teledentistry, which is so important during COVID-19.For people in need of care like geriatrics or patients with special needs telemedicine can eliminate some barriers (6).Besides to teledentirstry’s advantages, especially in a situation like a pandemic infection even with very primary facilities teledentistry can be performed and be useful for triage. By introducing dentistry as a very dangerous discipline, teledentistry can play a very specific role to solve the majority of patients’ problems as a helpful facility in this crisis and may be it can also persuade policy makers to perform teledentistry in a vast program.

Resistance (host capacity to reduce parasite burden) and tolerance (host capacity to reduce impact on its health for a given parasite burden) manifest two different lines of defence. Tolerance can be independent from resistance, traded-off against it, or the two can be positively correlated because of redundancy in underlying (immune) processes. We here tested whether this coupling between tolerance and resistance could differ upon infection with closely related parasite species. We tested this in experimental infections with two parasite species of genus Eimeria. We measured proxies for resistance (the (inverse of) number of parasite transmission stages (oocysts) per gram of feces at the day of maximal shedding) and tolerance (the slope of maximum relative weight loss compared to day of infection on number of oocysts per gram of feces at the day of maximal shedding for each host strain) in four inbred mouse strains and four groups of F1 hybrids belonging to two mouse subspecies, Mus musculus domesticus and M. m. musculus. We found a negative correlation between resistance and tolerance against E. falciformis, while the two are uncoupled against E. ferrisi. We conclude that resistance and tolerance against the first parasite species might be traded off, but evolve more independently in different mouse genotypes against the latter. We argue that evolution of the host immune defences can be studied largely irrespective of parasite isolates if resistance-tolerance coupling is absent or weak (E. ferrisi) but host-parasite coevolution is more likely observable and best studied in a system with negatively correlated tolerance and resistance (E. falciformis).

Background. Discharge against medical advice (DAMA) is used in healthcare facilities in a situation where patients refuse care or decide to leave the hospital before the treating physician recommends discharge. Previous studies have found DAMA to be prevalent among patients with various chronic conditions. The study had four objectives. The study aimed to investigate: 1) the prevalence of DAMA during COVID-19 (2020-2021) among Jordanian patients with chronic diseases, 2) the association between DAMA and sociodemographic and clinical characteristics of patients with chronic diseases, 3) the predictors of DAMA, and 4) the reasons behind DAMA at the patient, hospital, and environmental levels. Methods. A descriptive cross-sectional correlational design was used in the study. A convenience sampling approach was used to collect data from 1576 patients with chronic diseases from 3 private hospitals. Results. The study found that the prevalence rate of DAMA was 33.3%. There was a significant association between the sociodemographic and clinical characteristics of patients with chronic diseases and DAMA. Health insurance found to be the strongest predictor of DAMA. Finally, the study found that patient, hospital, and environmental- related factors had a low impact on DAMA. Conclusions: DAMA is prevalent among patients with chronic diseases in Jordan during COVID-19 pandemic. The current study’s findings can serve as an empirical basis for planning and implementing DAMA prevention programs and/or establishing or revising policies for the target population.

The ability to predict the onset of labour is seen to be an important tool in a clinical setting. Magnetomyography has shown promise in the area of labour imminency prediction, but its clinical application remains limited due to high resource consumption associated with its broad number of channels. In this study, five electrode channels, which account for 3.3% of the total, are used alongside a novel signal decomposition algorithm and low complexity classifiers (logistic regression and linear-SVM) to classify between labour imminency due within 0–48hrs and >48hrs. The results suggest that the parsimonious representation comprising of five electrode channels and novel signal decomposition method alongside the candidate classifiers could allow for greater affordability and hence clinical viability of the magnetomyography-based prediction model, which carries a good degree of model interpretability.

Food allergy is an increasingly common disease worldwide, and is thought to be driven by an uncontrolled type 2 immune response. Current knowledge about the underlying mechanisms that initiate and promote an inappropriate immune response to dietary allergens is limited. Sensitization through the skin in early life is considered to be a key event. Food allergy results from a dysregulated type 2 response to food allergens, characterized by enhanced levels of IgE, IL-4, IL-5 and IL-13 with infiltration of mast cells, eosinophils and basophils during acute reactions. Recent data implies a possible role of innate lymphoid cells (ILCs) in driving food allergy. ILCs represent a group of lymphocytes that lack specific, recombined antigen receptors. They contribute to immune responses not only through the release of cytokines and other mediators, but also by responding to cytokines produced by activated cells in their local microenvironment. Due to their localization at barrier surfaces of the airways, gut and skin, ILCs form a link between the innate and adaptive immunity. This review summarizes recent evidences on how skin and gastrointestinal mucosal immune system contribute to both homeostasis and the development of food allergy, as well as the involvement of ILCs towards inflammatory processes and regulatory mechanisms.

Coronavirus disease 2019 (COVID-2019) is a viral disease which is declared as a pandemic by WHO. This disease is posing a global threat, and almost every country in the world is now affected by this disease. Currently, there is no vaccine for this disease and because of this containing COVID-19 is not an easy task. It is noticed that elderly people got severely affected by this disease specially in Europe. In the present paper, we propose and analyze a mathematical model for COVID-19 virus transmission by dividing whole population in old and young groups. We find disease-free equilibrium and the basic reproduction number ($R_0$). We estimate the parameter corresponding to rate of transmission and rate of detection of COVID-19 using real data from Italy and Spain by least square method. We also perform sensitivity analysis to identify the key parameters which influence the basic reproduction number and hence regulate the transmission dynamics of COVID-19. Finally, we extend our proposed model to optimal control problem to explore the best cost-effective and time-dependent control strategies that can reduce the number of infectives in a specified interval of time.

Adhesion G protein-coupled receptors (aGPCRs) possess a unique topology including the presence of a GPCR proteolysis site (GPS) which upon autoproteolysis generates two functionally distinct fragments that remain non-covalently associated at the plasma membrane. A proposed activation mechanism for aGPCRs involves the release of a tethered agonist which depends on cleavage at the GPS. However, this hypothesis has been challenged by the observation that non-cleavable aGPCRs exhibit constitutive activity, thus making the function of GPS cleavage widely enigmatic. In this study, we sought to elucidate the function of GPS-mediated cleavage through the study of G protein coupling with Latrophilin-3/ADGRL3, a prototypical aGPCR involved in synapse formation and function. Using BRET-based G protein biosensors, we reveal that an autoproteolysis-deficient mutant of ADGRL3 retains constitutive activity. Surprisingly, we uncover that cleavage deficiency leads to a signaling bias directed at potentiating the activity of select G proteins such as Gi2 and G12/13. These data unveil the underpinnings of biased signaling for aGPCRs defined by GPS autoproteolysis.

Understanding the factors that regulate the functioning of our ecosystems in response to environmental changes can help to maintain the stable provisioning of ecosystem services to mankind. This is especially relevant given the increased variability of environmental conditions due to human activities. In particular, maintaining a stable production and plant biomass during the growing season (intra-annual stability) despite pervasive and directional changes in temperature and precipitation through time can help to secure food supply to wild animals, livestock, and humans. Here, we conducted a 29-year field observational study in a temperate grassland to explore how the intra-annual stability of primary productivity is influenced by biotic and abiotic variables through time. In particular, we analyzed the relationship of community biomass intra-annual stability with plant diversity and seasonal distribution patterns of temperature and precipitation. We found that lower accumulated precipitation between June and September during the 29-year investigated contributed to lower intra-annual community stability because of a decrease in compensatory mechanisms among species (species asynchrony). Additionally, higher precipitation in July contributed to higher intra-annual stability because higher species richness with higher precipitation led to higher average intra-annual stability of all species in the community (species stability). In contrast, we found no evidence that temperature influenced community intra-annual stability. Our results indicates that ongoing reduced seasonal precipitation leading to reduced intra-annual stability in the temperate grassland, which has important theoretical significance for us to take active measures to deal with climate change.

The coronavirus disease 2019 (COVID-19) is an infectious disease which has rapidly evolved into a pandemic. Though it has affected all disciplines of medical sciences but it has some serious implications pertaining to cardiovascular sciences which have presented unique challenges in front of cardiac surgeons in particular. To flatten the curve of this pandemic, routine cardiac surgeries are being deferred indefinitely resulting in the pool of sick cardiac patients rising day by day. A different perspective is presented on this global catastrophe from the viewpoint of a cardiac surgeon.

Phosphate (Pi) and jasmonic acid (JA) play critical roles in plant growth and development. In particular, crosstalk between JA and Pi starvation signaling has been reported to mediate insect herbivory resistance in dicot plants. However, its roles and mechanism in monocot-bacterial defense systems remain obscure. Here, we report that Pi starvation in rice activates the JA signaling and enhances resistance to Xanthomonas oryzae pv. oryzae (Xoo) infection. The direct regulation of OsPHR2 on the OsMYC2 promoter was confirmed by yeast one-hybrid, electrophoretic mobility shift, dual-luciferase, and chromatin immunoprecipitation assays. Molecular analyses and infection studies using OsPHR2-Ov1 and phr2 mutants further demonstrated that OsPHR2 enhances JA response and antibacterial resistance via transcriptional regulation of OsMYC2 expression, indicating a positive role of OsPHR2-OsMYC2 crosstalk in modulating the JA response and Xoo infection. Genetic analysis and infection assays using myc2 mutants revealed that Pi starvation-induced JA signaling activation and consequent Xoo resistance depends on the regulation of OsMYC2. Together, these results reveal a clear interlink between Pi starvation signaling and the JA signaling in monocot plants, and provide new insight into how plants balance growth and defense by integrating nutrient deficiency and phytohormone signaling.

Objectives: The aims of the study were to further elucidate the roles of M1 and M2 macrophages in the pathogenesis of EAE and the effects of treatment with M2 macrophages that target certain pro-inflammatory cytokines and with immunomodulatory preparations that beneficially influence the disease course should be in focus of future therapeutic trials. Results: Enhanced the total number of macrophages at the onset of clinical signs in the EAE group, consistent with an increased proportion of M1 cells and low numbers of M2 cells. As the disease progressed and the symptoms worsened, M1 cells were decreased and M2 cells were gradually increased till the peak. In the recovery stage, M2 cell numbers were gradually decreased. Treatment with M2 macrophages inhibited the NF-κb pathway, alleviated the symptoms of EAE, reduced inflammatory cell infiltration and demyelination in the central nervous system, and decreased the numbers of macrophages in the spleens. BAY-11-7082, an NF-κb blocking agent, could reduce the total number of macrophages both in vivo and in vitro, effectively prevented the EAE development, and significantly inhibited the symptoms EAE in mice. Conclusions: Macrophages may play a crucial role in the pathogenesis of EAE, while M2 macrophages have anti-inflammatory effects. Transfer of M2 macrophages to EAE mice can block the NF-κb pathway successfully and relieve the EAE symptoms. Application of NF-κb blockers is useful in the prevention and treatment of EAE.

Abstract. The Controlled Human Infection Model and specifically the Human Viral Challenge Model are not dissimilar to standard clinical trials while adding another layer of complexity and safety considerations. The models deliberately infect volunteers, with an infectious challenge agent (CA) to determine the effect of the infection and the potential benefits of the experimental interventions. The Human Viral Challenge Model studies can shorten the time to assess the efficacy of a new vaccine or treatment by combining this with the assessment of safety. The newly emerging SARS-COV-2 virus is highly contagious and the cause pandemic disease COVID-19. An urgent race in is on to develop a new vaccine against this virus in a timeframe never attempted before. The use of the Human Viral Challenge Model has been proposed to accelerate the development of the vaccine. In the early 2000’s the authors successfully developed a pathogenic Human Viral Challenge Model for another virus for which there was no effective treatment and established it to evaluate potential therapies and vaccines against Respiratory Syncytial Virus. The authors feel that the experience gained in the development of that model can help with the development of a COVID-19 HVCM and describe it here. Word count: 197

The nano/microelectromechanical systems (N/MEMS) have been caught much attention in the past few decades for their attractive properties such as small size, high reliability, batch fabrication, and low power consumption. The dynamic oscillatory behavior of these systems is very complex due to strong nonlinearities in these systems. The basic aim of this manuscript is to investigate the nonlinear vibration property of N/MEMS oscillators by the homotopy perturbation method coupled with Laplace transform (also called as He-Laplace method in literature). A generalized N/MEMS oscillator is systematically studied, and a fairly accurate analytic solution is obtained. Three special cases for electrically actuated MEMS, multi-walled Carbon nanotubes-based MEMS, and MEMS subjected to van der Waals attraction are considered for comparison, and a good agreement with exact solutions is observed.

Eurasian otters are apex predators of freshwater ecosystems and a recovering species across much of their European range; investigating the dietary variation of this predator over time and space therefore provides opportunities to identify changes in freshwater trophic interactions and factors influencing the conservation of otter populations. Here we sampled faeces from 300 dead otters across England and Wales between 2007 and 2016, conducting both morphological analysis of prey remains and dietary DNA metabarcoding. Comparison of these methods showed that greater taxonomic resolution and breadth could be achieved using DNA metabarcoding but combining data from both methodologies gave the most comprehensive dietary description. All otter demographics exploited a broad range of taxa and variation primarily reflected changes in prey distributions and availability across the landscape. This study provides novel insights into the trophic generalism and adaptability of otters across Britain, which is likely to have aided their recent population recovery, and may increase their resilience to future environmental changes.